Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncccc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
0.64 g of 5-(4-chlorophenyl)-4-(3-chloro-2-pyridyl)-6-methyl-2H-pyrida zin-3-one and 15 g of phosphorus oxychloride were mixed. The mixture was stirred for 6 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.67 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.50 g of 3-chloro-5-(4-chlorophenyl)-4-(3-chloro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (5) of the present invention.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:17])[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:17][O:27]1)=[O:18])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCC1CCCCCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCC2CCCCCCC2)CO1

Procedure:
2.2 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1a) from 5.42 g of 5-cyclooctyl-2-methylenevaleric acid ethyl ester and 5.55 g of m-chloroperbenzoic acid in 50 ml of methylene chloride.
Reaction SMILES: [CH2:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18]O)=[C:14]([CH3:20])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2].P(Br)(Br)[Br:22]>C1COCC1>[Br-:22].[CH2:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:20])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(CO)c(C)c1)c1cc(C)cs1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C)c(C)c1)c1cc(C)cs1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanol (6 g,) in THF (50 ml) is treated with PBr3 (2.2 ml, 23.3 mmol) and warmed to RT. After stirring for 2 h, the mixture is partitioned between EtOAc and brine. The organic layer is MgSO4 dried, concentrated, and dissolved in anhydrous THF (30 ml) to give a solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methane bromide. Separately, a solution of 3,3-dimethyl-butan-2-one (5.3 ml, 42.4 mmol) in THF (15 ml) is treated with LiHMDS (42.4 ml, 42.4 mmol, 1M in THF) at −70° C. for 1 h. This solution is transferred (via cannula) into a −70° C. solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanebromide/THF. The mixture is warmed to RT and stirred for 1 h. The reaction is diluted with EtOAc and washed with 0.2 N HCl until the aq layer is pH 2. The organic layer is concentrated to give the title compound (6.2 g, 79%).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:48][C:47]([CH3:49])=[C:46]([C:50](=O)[CH3:51])[CH:45]=2)=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:48][C:47]([CH3:49])=[C:46]([C:50]3[CH:51]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)[CH:45]=2)=[CH:40][CH:39]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)oc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(Cl)cc2)cc1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 59 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[5-(4-chloro-phenyl)-2-methyl-furan-3-yl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (83 mg, 59% yield). MS: 562.21 (M+H+); HPLC Procedure B, retention time=8.99 min.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [Ni]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: O=C(O)CC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-glucose and L-(+)-glutamic acid using Raney nickel or palladium/activated carbon (10%) as a catalyst. The product had a melting point of 94° C. and an RF -value of 0.61 (determined on DC-finished plates of silica gel G (Merck) with a transporting fluid made up of 85 parts by volume of methanol and 15 parts by volume of water).
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:14].[Na+]>CN1CCN(C)C1=O>[F:11][C:10]1[C:9]([F:12])=[C:8]([F:13])[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:14]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Reactant: [OH-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Product: O=C(O)c1cc(F)c(F)c(F)c1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
3.88 g (0.02 mole) of 2,3,4,5-tetrafluorobenzoic acid, 3.23 g (0.08 mole) of powdery 99% sodium hydroxide and 40 ml of 1,3-dimethyl-2-imidazolidinone were fed into a 200-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 130° C. for 3 hours to give rise to a reaction. Then, the same post-treatment as in Example 1 was conducted to obtain 1.14 g of 3,4,5-trifluorosalicylic acid. The isolated yield was 29.7% relative to the 2,3,4,5-tetrafluorobenzoic acid used.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([NH2:24])=[N:20]3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:5]=[CH:6][CH:7]=1.C=O.[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:18][N:19]3[CH:23]=[N:22][C:21]([NH:24][CH3:27])=[N:20]3)[CH:11]=[N:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncn(Cc2cnc(OC(F)F)c(-c3cccc(Cl)c3)c2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNc1ncn(Cc2cnc(OC(F)F)c(-c3cccc(Cl)c3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
To a solution of 1-((5-(3-chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-1,2,4-triazol-3-amine (Example 219, 120 mg, 0.34 mmol) in DCM (2 mL), was added formaldehyde (26 μL of 37 wt % solution, 0.35 mmol), sodium triacetoxyborohydride (145 mg, 0.68 mmol) and a few drops of AcOH. The mixture was stirred at room temperature for 16 h. Purification by reverse-phase PREP-HPLC gave the title compound (25 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.19-8.11 (m, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.71 (s, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 7.41-7.28 (m, 3H), 5.21 (s, 2H), 2.72 (s, 3H). [M+H]=366.21.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:8])[OH:7])=[O:2]>C(O)(=O)C>[CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
One example of method (ii) is described in U.S. Pat. No. 3,933,781. N-formyl-α-L-aspartyl-L-phenylalanine (hereinafter referred to as "F-α-AP") is formed by condensing N-formyl-L-aspartic acid anhydride and L-Phe in glacial acetic acid, followed by removal of the formyl group from the product to form α-L-aspartyl-L-phenylanine (hereinafter referred to as "α-AP"), isolation of the α-AP intermediate and finally esterification of the isolated intermediate to obtain α-APM.HCl. As with the other previously described method, this method also suffers the disadvantaqe of requiring isolation of an intermediate compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]=[C:6]([S:9][CH3:10])[S:7][CH3:8].CC([O-])(C)C.[K+].[CH2:18]([N:20]=C=S)[CH3:19]>C1COCC1>[CH3:10][S:9][C:6]1[S:7][C:8]([NH:20][CH2:18][CH3:19])=[C:4]([C:3]([O:2][CH3:1])=[O:11])[N:5]=1
Reactant: COC(=O)CN=C(SC)SC
Reactant: CCN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1sc(SC)nc1C(=O)OC
Reaction time: 0.5 h

