Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:11]=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:14][CH:15]=1.O>CN(C=O)C.CC(C)=O>[NH2:9][C:10]1[N:11]=[C:12]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:14][C:15]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)n1nc(-c2ncc(N)nc2-c2ccccc2)ccc1=O
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
N-bromosuccinimide (875 mg) was added to a solution of 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.51 g) in DMF (15 ml). The mixture was stirred at 50-55° C. for one hour and poured into water (150 ml). The precipitate was collected by filtration, dissolved in CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a solid. The solid was suspended in acetone and collected by filtration to give 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (1.26 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH3:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: Cc1c(Br)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)cccc1Cn1ncc2ccccc21
Temperature: 80 °C
Reaction time: 18.25 h

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-2-methylbenzene (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 250 mg, 0.947 mmol), 1H-indazole (112 mg, 0.947 mmol) and potassium carbonate (131 mg, 0.947 mmol) in acetonitrile (5 mL) was heated with stirring at 80° C. After 18.25 h, the mixture was cooled to rt, diluted with water and extracted three times with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 65:35 hexane-EtOAc) to provide 1-(3-bromo-2-methylbenzyl)-1H-indazole as an oil which crystallized on standing (Intermediate 31-1, 74 mg, 26%). 1H NMR (400 MHz, chloroform-d) δ 8.06 (1H, d, J=0.9 Hz), 7.76 (1H, dt, J=8.1, 1.0 Hz), 7.48 (1H, d, J=7.9 Hz), 7.30-7.37 (1H, m), 7.26-7.30 (1H, m), 7.16 (1H, ddd, J=8.0, 6.8, 1.0 Hz), 6.93 (1H, t, J=7.8 Hz), 6.70 (1H, d, J=7.7 Hz), 5.61 (2H, s), 2.45 (3H, s). Mass spectrum m/z 301, 303 (M+H)+. Also obtained was 2-(3-bromo-2-methylbenzyl)-2H-indazole as a pale yellow gum (Intermediate 31-2, 164 mg, 58%). 1H NMR (400 MHz, chloroform-d) δ 7.68-7.76 (2H, m), 7.54-7.63 (2H, m), 7.28 (1H, ddd, J=8.2, 7.2, 1.1 Hz), 6.97-7.10 (3H, m), 5.63 (2H, s), 2.37 (3H, s). Mass spectrum m/z 301, 303 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(Br)ccc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-4-bromo-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.72 (s, 3H), 6.75 (d, 2H, J=8.8 Hz), 7.19-7,26 (m, 2H), 7.37-7.43 (m, 4H), 7.57 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.96 (s, 1H), 10.09 (s, 1H). MS: m/z 447.9 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[N-:13]=[N+:14]=[N-:15].[Na+].C(O)C>O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:13]=[N+:14]=[N-:15]
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(CN=[N+]=[N-])cccc1[N+](=O)[O-]
Temperature: 45 °C
Yield: 48.3 %

