Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[O:10][C:9](=[O:20])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].Cl>C1COCC1.O.CCN(CC)CC>[OH:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9](=[O:20])[O:10]2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc2c(-c3ccccc3)cc(=O)oc2c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1cc(-c2ccccc2)c2ccc(CO)cc2o1
Reaction time: 0.75 h

Procedure:
To a solution of 4-phenyl-7-coumarincarboxylic acid from Step 4 (550 mg) and Et3N (560 μL) in THF (25 mL) at 0° C. was added isobutylchloroformate (560 μL) dropwise. After 45 min., NaBH4 (185 mg) in H2O was added and stirring continued for a further 20 min. The mixture was poured onto 1N HCl, extracted (3x Et2O), dried, and evaporated. Chromatography on silica gel using hexane/EtOAc 1:1 afforded the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([OH:17])[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].[CH3:21][O:22][C:23](=[O:53])[CH2:24][CH2:25][C:26]1[C:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]OS(C)(=O)=O)=[CH:30][CH:29]=[CH:28][C:27]=1[O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CCOCC.C(#N)C>[CH3:21][O:22][C:23](=[O:53])[CH2:24][CH2:25][C:26]1[C:27]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[CH:28][CH:29]=[CH:30][C:31]=1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:17][C:6]1[CH:5]=[CH:4][C:3]([C:18](=[O:20])[CH3:19])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Reactant: CC(=O)c1ccc(O)c(CCCc2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc(C(C)=O)c(O)c2CCCc2ccccc2)c1CCC(=O)OC
Yield: 90.8 %

Procedure:
A mixture of 0.81 g (3 mmol) of 1-[2,4-dihydroxy-3-(3-phenylpropyl)phenyl]ethanone from example 191, 1.6 g (3.29 mmol) of 2-[(6-methoxy-6-oxohexyl)oxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from example 156, 0.66 g (4.78 mmol) of anhydrous, granular potassium carbonate, 0.55 g (3.67 mmol) of sodium iodide, and 25 mL of acetonitrile was stirred and refluxed for 18.5 hr. The resulting thick slurry was cooled, diluted with ether, washed with water, 12% aqueous sodium bisulfite, and brine, and work-up was completed in the usual manner. Thin layer chromatographic analysis of the oily product revealed that alkylation was incomplete. Therefore, the product was dissolved in 5 mL of acetonitrile and 0.69 g (5 mmol) of anhydrous, granular potassium carbonate was added. The resulting mixture was stirred and refluxed for 24 hr before being worked-up as described above. The oily product (2.01 g) was chromatographed on 50 g of silica gel. Elution with 1:1 hexane-ether afforded 1.80 g (90.9%) of the title compound as an almost colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1=O.[CH3:18][CH:19]1[N:24]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O>[CH3:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH2:27][NH:28][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC1CCCCN1CCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1CCCCN1CCCNc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 75.1 %

Procedure:
2 g of para-fluoronitrobenzene were added to a solution of 20 ml of N-methyl-pyrrolidinone, 1.65 g of 1-(3-aminopropyl)-2-pipecoline and 1.72 g of triethylamine. The reaction medium was heated at 60° C. for 8 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 2.2 g of N-[3-(2-methyl-piperidin-1-yl)propyl]-4-nitro-1-aminobenzene (17) were obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:19])[CH:16]([F:18])[CH3:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([OH:19])[CH:16]([F:18])[CH3:17])(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(F)C(=O)c1ccccc1S(=O)(=O)NC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(F)C(O)c1ccccc1S(=O)(=O)NC(C)(C)C

Procedure:
10 g of N-t-butyl-2-(2-fluoropropionyl)benzenesulfonamide was dissolved in 100 ml of methanol, and herein 1.3 g of sodium borohydride was added in the solution at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)[NH2:6].Cl[C:17]1[N:22]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[C:19]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:17]2[N:22]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[C:19]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:33])[F:34])[N:18]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)Cc1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C
Reaction time: 0.03 h

