Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1C(=O)N([Br:21])C(=O)C1.O>CN(C=O)C>[Br:21][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCc1ccsc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a 250 mL of two-ported flask filled with 3-octylthiophene (10.00 g, 50.93 mmol) was added 60 mL of DMF. A solution of NBS (9.26 g, 52.03 mmol) in 60 mL of DMF was added dropwise in an iced saline bath. After addition was completed, the mixture was warmed to the room temperature and then stirred at this temperature overnight. The reaction was stopped and the resultant product was poured into 200 mL of water. The mixture was extracted with dichloromethane (60 mL×4). The organic phase was washed with aqueous potassium hydroxide solution (2 M, 100 mL), saturated saline (100 mL) and water (100 mL×2), successively. The organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant product was separated with chromatographic column, in which eluant was petroleum ether, to give a liquid as oil (12.60 g, yield: 89%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:16][CH2:17][S:18]([CH2:21][CH2:22]Br)(=[O:20])=[O:19]>CS(C)=O.C1COCC1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:22][CH2:21][S:18](=[O:20])(=[O:19])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=S(=O)(CCBr)CCBr
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 98.3 %

Procedure:
A slurry of NaH (71.4 mg, 1.79 mmol, 60% dispersion) in DMSO (3 mL) and THF (1 mL) was treated with solid (4-nitro-phenyl)-acetonitrile (121 mg, 0.744 mmol) and stirred at RT for 3 min. A solution of 1-bromo-2-(2-bromoethanesulfonyl)-ethane (250 mg, 0.893 mmol) in THF (3 mL) was added, and the mixture was heated to 70° C. for 1.5 h. The mixture was partitioned between EtOAc (100 mL) and water (75 mL), and brine (25 mL) was added. The aqueous layer was extracted with EtOAc (1×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column with 10-50% EtOAc-hexane afforded the title compound (205 mg, 98%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 8.33 (d, 2H, J=8.8 Hz), 7.75 (d, 2H, J=8.8 Hz), 3.64-3.52 (m, 2H), 3.29-3.19 (m, 2H), 2.88-2.76 (m, 2H), 2.54-2.44 (m, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([Br:16])[CH:10]=1)=S)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl>[C:1]([N:5]=[C:6]=[N:8][C:9]1[CH:10]=[C:11]([Br:16])[CH:12]=[C:13]([Br:15])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=S)Nc1cc(Br)cc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)N=C=Nc1cc(Br)cc(Br)c1

Procedure:
To a solution of 3.5 g N-t-butyl-N'-(3,5-dibromophenyl)thiourea produced in Example A-9 in 80 ml of dichloromethane were added 5.0 g of triphenylphosphine, 3.0 g of carbon tetrachloride and 1.9 g of triethylamine. The mixture was refluxed for 4 hours and evaporated in vacuo. The residue was extracted with petroleum ether and the extract evaporated in vacuo to give N-t-butyl-N'-(3,5-dibromophenyl)carbodiimide as an oil. To a solution of this oil in 30 ml of DMF were added 1.9 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 4 hours, cooled to room temperature and poured into 700 ml of water. The resulting crystals were collected, washed with small amount of cyclohexane and recrystallized from benzene to give 2.0 g of the title compound as colorless needles melting at 189.0°-191.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[C:14]3[S:21][CH:20]=[CH:19][C:15]=3[CH2:16][CH2:17][CH2:18][C:12]=2[C:11]([C:22]([O:24]CC)=[O:23])=[N:10]1.[OH-].[Li+].O.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[C:14]3[S:21][CH:20]=[CH:19][C:15]=3[CH2:16][CH2:17][CH2:18][C:12]=2[C:11]([C:22]([OH:24])=[O:23])=[N:10]1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1ccsc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1ccsc1-2
Temperature: 60 °C
Yield: 71.6 %