Procedure:
A solution of N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole) in anhydrous THF (10 mL) at −78° C. and the mixture was stirred for 30 min. Then a solution of ethyl isothiocyanate (1 mmole) in anhydrous THF (2 mL) was added and the reaction was stirred at −78° C. for 30 min and at room temperature for 2 h. The reaction was quenched with water. Extraction and chromatography gave 2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow solid, which was subjected to Step B and C of Example 18 followed by Step C of Example 3 to give 2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole (18.4) as a solid. Mp>200° C. (decomp). Anal. Calcd. for C8H13N2O5PS2+0.1 HBr: C: 29.99; H: 4.12; N: 8.74. Found: C: 29.71; H: 4.10; N: 8.60.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[C:40](=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=1)([CH3:36])([CH3:35])[CH3:34].O>C(OCC)C>[C:33]([C:37]1[CH:38]=[C:39]([CH3:55])[CH:40]([C:42]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:41]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccccc1)(c1ccccc1)c1cc(C(C)(C)C)cc2c1Cc1ccc(C(C)(C)C)cc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 3.01 g of 3,6-di-tert-butyl-fluorene (10.8 mmol) was dissolved in 80 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 7.6 ml of a n-butyl lithium/hexane solution (1.56M: 11.9 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 50 ml of a solution prepared by dissolving 4.86 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (16.2 mmol) in 50 ml of dehydrated diethyl ether was added and stirred with refluxing for 13 days. To the reaction mixture, 30 ml of distilled water was gradually added dropwise in an ice bath, and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give red solid. The red solid was re-crystallized using ethanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 4.42 g (7.63 mmol) as a pale yellow solid (yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=S)[NH:11][NH2:12].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:21]([CH3:23])[NH:12][N:11]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2c(Cl)cccc2Cl)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A slurry of 9.4 g (0.04 mole) of 4-(2,6-dichlorophenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was stirred under nitrogen atmosphere while 6.8 g (0.04 mole) of ethyl 2-choroacetoacetate was added. The reaction mixture became yellow as it stirred for 1 hr at room temperature. Then 40 mL of 2N ethanolic hydrogen chloride was added and the reaction mixture heated at reflux for 3 hr. Insoluble sulfur was removed by filtration and the filtrate concentrated in vacuo to give an orange solid, which when triturated with hot acetone yielded 11.3 g of pale yellow crystals, mp: plastic 175°-191° C., degasses at 195° C., and forms a clear melt at 215° C. Recrystallization from acetonitrile gave 6.5 g of product, mp 180°-190° C. Additional material was obtained from the reaction mixture filtrate upon setting. The filtrate was then concentrated to a solid. All crude materials were combined and dissolved in 125 mL of benzene, treated with charcoal, filtered, and the volume reduced to 40 mL. The benzene solution was treated with 25 mL of ligroin and the product crystallized from the hot solution to give 9.7 g of crystalline product which had a pink color, mp 191°-192° C.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][NH:31][CH2:32]3)(=[O:26])=[O:25])[CH2:20][CH2:19]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([N:31]1[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][CH:35]=[CH:36][C:27]=3[S:24]([N:21]3[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]3)(=[O:26])=[O:25])[CH2:32]1)[NH:11][C:10]2=[O:12]
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: CN1CCN(S(=O)(=O)c2cccc3c2CCNC3)CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCc4c(cccc4S(=O)(=O)N4CCN(C)CC4)C3)[nH]c(=O)c2cc1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b, (0.77 g, 3.23 mmol), 5-(4-methyl-piperazine-1-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline 11a (1.25 g, 3.41 mmol) and triethylamine (0.75 g, 1.04 mL, 7.46 mmol) in DMSO (15 mL) was heated at 80° C. with stirring for 18 h. After cooling to room temperature the reaction was diluted with water. The precipitated white product was collected by filtration, washed with water, and dried to give 0.6 g of 6,7-dimethoxy-2-[5-(4-methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-isoquinolin-2-yl]-3H-quinazolin-4-one 401, mp. 230-237° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].CN(C)C=O.Br[CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1>O1CCCC1>[S:16]1[CH:17]=[CH:18][C:14]([CH2:13][O:3][CH2:2][CH2:1][OH:4])=[CH:15]1
Reactant: OCCO
Reactant: BrCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCCOCc1ccsc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.3 %

