Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([Cl:18])[CH:7]=1)[CH3:2].[CH2:20]([O:22][C:23](=[O:26])[CH:24]=[CH2:25])[CH3:21].[Na].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:8]([Cl:18])[CH:7]=1)[CH2:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: C=CC(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCC(C(=O)OCC)c1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A mixture of 40.5 g of 3-chloro-4-cyclohexylphenylacetic acid ethyl ester and 16 g of acrylic acid ethyl ester is added dropwise to a solution of 3.6 g of sodium in 60 ml of ethanol. The solution is refluxed overnight and then poured into a mixture of 10 ml of glacial acetic acid and 170 ml of ice water. The ethanol is distilled off and the residue extracted with ethyl acetate and evaporated; the residue is distilled under a high vacuum, to yield 24.3 g of 2-(3-chloro-4-cyclohexylphenyl)-glutaric acid diethyl ester boiling at 203°-205°C under 0.4 mm Hg pressure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[NH:18][CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:20][C:21](=[O:22])[N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: COC(=O)c1nc2[nH]ccn2c(=O)c1OC(C)=O
Reactant: O=C(CCl)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OC(C)=O
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a solution of compound 6-acetoxy-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (PCT/AU2007/001980) (2.0 g, 7.96 mmol) in anhydrous acetonitrile (20 ml) was added compound 2-chloro-1-piperidin-1-yl-ethanone (2.0 g, 12.42 mmol), K2CO3 (1.7 g, 12.32 mmol), KI (133 mg, 0.8 mmol) successively. The mixture was heated at refluxed for 3 hours. After cooling to the room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give titled compound (2.0 g, yield 66.7%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH2:13]([NH:16][CH2:17][CH:18]=[O:19])[CH:14]=[CH2:15]>C1C=CC=CC=1>[CH2:13]([N:16]([CH2:17][CH:18]=[O:19])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])[CH:14]=[CH2:15]
Reactant: C=CCNCC=O
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-allylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)-ureido] acetaldehyde.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][CH2:4][O:3]1.[N:7]([Si](C)(C)C)=[N+:8]=[N-:9]>Cl[Sn](Cl)(Cl)Cl>[N:7]([CH:2]([O:3][CH2:4][CH2:5][OH:6])[CH3:1])=[N+:8]=[N-:9]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1OCCO1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CC(N=[N+]=[N-])OCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methyl dioxolane (0.897 ml, 10 mmol) and azidotrimethylsilane (1.6 ml, 12 mmol) was added SnCl4 (40 μl) at −78° C. After addition, the cooling bath was removed and the reaction was warmed up to room temperature. After 1 hr, the reaction was worked up by partitioning between DCM (50 ml) and saturated aqueous NaHCO3 (50 ml). The aqueous layer was further extracted with DCM (20 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in 10% aqueous methanol. After 2 hr at room temperature, all the solvents were removed under reduced pressure. The title compound was obtained as a colourless oil (224 mg, 17.1%).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[N:12][C:13]([Cl:17])=[CH:14][C:15]=1Cl)=[O:9])[CH3:6].Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[N:12][C:13]([Cl:17])=[CH:14][C:15]=1[O:1][CH2:2][CH3:3])=[O:9])[CH3:6]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nnc(Cl)cc1OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium ethoxide (1.16 g, 17 mmol) is added to a stirred solution of 4,6-dichloropyridazine-3-carboxylic acid ethyl ester (3.73 g, 17 mmol) in THF (45 mL) cooled to 0° C. The reaction mixture is stirred at room temperature overnight and then poured into 1N HCl (20 mL). The resulting solution is then neutralized with saturated NaHCO3. EtOAc (20 mL) is added and the layers are separated. The aqueous layer is extracted twice with EtOAc (20 mL) and the combined extracts are washed with brine (25 mL), dried (Na2SO4), and evaporated. The residue is then purified by flash column chromatography (silica gel, eluted with 2:1 Hexane, EtOAc) to give the title product as a white solid. H1 NMR δ (CDCl3) 7.02 (s, 1H), 4.47 (q, 2H, J=7.2 Hz), 4.19 (q, 2H, J=7.2 Hz), 1.50 (t, 3H, J=7.2 Hz), 1.41 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:29])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([Cl:29])=[O:25])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