Procedure:
300 mg of ethyl 1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-thieno[3′,2′:6,7]cyclohepta[1,2-c]pyrazol-3-carboxylate prepared in example 9e are solubilized in THF/H2O 4:1 (7 mL). Lithium hydroxide (72 mg; 2.7 mmoles) is added and the mixture is heated to 60° C. for 5 hours. After cooling at room temperature, it is diluted first by adding water (5 mL) and then a HCl 1N solution to lower the pH to 1-2. A precipitate is formed which is recovered by filtration and then washed with ethyl ether (2×10 mL). 200 mg of 1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-thieno[3′,2′:6,7]cyclohepta[1,2-c]pyrazol-3-carboxylic acid are obtained (white solid; yield 72%). Rf=0.76 (chloroform/methanol 9/1 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.58 (d, 1H, ArH), 7.45 (m, 2H, ArH), 7.04 (d, 1H, ArH), 6.80 (d, 1H, ArH), 3.30 (m, 2H, CH2), 3.00 (m, 2H, CH2), 2.07 (m, 2H, CH2); 13C NMR (CDCl3) δ (ppm): 163.4, 143.6, 141.3, 139.3, 137.5, 136.0, 135.0, 131.6, 130.5, 130.2, 128.2, 125.1, 123.8, 122.4, 31.0, 25.9, 24.1; FT-IR (film) νmax: 3078.0, 2929.3, 2854.1, 2715.1, 1683.4, 1450.3, 1386.6, 1251.4, 1204.2, 705.8, 665.3 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[CH:9][CH:8]=[C:7]([S:20]([N:23](CC1C=CC(OC)=CC=1)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:22])=[O:21])[CH:6]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[CH:9][CH:8]=[C:7]([S:20]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)(=[O:21])=[O:22])[CH:6]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)c(Br)cnc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1-c1c(Br)cnc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 3-bromo-N-(4-methoxybenzyl)-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (from STEP 1 of EXAMPLE 324, 15 mg, 0.025 mmol) in DCM (1 mL) was treated with TFA (0.5 mL). After 30 min, the mixture was diluted with MeOH, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 3-bromo-4-(2-methoxyphenyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (11.8 mg, 0.025 mmol, 99% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.12 (br. s., 1H), 9.06 (d, J=4.4 Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 7.85 (dd, J=1.9, 8.9 Hz, 1H), 7.69 (s, 1H), 7.62-7.48 (m, 3H), 7.34-7.22 (m, 2H), 7.14 (dt, J=0.7, 7.4 Hz, 1H), 3.67 (s, 3H). m/z (ESI) 476.2 (M+H)+.
Reaction SMILES: [C:1]([O:4]O)(=[O:3])[CH3:2].[C:6]([O:9]CC)(=[O:8])[CH3:7].[C:12](O)(=O)[CH3:13]>>[C:1]([OH:4])(=[O:3])[CH2:2][CH2:12][CH2:13][CH2:7][C:6]([OH:9])=[O:8]
Reactant: CC(=O)O
Reactant: CC(=O)OO
Reactant: CCOC(C)=O
Product: O=C(O)CCCCC(=O)O