Procedure:
Palladium acetate (21 mg, 0.095 mmol) was added to a degassed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (155 mg, 0.76 mmol), ethyl 2-{2-chloro-6-[(2,2,2-trifluoro-ethoxy)methyl]pyrimidin-4-yl}acetate (180 mg, 0.63 mmol), Cs2CO3 (411 mg, 1.26 mmol), (2-biphenyl)dicyclohexylphosphine (33 mg, 0.95 mmol) in 1,4-dioxane (4 mL). The microwave tube was capped and the heterogeneous solution was immersed in a sonic bath for 2 min prior to heating it in a microwave reactor at 120° C. for 1.5 h. The reaction was cooled down to rt and concentrated in vacuo with diatomaceous earth. The resulting mixture was purified on silica gel eluting with 0% to 5% MeOH/DCM (1% ammonium hydroxide). The residue obtained was purified on a C18 reverse phase cartridge eluting with 0% to 40% MeOH/H2O (containing 0.05% TFA) to give the title compound as a gum, 110 mg (38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1>C(OCC)(=O)C.C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1

Procedure:
2.87 g 1-chloro-2-(4-ethynyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene are dissolved in 10 ml of ethyl acetate and 5 ml of ethanol. 0.3 g 10% palladium on carbon are added and the resultant mixture is stirred under hydrogen atmosphere (1 atm) overnight. The reaction mixture is filtered over Celite and the filtrate is concentrated. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->5:1).
Reaction SMILES: O=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.C1(C)C=CC(S([CH2:26][N+:27]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].C(O)C>COCCOC>[C:26]([CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(C#N)C2

Procedure:
tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate was reacted in the presence of p-toluenesulfonylmethylisocyanide, potassium tert-butoxide and ethanol in 1,2-dimethoxyethane to produce tert-butyl 3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22](OS(C(F)(F)F)(=O)=O)=[CH:21][C:20]=3[Cl:34])[C:14]2=[O:35])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[C:1]([Si:5]([CH3:36])([CH3:37])[O:6][C@@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[C:20]([Cl:34])=[CH:21][C:22]([C:40]4[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=4)=[CH:23][C:24]=3[Cl:25])[C:14]2=[O:35])[CH2:11][CH2:12]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(-c4cccnc4)cc3Cl)C2=O)CC1

Procedure:
Using the method of Example 81 and trifluoro-methanesulfonic acid 4-{1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-2-oxo-pyrrolidin-3-yl methyl}-3,5-dichloro-phenyl ester (Preparation 74) (0.204 g, 0.337 mmol), 3-pyridineboronic acid (0.124 g, 1.01 mmol), tetrakis(triphenylphosphine)palladium (0.039 g, 0.0337 mmol), dimethoxyethane (5 mL) and sodium carbonate (2M, 0.9 mL) gives the title compound. Purify the crude material over silica gel (3/1 hexane in ethyl acetate to ethyl acetate) to yield 0.027 g (15%) of the title compound: mass spectrum (m/z): 535(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][OH:27])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[ClH:29]>C(O)C>[ClH:29].[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][OH:27])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Agent: Cl
Solvent: CCO
Product: O=C1O[C@@H](CO)CN1c1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(3-Fluoro-4-(4-t-butoxycarbonylpiperazin-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (WO 93/23384; 43.1 g, 0.11 M) was suspended by stirring in ethanol (1000 ml) under nitrogen. An ethanol solution of hydrogen chloride (3.8 M, 400 ml) was added slowly, to give a solution. The mixture was stirred at ambient temperature for 18 hours. The resulting precipitate was filtered, washed with diethyl ether (3×250 ml), and dried, to give the title product. A further crop was obtained by evaporation of the mother liquors. Total vield: 38.7 g.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>C1COCC1.C(OC(=O)C)C>[CH:5]1([CH2:4][N:10]2[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1CCN(CC2CC2)CC1
Reaction time: 8 h
Yield: 46.7 %