A mixture of 21.7 g of p-tetradecyloxyphenylacetic acid and 11.85 g of oxalyl chloride, 45.5 mg of N,N-dimethylformamide and 250 ml of methylene chloride is stirred at ambient temperature for 24 hours. The solvent is removed by evaporation and the residue is dissolved in ether and filtered through diatomaceous earth. The filtrate is evaporated to give 22.3 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si](C)(C)C)=[CH:13][N:12]=2)[CH2:7]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][N:12]=2)[CH2:7]1
Reactant: C[Si](C)(C)C#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Dissolve (S)-(2,4-dichlorbenzyl)-[1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-3-yl]-amine (190 mg, 0.45 mmol) in THF (10 mL). Add tetrabutylammonium fluoride (1 mL, 1.0 M in THF) dropwise. Stir for 2 h at room temperature. Add water. Extract with ethyl acetate (3×), wash the organic layers with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with a 20:80 to 1:1 ethyl acetate:hexanes, to give the title compound as a yellow oil (141 mg, 90%). Dissolve the oil in methanol and add fumaric acid (47 mg, 0.41 mmol) in methanol. Concentrate most of the solvent, add acetonitrile and stir overnight. Filter the solid and dry in a vacuum oven at 60° C. overnight to give the title compound as its fumarate salt (139 mg, 74%). 1H NMR (400 MHz, MeOH-d4) 8.15 (d, 1H, J=2.4 Hz), 7.59-7.54 (m, 3H), 7.39 (dd, 1H, J=8.0, 2.0 Hz), 6.72 (s, 2H), 6.50 (d, 1H, J=8.8 Hz), 4.20-4.12 (m, 2H), 3.83-3.76 (m, 2H), 3.70-3.64 (m, 1H), 3.59-3.47 (m, 2H), 3.44 (s, 1H), 2.46-2.38 (m, 1H), 2.18-2.09 (m, 1H), MS (ES): m/z=346 [M+H].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=1.O.NN>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=1
Reactant: Cc1cn(CCCN2C(=O)c3ccccc3C2=O)cn1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cn(CCCN)cn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
2-(3-(4-Methyl-1H-imidazol-1-yl)propyl)isoindoline-1,3-dione (3.42 mmol, 1 eq., which may be prepared as described in D6) and hydrazine monohydrate (6.84 mmol, 2 eq.) were dissolved in 20 mL of ethanol and the mixture was stirred for 12 h under reflux. The mixture was kept under reflux over night, then the mixture was concentrated down to a volume of 25 mL. Hydrochloric acid (conc., 55 mL) was then added and the mixture was heated to 50° C. and kept at this temperature for 30 min. The formed precipitate was then filtered. The filtrate was cooled to 0° C. and solid NaOH was added until a final pH-value of 10-12 was reached. The aqueous solution was extracted by means of CHCl3 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed. The product was purified by means of flash-chromatography using silica gel and a CHCl3/MeOH-gradient containing aqueous ammonia (2% v/v).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17][C@H:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:19]([NH:21]S(CC[Si](C)(C)C)(=O)=O)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17][C@H:18]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](NS(=O)(=O)CC[Si](C)(C)C)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: CN(C)C=O
Product: C[C@H](N)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 95 °C
Yield: 79.5 %

Procedure:
To N-((1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-yl)-2-(trimethylsilyl)ethanesulfonamide (103a, 0.042 g, 0.08 mmol) in DMF (2 mL) cesium fluoride (8.60 μL, 0.23 mmol) was added and the mixture was stirred at 95° C. Stirring was continued at that temperature O/N. Cooled at rt the solvent was removed and the mixture was partitioned between EtOAc/water the organic phase was than purified with HPLC The relevant fractions were collected freeze dried to give 24 mg of product (84% yield) which was analysed by LC/MS.