Procedure:
A mixture of 2-methyl-3-nitrobenzylchloride (0.70 g, 3.77 mmol), sodium azid (1 g, 15.4 mmol), ethanol (10 ml) and water (2 ml) was heated at 45° C. over night. The mixture was filtered, the filtrate was concentrated, and the residue was purified by chromatography on silica (heptane/EtOAc) to give the compound 2-methyl-3-nitrobenzylazide 0.35 g, which was hydrogenated over 5% palladium-charcoal 80 mg in EtOAc/EtOH 1:1 (14 ml), over night. The mixture was filtered through Celite, and the filtrated was concentrated to give 0.23 g (45%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[Cl:15])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][SH:27].O>CN(C)C=O>[Cl:15][C:7]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][S:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23]
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: CN(C)CCS
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSCC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(chloroacetyl)-2-chloro-4-nitroaniline (3.01 g) in N,N-dimethylformamide (100 mL) is added powdered sodium carbonate (6.0 g) and 2-dimethylaminoethanethiol hydrochloride (6.0 g). The mixture is stirred for 1 hour at 25° C., poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous potassium carbonate and concentrated under reduced pressure to give an oil. The oil is crystallized from toluene-hexanes (3:1) to yield a pale yellow crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([OH:9])=[CH:4][C:3]=1[OH:10].[CH3:11][C:12]([CH3:14])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O1C[CH2:32][CH2:31][CH2:30]1>>[CH3:11][C:12]1([CH3:14])[O:10][C:3]2[CH:4]=[C:5]3[O:9][C:31]([CH3:32])([CH3:30])[O:8][C:6]3=[CH:7][C:2]=2[O:1]1
Reactant: CC(C)=O
Reactant: Oc1cc(O)c(O)cc1O
Reactant: C1CCOC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
18.6 g of the 1,2,4,5-tetrahydroxybenzene prepared according to Example 4 (0.13 mole) and 70 ml acetone (58.6 g, 1.0 mole) was dissolved in 1 1 tetrahydrofuran. 168 g P2O5 (1.18 mole) was added to the vigorously stirred mixture in portions as fast as possible. The mixture was heated to reflux for 4 hours. After cooling to room temperature the solids were filtered with suction and washed with 0.5 L ether. The combined filtrates were treated with 10 g K2CO3 and stirred 1 hour, filtered and evaporated to dryness yielding a yellow-brown oily solid. The product was triturated with petroleum ether, decanted and evaporated to yield 13.8 g of the title compound (48%) as white-yellow crystals, mp=122° C., which can be recrystalized from a small amount of petroleum ether.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[CH3:5][C@:6]12[CH2:22][CH2:21][C@H:20]3[C@@H:11]([CH:12]=[CH:13][C:14]4[C@@H:19]3[CH2:18][CH2:17][C:16](=[O:23])[CH:15]=4)[C@@H:10]1[CH2:9][CH2:8][C:7]2=[O:24].[NH4+].[Cl-].CCOC(C)=O.CCCCCC>C1COCC1>[CH2:1]([C@H:12]1[CH2:13][C:14]2[C@H:19]([CH2:18][CH2:17][C:16](=[O:23])[CH:15]=2)[C@@H:20]2[C@@H:11]1[C@H:10]1[C@@:6]([CH2:22][CH2:21]2)([CH3:5])[C:7](=[O:24])[CH2:8][CH2:9]1)[CH3:2]
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[C@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a mixture of CuI(Bu3P)4 (15.7 g, 40 mmol) in THF (50 mL) was added a 1.0 M solution of EtMgBr in THF (40 mL, 40 mmol) at −30° C., and stirred for 20 min. The reaction mixture was cooled to −78° C. and dione 54 (3.5 g, 12.94 mmol) was added. The reaction mixture was warmed to −30° C. for 0.5 h, and poured into saturated aqueous NH4Cl. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and then concentrated to afford a solid. Chromatography (20% EtOAc/hexane) yielded dione 55 as a yellow solid (1.5 g, 39%). The major 7α-ethyl isomer of 55: 1H NMR (300 MHz, CDCl3) δ0.89 (t, J=7.0 Hz, 3, CH2CH3), 0.93 (s, 3, CH3), 2.60 (dd, J=2.4, 14.3 Hz, 1), 5.85 (s, 1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([NH2:19])[N:12]=1)(C)(C)C.[ClH:21]>O1CCOCC1>[ClH:21].[ClH:21].[NH2:19][C:13]1[C:14]([C:17]#[N:18])=[CH:15][CH:16]=[C:11]([NH:10][CH2:9][CH2:8][NH2:7])[N:12]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc(C#N)c(N)n1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(NCCN)nc1N
Reaction time: 0.5 h

Procedure:
6.76 g (24.38 mmol) of tert-butyl{2-[(6-amino-5-cyanopyridin-2-yl)amino]ethyl}carbamate (Example 8A) were dissolved in 122 ml of a 4 N solution of hydrogen chloride in dioxane and stirred for 30 min. The reaction mixture was concentrated to half of its original volume, and the same amount of diethyl ether was added. The reaction mixture was stirred for 20 min, and the product was filtered off and washed with diethyl ether. This gave 5.43 g (89% of theory) of the product as a solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:12]=O.[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:6]=1)[CH2:12][N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: C=O
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(O)c(CN2CCC(NC(=O)c3ccccc3)CC2)c1
Reaction time: 8 h

Procedure:
4-Acetamidophenol (1.51 g.) and 39.4% aqueous formaldehyde (1.25 ml.) were dissolved in 50% aqueous ethanol, and 4-benzamidopiperidine (2.04 g.) was added. The resulting solution was heated under reflux for 30 minutes then left overnight at room temperature. The white solid was collected and purified by suspending in boiling ethanol and filtering to give the title compound (1.32 g.), m.p. 242° C. (Found: C, 68.15; H, 7.1; N, 11.3.C21H25N3O3 requires C, 68.6; H, 6.9; N, 11.4%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[CH2:19][NH:20][C:21]([NH:23][CH3:24])=[S:22]>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:22][C:21](=[N:20][CH2:19][C:18]3[CH:25]=[CH:26][CH:27]=[CH:28][C:17]=3[Cl:16])[N:23]2[CH3:24])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: CNC(=S)NCc1ccccc1Cl
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: CN1C(=NCc2ccccc2Cl)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 3.1 g of 1-(2-chlorobenzyl)-3-methylthiourea were reacted according to Example 23 and the crystalline end product was filtered off. Colorless crystalline solid body: melting point: 182° C (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Reactant: OC[C@@H]1CC(c2ccc(Br)cn2)=NO1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Temperature: 75 °C
Yield: 48.9 %