Procedure:
According to the flow chart of FIG. 1, ε-caprolactone was produced. Initially, a crude reaction mixture A produced according to the procedure of Reference Example 1 was fed to a first distillation column and was subjected to distillation for removing low boiling components at a bottom temperature of 180° C. and a column top pressure of 90 mmHg (12.0 kPa). In the first distillation column, low boiling components including unreacted cyclohexanone ANO, unreacted peracetic acid, ethyl acetate and acetic acid were distilled as a first distillate A1 and a first side-cut fraction A2. The first side-cut fraction A2 contained ANO in a higher concentration than in the first overhead distillate A1. The first side-cut fraction A2 was introduced into a second distillation column, was subjected to distillation at a bottom temperature of 100° C. and a column top pressure of 225 mmHg (30.0 kPa) and thereby yielded a second distillate A21 containing unreacted peracetic acid, ethyl acetate, and acetic acid from the column top and a second bottom liquid A22 containing ANO and part of acetic acid from the bottom. The recovered second bottom liquid A22 was recycled as a reaction raw material to the reaction system. In the first distillation column, a first bottom liquid A3 containing the target ε-caprolactone CL-M, by-produced adipic acid ADA and a polymerization product of ε-caprolactone HB was recovered from the bottom. The recovered first bottom liquid A3 was introduced into a third distillation column and was subjected to distillation at a bottom temperature in a range from 120° C. to 200° C. and a column top pressure of 5 mmHg (0.67 kPa). In the third distillation column, the target ε-caprolactone was yielded as a third side-cut fraction A31 not from the column top but from an intermediate tray between the column top and a tray from which the first bottom liquid A3 was charged. A third bottom liquid A32 containing by-produced adipic acid ADA and a polymerized product of ε-caprolactone HB was drained from the bottom. Separately, a third overhead distillate A30 was recovered from the column top and was introduced into the first distillation column for removing low boiling components.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([CH3:12])[CH:4]=1.N1C=CC=CC=1.CC(C)=O.[C:23](Cl)(=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH3:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:9]([O:10][CH3:11])=[CH:8][C:6]=1[NH:7][C:23](=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COc1cc(C)c(N)cc1OC
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C)c(NC(=O)C=Cc2ccccc2)cc1OC
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
To a solution of 4,5-dimethoxy-2-methylaniline (40.1 g), pyridine (48.5 ml), and acetone (350 ml), cinnamoyl chloride (44.0 g) was added dropwise at room temperature over 15 minutes. After allowing to react at room temperature for 2 hours, water (15 ml) was added and the mixture was stirred for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform, followed by washing with 1N HCl, 1N caustic soda and water in this order, and drying. Chloroform was evaporated. Precipitated crystals were collected by filtration with ether. 69.8 g of the title compound was obtained as yellow crystals (97.8%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[C:21]([CH:36]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)=[O:23]>CC(O)C.CCOC(C)=O>[Br:16][C:17]1[C:18]([N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)=[N:19][CH:20]=[C:21]([CH:36]=1)[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:33])[F:35])=[CH:29][CH:30]=1)=[O:23]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
(R)-Pyrrolidin-3-ol (17.1 ml, 211.2 mmol) and DIPEA (67.6 ml, 387.6 mmol) were added to a suspension of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.3, 69.6 g, 175.9 mmol) in iPrOH (120 mL) and stirred at 140° C. for 1 h. The mixture was diluted with EtOAc (1 L), washed with 1N HCl (2×200 mL), a sat. solution of NaHCO3 (200 mL) and brine (2×200 mL) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/iPr2O to afford the title compound as a white crystalline solid. HPLC (Condition 5) tR=6.58 min, UPLC-MS (Condition 6) m/z=446.0/448.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.01 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.64-3.76 (m, 1H) 3.79-3.91 (m, 2H) 4.33 (br. s, 1H) 4.97 (d, J=3.13 Hz, 1H) 7.33 (d, J=9.38 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.30-8.36 (m, 1H) 8.66 (d, J=2.35 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:24](I)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][CH:19]=3)=[CH:10][N:9]2[CH2:24][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1cccc(Cl)c1
Reactant: CCI
Product: CCn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1cccc(Cl)c1