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]([F:15])([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]=2[CH:3]=1.[C:19]1(=O)[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21](=[O:28])[O:20]1>C(O)(=O)C>[F:15][C:7]1([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]2[CH:3]=[C:2]([N:1]3[C:19](=[O:20])[C:27]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=4[C:21]3=[O:28])[C:17]([F:18])=[CH:16][C:5]=2[O:6]1
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 15.3 %

Procedure:
6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (20 g, 78 mmol) and 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (12.47 g, 82 mmol) in acetic acid (500 ml) were stirred at 120° C. overnight, after which time tlc (thin layer chromatography) analysis indicated that the reaction was complete. The reaction mixture was concentrated in vacuo and triturated with toluene to yield 34.6 g of crude product. This material was combined with a further quantity (6.23 g) of crude product which had been obtained in a similar manner, and the combined product was coated on isolute absorbens (˜70 g). Filtration over silica afforded 2 fractions: F1: 12.9 g and F2: 19.35 g. Both fractions were triturated with di-isopropyl ether to yield: T1: 6.04 g (88% purity) and T2: 14.7 g (>95% purity). T1 was recrystallised from MeOH to yield a further 4.65 g of product (>95% purity).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:17])[CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][CH2:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCN
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
tert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate (3.6 g, 15.1 mmol) was dissolved in DCM (60 mL). Then CF3COOH (1.1 mL, 0.3 mmol, 20 equiv) was added to the mixture at 0° C. and stirred for 2 h at 0° C. The reaction mixture was concentrated. The residue was purified by flash chromatography to give 3-amino-N-(methylsulfonyl)propanamide as a transparent solid (1.8 g, 80%). (mobile phase: CH3OH/H2O=0˜5%). ESI-MS (M+1)+: 167.0. 1H NMR (400 MHz, CD3OD) δ: 3.21˜3.11 (m, 2H), 3.07 (s, 3H), 2.60˜2.54 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([Cl:23])[CH:17]=1>>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[C:18]([Cl:23])[CH:17]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(Br)cc1Cl
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Br)cc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-bromo-2-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[N:25]1([C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[N:26]1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([N:25]5[CH:29]=[CH:28][CH:27]=[N:26]5)[CH:35]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(-n5cccn5)c4)cc23)CC1
Yield: 10 %

Procedure:
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20 mg, 0.048 mmol) was added [3-(1H-pyrazol-1-yl)phenyl]boronic acid (36 mg, 0.193 mmol), dioxane (2.8 mL) and a solution of potassium carbonate (20 mg) in water (1.2 mL). To this mixture was added chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (3 mg, 0.005 mmol). The resulting mixture was reacted in a CEM microwave for 10 min at 160° C. then concentrated under a stream of nitrogen (greenhouse) at 80° C. The crude product was partitioned between water (2 mL) and CH2CL2 (2 mL). The layers were separated with a hydrophobic frit, and the aqueous layer was extracted with CH2CL2 (2×2 mL). The organic layers were pooled and concentrated under a stream of nitrogen at 80° C. Dimethyl sulfoxide (0.8 mL) was added to residue, which was sonicated for 10 sec. filtered through a cotton plug, and then filtered through a 0.2 μm filter. The crude product was purified on an Agilent MDAP using a Zorbax Eclipse XDB 610 21.2×50 mm column to afford 2.3 mg of the title compound (10%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.S(OC)(O[CH3:21])(=O)=O>O>[CH3:21][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2ccc(O)cc2)cc1
Yield: 43.8 %

Procedure:
120 ml of water and sodium hydroxide (14.00 g, 0.35 mol) were placed in a conical flask and dissolved. 4,4'-Dihydroxybiphenyl (28.00 g, 0.15 mol) was then added and heated to reflux for 2 hours with stirring using a condenser. Dimethyl sulfate (14.5 ml, 0.15 mol) was added dropwise over about 40 minutes. After addition, the mixture was heated while stirring for 2 hours, and then allowed to cool and filtrated. The filter cake was transferred into 700 ml of water, which was then heated to boiling temperature, and filtrated while still keeping warm. The filtrate was kept at 70° C., and 20% hydrochloric acid was added. White precipitation: formed was washed extensively. Recrystallization from ethanol yielded 4'-methoxy-4-hydroxybiphenyl (13.17 g, Yield: 48.0%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33]>CN(C=O)C.CCOC(C)=O>[N:34]1([C:32](=[O:33])[CH2:31][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:22][C:21]4([CH3:24])[CH2:23][CH:17]3[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]4)=[O:15])=[CH:12][CH:13]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Reactant: O=C(CCl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NCC(=O)N3CCOCC3)cc2)C1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (0.5 g, 1.34 mmol) in dry DMF (40 ml) was added sodium hydride (80 mg, 3.33 mmol in 60% mineral oil) and the mixture was stirred for 30 min. 2-Chloro-1-morpholin-4-yl-ethanone (264 mg, 1.61 mmol) was added and the stirring was continued for an additional 1 hr. at 50° C. The reaction was quenched by addition of water (50 ml) and extracted with diethyl ether (2×25 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (20 ml) and TFA (10 ml) was added. The resulting mixture was stirred for 4 hrs. at room temperature and evaporated in vacuo. The residue was purified by column chromatography (silica gel) using first EtOAc (500 ml) followed by 4% TEA in EtOAc as eluents. Semi-pure fractions were collected and evaporated to dryness affording 0.4 g as an oil which was dissolved in EtOAc (25 ml) and washed with water (2×25 ml), dried (Na2SO4), filtered and evaporated in vacuo affording 180 mg (34%) of the title compound as a oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccccc1Oc1ncc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Oc2ncc(Cl)cn2)nc1
Yield: 99.6 %

Procedure:
After heating at reflux a mixture of 1.5 grams (0.0067 mole) 2-(5-chloropyrimidin-2-yloxy)phenol, 1.2 grams potassium carbonate, 1.3 grams 2-chloro-5-nitropyridine and 40 ml of methyl ethyl ketone, the reaction mixture was poured into excess H2 0 and the aqueous mixture extracted with ethyl ether (200 ml). The ether layer was washed with saturated NaHCO3, H2O, brine, dried (MgSO4), filtered, and evaporated to yield 2.3 grams of a yellow-orange oil which was purified by silica gel column chromatography (CH2Cl2 as the eluent). NMR (CDCl3): δ6.90 (d, 1H, pyridine ring proton), 7.35 (s, 4H, ArH), 8.25-8.50 (m, 1H, pyridine ring proton), 8.45 (s, 2H, pyrimidine ring protons), 8.95 (d, 1H, pyridine ring proton).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=O)=[CH:5]2.[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:6]2[NH:7][C:8]3[C:4](=[CH:3][C:2]([F:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:5]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1F
Agent: CCN=C=NCCCN(C)C
Product: COc1cc2[nH]c(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)cc2cc1F

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-fluoro-6-methoxyindole-2-carboxylic acid (PREPARATION 92, 0.30 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.32 g) and 1-(ethyl)-3-(dimethylaminopropyl) carbodiimide (0.33 g), the title compound is obtained, mp 193°-194°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:26][C:27]#[N:28])C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])/[CH:15]=[CH:26]/[C:27]#[N:28])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(/C=C/C#N)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
To the stirred solution of 2-(4-(4-fluorophenyl)piperazin-1-yl)-2-methylpropanal (1.0 g, 4 mmol) in 10 ml of dichloromethane was added 2-(triphenylphosphoranylidene)acetonitrile (1.445 g, 4.8 mmol) at 25° C. The reaction was stirred for 2 days at room temperature. After completion of reaction, the solvent was evaporated to give a crude product. The crude product was purified by column chromatography using 10% ethyl acetate in hexane as an eluent to obtain the title compound (0.7 g, 64.1%).
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(Cl)c(C(F)(F)F)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (100 mg, 0.38 mmol) and 4-chloro-3-trifluoromethyl-phenylboronic acid (150 mg, 0.45 mmol) were coupled to yield 2-(4-chloro-3-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 121 mg (88%) as a pale yellow solid: m.p. 118.5-119° C.; 1H NMR (300 MHz, d6-DMSO) δ3.06 (m, 2H), 3.41 (m, 2H), 7.27 (app t, J=7.8 Hz, 1H), 7.60 (dd, J=7.8, 0.9 Hz, 1H), 7.73 (dd, J=7.2, 0.9 Hz, 1H), 7.89 (m, 2H), 8.08 (d, J=1.5 Hz, 1H), 8.14 (br t, 1H), 11.82 (br s, 1H). MS (FAB, MH+) 365. Anal. (C18H12ClF3N2O.0.45 H2O.0.2 CHCl3) C, H, N.