Procedure:
Add bromomethylcyclopropane (2.025 g, 15 mmol) to a solution of 4-hydroxypiperidine (3.035 g, 30 mmol) in THF (10 mL) and stir the mixture overnight. Dilute the mixture with ethylacetate, wash with saturated NaHCO3 solution, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel, eluting with 8% 2M NH3-methanol in CH2Cl2) provides 1.087 g (47%) of the title compound: mass spectrum (ion spray): m/z=156.2 (M+1); 1H NMR (CDCl3, ppm): 3.60 (m, 1H), 2.81 (m, 2H), 2.16 (d, 1H), 2.10 (m, 3H), 1.84 (m, 2H), 1.53 (m, 3H), 0.79 (m, 1H), 0.44 (m, 2H), 0.00 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1>CC(O)C>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:6]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:2]([O:15][CH:14]([CH3:18])[CH3:6])[N:3]=[C:4]([NH2:19])[N:5]=1
Reactant: Nc1nc(Cl)c(-c2ccncc2)c(-c2ccco2)n1
Solvent: CC(C)O
Product: CC(C)Oc1nc(N)nc(-c2ccco2)c1-c1ccncc1

Procedure:
The title compound was synthesized in a similar manner to Example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and 2-propanol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([N:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[NH3:29]>C(OCC)C.C1COCC1>[CH:7]1([N:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]([NH2:29])=[N:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N
Reactant: O=C(NN1CCCCC1)N(C1CCCCC1)C1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=NN1CCCCC1)N(C1CCCCC1)C1CCCCC1

Procedure:
A solution of dicyclohexylamine (4.0 mL, 20 mmol) and triethylamine (6 mL, 43 mmol) in diethyl ether (63 mL) was added dropwise to a stirred solution of triphosgene (2.0 g, 6.7 mmol) in diethyl ether (30 mL) at room temperature. The reaction mixture was stirred overnight under refluxing conditions. Then, a solution of piperidine (1.9 mL, 19 mmol) and triethylamine (5.8 mL, 42 mmol) in diethyl ether (37 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding N,N-dicyclohexylpiperidylurea as a yellow oil. Yield: 2.0 g (35%). Oxalyl chloride (1.0 mL, 12 mmol) was added to a stirred solution of the urea (2.0 g, 6.9 mmol) in diethyl ether (30 mL). The reaction mixture was evaporated to dryness after stirring at reflux temperature for 5 h. Ammonia (3 mL, 21 mmol, 7 M solution in methanol) was added to a solution of the resulting solid in diethyl ether (50 mL) and THF (5 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. The product mixture was treated with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over sodium sulfate. Filtration and evaporation to dryness yielded the desired guanidine as a yellow solid. Yield: 1.76 g (87%). 1H NMR (CDCl3, 300 MHz): δ 1.18-1.89 (m 20 H), 3.03 (m, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ 25.2, 26.1, 26.2, 32.4, 49.0, 57.8, 165.2 ppm.
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5](=O)[CH3:6].[CH:10]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:10]([NH:23][CH:5]([CH3:6])[CH2:4][CH2:3][C:2]([CH3:9])([OH:1])[CH3:8])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCC(C)(C)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(CCC(C)(C)O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
The obtained 5-hydroxy-5-methylhexan-2-one (14.23 g) was dissolved in methylene chloride (520 ml). Thereafter, benzhydrylamine (21.00 g) was added to the solution, and the obtained mixture was stirred at a room temperature overnight. Thereafter, sodium triacetoxy borohydride (46.30 g) was added to the reaction solution, and the obtained mixture was stirred at a room temperature for 4 hours. Thereafter, distilled water (173 ml) was added to the reaction solution, and the obtained solution was then adjusted to be pH 12 by addition of an aqueous 6 M sodium hydroxide solution. After extraction with chloroform, the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with 67% ethyl acetate-hexane) to obtain 5-benzhydrylamino-2-methylhexan-2-ol (22.80 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1>>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 42 %

Procedure:
As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (200 mg, 1.06 mmol) was converted using methyl 6-chloronicotinate instead of 6-chloronicotinonitrile to the title compound (SiO2, heptane:ethyl acetate=100:0 to 70:30, 191 mg, 42%) which was obtained as a colourless oil. MS: m/e=325.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27]C(O)=O)=[CH:23][CH:22]=1)([O-:20])=[O:19].N1CCCCC1>O>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:24]2[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: -30 °C