Procedure:
A 2.6 gram portion of 1-(3-chlorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, prepared in Example 3, was alkylated with ethyl iodide to produce 0.25 grams of the desired product, an oily liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)nn(-c3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.3 mmol) in CH2Cl2 (5 mL) was treated with phenylboronic acid (0.6 mmol), pyridine (0.6 mmol), and copper(II) acetate (4.5 mmol). The mixture was stirred at RT for 16 h. After concentration and purification (SiO2, EtOAc/hexanes), 3-(4-chloro-phenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained. This intermediate was then diluted with CH2Cl2 (10 mL), and TFA (1 mL) was added. The mixture was stirred at RT for 4 h. The mixture was concentrated and the residue was purified (SiO2, 2 M NH3 in MeOH/CH2Cl2) to provide the title compound (40 mg). MS (ESI): exact mass calculated for C19H18ClN3, 323.12. found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.46-7.40 (m, 4H), 7.36-7.32 (m, 5H), 3.09-3.07 (br m, 4H), 3.00-2.98 (br m, 2H), 3.92-2.90 (br m, 2H).
Reaction SMILES: [C:1]([Cu])#[N:2].[CH2:4]([C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10](I)[C:9]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)[CH2:5][CH2:6][CH3:7]>N1C=CC=CC=1.C(Cl)Cl>[CH2:4]([C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:1]#[N:2])[C:9]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([I:23])=[CH:21][CH:22]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1nc(C)nc(I)c1Cc1ccc(I)cc1
Reactant: N#C[Cu]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(C)nc(C#N)c1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
A mixture of 800 mg (8.94 mmol) CuCN and 10 mL pyridine was heated to 110° C. until all of the CuCN went into solution (7 minutes). To this mixture was added a solution of 440 mg (0.894 mmol) 6-butyl-4-iodo-2-methyl-5-[(4-iodophenyl)methyl]pyrimidine in 3 mL pyridine. After 5 minutes, the reaction mixture was cooled to room temperature, diluted with CH2Cl2, filtered through powdered cellulose flock, stripped of solvent in vacuo, and was medium pressure chromatographed on silica gel using 13% EtOAc/hexane to give 306 mg of the title compound, 87% yield. Rf 0.29 in 15% EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfate stain;
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[C:28]([O:36][CH3:37])=[C:29]([OH:35])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1>CN(C)C=O.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>[OH:35][C:29]1[C:30]([O:33][CH3:34])=[C:31]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)[CH:32]=[CH:27][C:28]=1[O:36][CH3:37]
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: COc1ccc(Br)c(OC)c1O
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: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Temperature: 85 °C
Yield: 40.7 %

Procedure:
A stirring solution of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one (2.23 g, 8.58 mmol) in dimethylformamide (30 mL) was purged with argon for 1 h, to this cesium carbonate (8.37 g, 25.74 mmol), Pd(PPh3)4 (495 mg, 0.429 mmol) and 3-bromo-2,6-dimethoxy-phenol (2.0 g, 8.58 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-10% ethyl acetate in pet ether) afforded the title compound as a solid (1 g, 40.7%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1C=O.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-])=O.[C]=O>N1C=CC=CC=1.[OH-].[Rh+3].[OH-].[OH-]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[N:13][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Rh+3]
Agent: [C]=O
Agent: [OH-]
Solvent: c1ccncc1
Product: C1=Cc2ccccc2CC1=Nc1ccccc1
Temperature: 170 °C
Yield: 75 %