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (Intermediate 11, 0.277 g, 1.08 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H -1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 7, 0.35 g, 0.9 mmol), potassium carbonate (0.622 g, 4.5 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.1 g, 0.09 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane (2×10 ml), the solids were then dissolved in warm trifluoroethanol (2 ml), and further purified by column chromatography, eluting with 8% methanol in dichloromethane to give the title compound as a white solid (0.193 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14]N(CC2C=CC=CC=2)[CH2:12][CH:11]1[CH2:23][C:24]([OH:26])=O.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.CN(C)[CH2:36][CH2:37]CN=C=NCC>CN(C)C=O>[CH2:32]([N:27]1[CH2:14][CH2:15][N:10]2[C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[NH:1][C:24](=[O:26])[CH2:23][CH:11]2[CH2:12]1)[C:31]1[CH:37]=[CH:36][CH:28]=[CH:29][CH:30]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(N)c(N2CCN(Cc3ccccc3)CC2CC(=O)O)c1
Reactant: c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N1CCN(Cc3ccccc3)CC1CC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 12E (0.390 g, 1.097 mmol) in N,N-dimethylformamide (3.66 mL) were added pyridine (4.44 mL, 54.9 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.421 g, 2.195 mmol) and the mixture was stirred at room temperature for 1 hour. The solution was concentrated, water was added to the residue, and the product was extracted twice with ethyl acetate. The combined organic washes were dried over sodium sulfate, concentrated and dried under vacuum at room temperature overnight. It was then passed through a 5 gram silica gel cartridge eluting first with dichloromethane, then with 2% methanol/dichloromethane and finally with 5% methanol/dichloromethane to obtain the title compound. An aliquot of material was further purified for analytical purposes by preparative HPLC to afford the title compound as the trifluoroacetic acid salt. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 9.52 (s, 1H), 7.54-7.48 (m, 5H), 6.90 (d, J=8.6, 1H), 6.70-6.60 (m, 2H), 4.45 (s, 2H), 3.74 (s, 3H), 3.67-3.07 (m, 7H), 3.22-3.04 (m, 2H), 2.61 (dd, J=7.0, 13.5, 1H), 2.00 (d, J=13.5, 1H); MS (ESI) m/z 338.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:38][CH2:39][OH:40])[CH2:9][C@@H:10]([C:19]1[CH:20]=[CH:21][C:22]([Cl:37])=[C:23]([N:25]([S:33]([CH3:36])(=[O:35])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=1)[O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41]1([CH3:47])C=CC=C[CH:42]=1.C(N(CCO)C[C@@H]([C:66]1[CH:67]=[CH:68][C:69](Cl)=[C:70]([N:72](S(C)(=O)=O)[C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76])[CH:71]=1)O[Si](CC)(CC)CC)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[N:108](C(/N=N/C(N(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]([CH2:9][C@@H:10]([C:19]1[CH:20]=[CH:21][C:22]([Cl:37])=[C:23]([N:25]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[S:33]([CH3:36])(=[O:34])=[O:35])[CH:24]=1)[O:11][Si:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:17][CH3:18])[CH2:38][CH2:39][O:40][C:66]1[CH:71]=[C:70]2[C:69]([C:42]([CH2:41][CH3:47])=[N:108][N:72]2[C:73]([O:74][C:75]([CH3:76])([CH3:77])[CH3:78])=[O:79])=[CH:68][CH:67]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCO)Cc1ccccc1)c1ccc(Cl)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c1
Reactant: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1nn(C(=O)OC(C)(C)C)c2cc(OCCN(Cc3ccccc3)C[C@H](O[Si](CC)(CC)CC)c3ccc(Cl)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c3)ccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tert-butyl 3-ethyl-6-hydroxyindazole-1-carboxylate (27.9 mg) that can be produced by the method described in Reference Example 14 or the like, and a (R)-tert-butyl 5-(2-(benzyl(2-hydroxyethyl)amino)-1-(triethylsilyloxy)ethyl)-2-chlorophenyl(methylsulfonyl)carbamate-toluene solution [0.5 mL; solution prepared by dissolving (R)-tert-butyl 5-(2-(benzyl(2-hydroxyethyl)amino)-1-(triethylsilyloxy)ethyl)-2-chlorophenyl(methylsulfonyl)carbamate (1.5265 g) that can be produced by the method described in Reference Example 75 or the like in dehydrated toluene (10 mL)] were dissolved in dehydrated toluene (0.5 mL), and triphenylphosphine (54.9 mg; manufactured by Wako Pure Chemical Industries, Ltd.) and TMAD (41.4 mg; manufactured by Masuda Chemical Industries, Co., Ltd.) were added to the solution. The mixture was stirred for 3 days at room temperature. The reaction solution was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=85:15→64:36), and thus the title compound (85.6 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Mg]Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[CH:17](OC(C)=O)[O:18]C(C)=O.Cl.CCCCCCCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH2:17][OH:18])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC(C)OC(C)=O
Reactant: Cc1c([Mg]Cl)cccc1-c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCCCC
Product: Cc1c(CO)cccc1-c1ccccc1
Temperature: 53 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
Under a nitrogen atmosphere, the reaction mixture from above was decanted into a clean, dry flask, leaving the unreacted magnesium turnings in the first flask. This solution, which contains (2-methyl[1,1'-biphenyl]-3-yl)magnesium chloride, was heated to reflux, and 16.5 g (0.55 mole based on formaldehyde) of polyoxymethylene diacetate (avg. mol. wgt. approx. 50,000, available commercially from E.I. du Pont de Nemours & Co., Inc., Wilmington, Delaware under the trade name Delrin 500 acetal homopolymer resin), milled to about 80 mesh, was added with stirring over three hours. Refluxing was continued for four additional hours after which the reaction mixture was allowed to cool and stand overnight. The mixture was then heated to 53° C. and was poured into a mixture of 100 g of ice, 52 g of concentrated hydrochloric acid, and 200 g of a mixture containing 95% n-octane and 5% toluene (wt/wt). This mixture was filtered and the organic phase separated. The organic solvents were distilled off, boiling range 65°-93° C. During a four hour period the solution was cooled with stirring to approximately 5° C. and was then filtered. The filter cake was washed with 100 mL of cold n-octane and air-dried for 0.5 hour. The filter cake was broken up and dried under a vacuum at 55° C. for four hours, yielding 78.9 g of (2-methyl[1,1'-biphenyl]-3-yl)methanol (89.9% purity), a yield of 70.8% of theory.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([C:21](OC)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>O.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[C:6]([C:21]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C1COCCN1
Agent: COc1nc(Cl)nc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=C(c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Temperature: 20 °C
Reaction time: 4 h
Yield: 50.3 %