Procedure:
A mixture of 5.00 g (21 mmol) of 4-dibutylaminobenzaldehyde, 4.27 g (24 mmol) of 4-nitrophenylacetic acid, 1.80 g (21 mmol) of piperidine, and 50 mL of xylenes was heated with stirring at reflux of 20 hours with continuous removal of water using a Dean-Stark apparatus. The mixture turned dark red. Approximately half the xylenes was distilled, 20 mL of heptane was added, and the residue was cooled to -30° C. Red crystals separated which were collected and then recrystallized from toluene/heptane. Yield: 2.81 g (37%), mp 117-119 (lit2 182°-182.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:12][CH3:13])([O:9][CH2:10][CH3:11])[C:7]([O:14][CH3:15])=[CH:6][C:5](OCC)([CH3:16])[CH:4]=1.Cl(O)(=O)(=O)=O>C(Cl)Cl>[CH3:15][O:14][C:7]1[C:8]([O:12][CH3:13])([O:9][CH2:10][CH3:11])[C:3]([O:2][CH3:1])=[CH:4][C:5](=[CH2:16])[CH:6]=1
Reactant: CCOC1(C)C=C(OC)C(OC)(OCC)C(OC)=C1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: C=C1C=C(OC)C(OC)(OCC)C(OC)=C1
Yield: 97.4 %

Procedure:
The same procedure as in Example 9 was repeated using 272 mg of 1,5,6-trimethoxy-3,6-diethoxy-3-methyl-1,4-cyclohexadiene, 10 mg of methylene chloride and 10 mg of perchloric acid recovering 230 mg of an oily crude product. The crude product was purified by silica gel column chromatograph using a 20:1 benzene-ethyl acetate mixture giving 220 mg of 1,5,6-trimethoxy-6-ethoxy-3-methylidene-1,4-cyclohexadiene in 92% of theoretical yield. The compound thus obtained was identified by NMR.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:34])[F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:37][C:38](=[O:41])[CH2:39]Br>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:39][C:38]([OH:41])=[O:37])=[CH:24][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:32]([F:35])([F:33])[F:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Product: O=C(O)COc1ccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 4-{3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]-phen-oxy}phenol and Bromo-acetic acid methyl ester with subsequent hydrolysis following the procedure of Example 515: MS (ES) m/z 527.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O-])=O.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]3[NH:20][C:19]4[CH:18]=[CH:17][C:6]([NH:7][C:8](=[O:16])[C:9]5[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(O)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccc(O)cc1

Procedure:
Compound 426 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-hydroxybenzoyl) aniline and 4-morpholinobenzaldehyde. [M+H]+ calcd for C24H22N4O3: 415.18; found: 415.17.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[C:41]([CH3:54])=[N:40]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Yield: 50.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (intermediate 22) (140 mg, 0.234 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (154 mg, 0.469 mmol), Pd(PPh3)2Cl2 (3.22 mg, 0.011 mmol), sodium carbonate (75 mg, 0.702 mmol), Toluene/ethanol (3/5 ml) to afford 80 mg (51% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 8.63 (s, 1H), 8.14-8.12 (d, 2H), 8.04 (s, 1H), 7.73-7.64 (m, 3H), 7.49-7.46 (m, 1H), 7.33-7.30 (m, 3H), 7.15-7.12 (d, 1H), 7.01-6.95 (m, 2H), 6.86-6.83 (d, 1H), 5.31 (s, 2H), 4.84-4.83 (m, 1H), 4.03 (s, 3H), 2.63-2.61 (d, 3H), 2.39 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H). MS: m/z=674.2 (M+1).
Reaction SMILES: [CH2:1](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[I-:20].[Na+]>CC(C)=O>[I:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8]
Reactant: C#CCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCCCCCCI
Yield: 94.2 %

Procedure:
A mixture of 7-octynyl-p-toluenesulfonate (18.3 g, 65.2 mmol), sodium iodide (9.77 g, 65.2 mmol) and acetone (91 ml) was allowed to react for four hours under reflux. After cooling, the precipitates were removed by filtration, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent; hexane) to afford 14.5 g of 8-iodo-1-octyne (yield; 94.2%).