Procedure:
A solution of β-naphthaldehyde (0.1 mole), nitrobenzene (0.11 mole) and rhodium hydroxide [Rh(OH)3 ] in 50 ml of pyridine were charged into a stainless steel rocking autoclave of 0.5 l capacity. The autoclave was pressurized to 140 atm with carbon monoxide and heated to 170°C for 3 hours. On completion of the reaction period, the pressure vessel was allowed to cool and the gases vented. Work-up of the reaction mixture gave 75% yield of β-naphthylideneaniline, the product being unequivocally identified by mixed melting point and spectroscopic (ir and nmr) comparison with an authentic sample.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:20][CH3:21])=[C:17]([OH:19])[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:22]N(C)C=O.CI.C(OCC)(=O)C>O>[CH3:22][O:19][C:17]1[CH:18]=[C:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][C:16]=1[O:20][CH3:21]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1O
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
5-[1-(4-Fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol (50.0 mg, 0.176 mmol), 5 mL of N,N-dimethylformamide and methyl iodide (16.4 uL, 0.264 mmol) were combined in a vial and stirred at room temperature overnight. An additional 0.5 mL of methyl iodide was added and stirring continued for 2 days at room temperature and then 10 mL of ethyl acetate and 10 mL of water were added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of 10% ethyl acetate in hexanes to 50% ethyl acetate in hexanes over 20 minutes to give 5-(3,4-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole (25 mg, 48%) as a white solid. LC/MS (EI) tR 4.14, m/z 299.1 (M++1). 1H NMR (CDCl3 300 MHz) δ 3.7 (s, 3H); 3.9 (s, 3H); 6.5 (s, 1H); 6.7 (s, 1H); 7.0 (s, 2H); 7.1 (m, 2H); 7.3 (m, 2H); 7.7 (s, 1H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:32][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: NC1CCCCC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NC1CCCCC1

Procedure:
5-Cyclohexylamino-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and cyclohexylamine. Mass spectrum (ES) MH+=419.
Reaction SMILES: [F:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=O)[NH:7][CH:6]=[N:5][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:8]1[C:9]2[CH:10]=[N:11][C:2]([F:1])=[CH:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(F)ncc12
Product: Fc1cc2ncnc(Cl)c2cn1

Procedure:
A suspension of 7-fluoro-4-oxo-3H-pyrido[4,3-d]pyrimidine (0.23 g, 1.39 mmol) in POCl3 (10 mL) is stirred under reflux for 3.5 h, and is then concentrated under vacuum. The resulting oil is ice-cooled, diluted with CH2Cl2 (100 mL), saturated aqueous Na2CO3 (40 mL) and ice, and stirred at 20° C. for 2 h. The CH2Cl2 extract is separated and the aqueous portion further extracted with CH2Cl2 (2×100 mL), and then the combined extracts are dried (Na2SO4) and filtered to give crude 4-chloro-7-fluoropyrido[4,3-d]pyrimidine. 3-Bromoaniline (1.26 g, 7.35 mmole), 3-bromoaniline hydrochloride (20 mg) and dry isopropanol (5 mL) are added, then the resulting solution is concentrated under vacuum to remove the CH2Cl2 and stirred at 20° C. for 1 h. Upon addition of dilute NaHCO3 and water, the product crystallises. Filtration, washing with water and CH2Cl2, gives pure 4-(3-bromoanilino)-7-fluoropyrido[4,3-d]pyrimidine (297 mg, 67%) as a cream solid. 1H NMR (DMSO) δ 10.38 (1H, brs), 9.59 (1H, s), 8.72 (1H, s), 8.17 (1H, s), 7.85 (1H, m), 7.38 (3H, m).
Reaction SMILES: [Br:1]C[C:3]1([C:6]([C:8]2(CBr)[CH2:10][CH2:9]2)=[O:7])CC1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[Br-:1].[CH:8]1([C:6]([CH2:3][N+:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])[CH2:9][CH2:10]1
Reactant: O=C(C1(CBr)CC1)C1(CBr)CC1
Reactant: c1ccncc1
Solvent: CCO
Product: O=C(C[n+]1ccccc1)C1CC1
Product: [Br-]

Procedure:
2.4 g of 1-bromomethylcyclopropylketone and 5.8 cm3 of pyridine are introduced into a three-necked flask containing 40 cm3 of ethanol and then the mixture is heated for 2 hours under reflux. After concentrating to dryness at 40° C. under reduced pressure (2.7 kPa), the residue is taken up in twice 30 cm3 of diethyl ether. After filtration, washing with diethyl ether, the precipitate is dried under reduced pressure (90 Pa) to give 3.4 g of 1-cyclopropylcarbonylmethylpyridinium bromide in the form of a cream-coloured solid melting at 160° C.