Procedure:
KOH (0.419 L, 4889 mmol) was added portionwise to methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (900 g, 2444 mmol) in water (5 L) at 20° C. over a period of 1 hour. The resulting suspension was stirred at 20° C. for 4 hours until saponification was complete. The reaction was filtered to remove insoluble particles and transferred into a vessel containing water (2 L) (vessel 1). Morpholine (0.639 L, 7333 mmol) was added and agitation continued. 2-chloro-4,6-dimethoxy-1,3,5-triazine (1931 g, 11000 mmol) and water (8 L) was charged to vessel 2 and the temperature adjusted to approximately 7° C., 4-methylmorpholine (134 mL, 1222 mmol) was charged at a rate to maintain the contents at 10° C. and the contents agitated for 4 hours. The contents of vessel 2 was transferred to vessel 1 and agitated at room temperature overnight. DCM (5 L) was then added and the mixture transferred to a 30 litre separator, extracted with a further portion of DCM and the organic extracts combined, dried (Na2SO4) and evaporated to dryness. The solid was stirred in ethyl acetate and filtered to give 8-bromo-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (520 g, 50.3%) as a slightly grey solid. Mass Spectrum: m/z [M+H]+=425.
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[F:8][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[CH2:41]([Si:46]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:51][CH2:50][CH:49]([CH:52]2[CH2:57][CH2:56][CH:55]([CH:58]=O)[CH2:54][CH2:53]2)[CH2:48][CH2:47]1)[CH2:42][CH2:43][CH2:44][CH3:45]>CCCCCC.O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:58][C@H:55]2[CH2:54][CH2:53][C@H:52]([CH:49]3[CH2:48][CH2:47][Si:46]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])([C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[CH2:51][CH2:50]3)[CH2:57][CH2:56]2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2CCC(C=O)CC2)CC1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](C=Cc3ccc(F)c(F)c3)CC2)CC1
Reaction time: 2 h

Procedure:
12.0 g of potassium t-butoxide was added to a mixture of 47.0 g of 3,4-difluorobenzyltriphenylphosphonium bromide and 200 ml of tetrahydrofuran (hereinafter referred to as THF) to obtain an orange-colored ylide solution. 50 ml of a THF solution of 35.0 g of 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)cyclohexane carbaldehyde was added to the solution, followed by agitation at room temperature for 2 hours. Thereafter, the reaction solution was poured into iced water and extracted with ethyl acetate. The resultant extract was washed with brine, dried and concentrated to obtain a residue, to which 100 ml of n-hexane was added. The resultant crystals of triphenylphosphine oxide were separated by filtration and the resultant filtrate was concentrated. The resultant residue was purified through silica gel chromatography to obtain 41.7 g of 4-(trans-4-(2-(3,4-difluorophenyl)ethenyl)cyclohexyl)-1-n-pentyl-1-phenyl-1-silacyclohexane. This product was subjected to IR analysis with the results shown below.