Procedure:
621 mg of ethylene glycol was dissolved in 1 ml of tetrahydrofuran, and 88 mg of 60% oily sodium hydride and 0.5 ml of dimethylformamide were added. After the mixture was stirred at room temperature for 5 minutes, a tetrahydrofuran solution(1 ml) of 200 mg of 3-bromomethylthiophene was added. The mixture was stirred at 60 ° C. for 2 hours, and then the solvent was evaporated. The residue was worked up in a customary manner to give 181 mg of the captioned compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.COCCOC>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 400.7 %

Procedure:
5.4 g (21.1 mmol) of 9-bromoanthracene, 2.6 g (21.1 mmol) of phenylboronic acid, 60 mg (0.21 mmol) of palladium acetate(II) (Pd(OAc)2), 10 mL (20 mmol) of an aqueous potassium carbonate (K2CO3) solution (2 mol/L), 263 mg (0.84 mmol) of tri(o-tolyl)phosphine (P(o-tolyl)3), and 20 mL of 1,2-dimethoxyethane (abbr.: DME) were mixed and stirred for 9 hours at 80° C. After the reaction, the precipitated solid was recovered by suction filtration, dissolved into toluene, and filtered through florisil, Celite®, and alumina. The filtrate was washed with a saturated aqueous sodium chloride solution and then dried with magnesium sulfate. After natural filtration, the filtrate was concentrated, thereby obtaining 21.5 g of objective 9-phenylanthracene as a light-brown solid with a yield of 85. %.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:15](=[O:16])[NH:14][N:13]=[CH:12][C:7]3=[CH:8][NH:9][C:10]([CH:11]=1)=[C:6]23.Br[CH2:18][C:19]([OH:21])=O.F[P-](F)(F)(F)(F)F.[N:29]1([O:38]C(N(C)C)=[N+](C)C)[C:33]2[N:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[N:30]1.C(N(CC)CC)C>CN(C)C=O>[O:16]=[C:15]1[C:5]2[C:6]3[C:7](=[CH:8][NH:9][C:10]=3[CH:11]=[C:3]([NH:2][C:19](=[O:21])[CH2:18][O:38][N:29]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:32]4[N:31]=[N:30]3)[CH:4]=2)[CH:12]=[N:13][NH:14]1
Reactant: Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Reactant: O=C(O)CBr
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(COn1nnc2cccnc21)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
In a manner analogous to that of Example 19, to a stirred suspension of 8-amino-1,5-dihydro-6H-[1,2]diazepino[4,5,6-cd]indol-6-one hydrochloride in anhydrous N,N-dimethylformamide (9 mL) was added bromoacetic acid (168 mg. 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (553 mg, 1.4 mmol) and triethylamine. The reaction was stirred at room temperature for 16 hours. The volatile components were evaporated and water was added to the residue. The precipitated orange solids were collected by filtration and washed with water and ethyl acetate. After drying, the title compound (158 mg) was obtained as an orange powder in 35% yield.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C(N)CCC.O>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: CCCCN
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
Triethyl orthoformate (3 ml, 18 mmol) and p-Toluenesulfonic acid (30 mg, 0.16 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (3 g, 8.72 mmol) in ethanol (20 ml). The mixture was stirred at room temperature for 1 h. Butylamine (1 ml, 9.72 mmol) was added and the mixture was heated at 30° C. for 2 h, cooled to 10° C. and water (10 ml) was then added. The precipitate was filtered, washed with water and dried under vacuum, to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (2.2 g, yield: 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:33])([CH3:32])[CH2:10][C:11]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[O:24])[O:22][N:21]=[C:20]([CH3:25])[C:19]=2[CH:26]=1)=[O:13].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:33])([CH3:32])[CH2:10][C:11]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[O:24])[O:22][N:21]=[C:20]([CH3:25])[C:19]=2[CH:26]=1)=[O:13])(=[O:36])[CH3:35]
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3N)C(F)(F)F)cc12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(F)cc1C(C)(C)CC(O)(C(=O)Nc1ccc2c(=O)onc(C)c2c1)C(F)(F)F

Procedure:
9.4 mg of 6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one and 0.04 ml of acetic acid anhydride in 0.5 ml of tetrahydrofuran are stirred for 2 days at room temperature, and mixed with ethyl acetate and sodium bicarbonate solution. The ethyl acetate solution is dried and concentrated by evaporation. After chromatography on silica gel, 8 mg of 6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one is obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([I:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([I:30])=[C:25]([CH:29]=1)[C:26]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:27]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1cc(Cl)ccc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.70 g, 2.71 mmol), 5-chloro-2-iodobenzoic acid (0.66 g, 2.32 mmol), DIPEA (1.21 mL, 6.97 mmol) and HATU (1.06 g, 2.79 mmol) in DMF (5 ml) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 523 (M+H).