Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[S:5][C:4]=1[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[S:5][C:4]3[C:25](=[O:27])[O:26][CH2:2][C:3]=3[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc(C(=O)O)c2CO)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To a solution of 110 mg of the product of Step 7 in 15 mL of CH2Cl2 was added 110 mg of 1-(3-dimethylamninopropyl)-3-ethyl-carbodiimide hydrochloride. After stirring for 20 min, the reaction was quenched with 20 mL of sat. NaHCO3 and extracted with 50 mL of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The crude product was suspended in 10 mL of 2:1 EtOAc/hexane with vigorously stirring for 2 h, and filtered to provide 75 mg of the title product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(OC)cc4)c3)csc12

Procedure:
3-[3-(4-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and p-anisoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:32](Br)([CH3:35])([CH3:34])[CH3:33]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC(N(C)C)=O.O>[CH3:33][C:32]([O:24][C:23](=[O:25])[C@H:12]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])([CH3:35])[CH3:34]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 550 °C
Reaction time: 19 h
Yield: 92.8 %

Procedure:
Into a suspension of N-[(phenylmethoxy)carbonyl]-L-tryptophan (33.27 g; 98.32 mmol), benzyltriethylammonium chloride (BTEAC) (22.4 g; 98.32 mmol) and K2CO3 (176.91 g; 1.28 mol) in dimethylacetamide (750 mL), tert-butyl bromide (265 mL; 2.36 mol) was dropped. The solution was heated to 550° C. and maintained under vigorous stirring for 19 h. The reaction was monitored by HPLC (Chromatographic method of Example 3, A)). The solution was cooled to r.t., diluted with H2O (3 L) and then extracted with EtOAc (2 L). The organic layer was washed with H2O (2 L) and, after elimination of the solvent, N-[(phenylmethoxy)carbonyl]-L-tryptophan 1,1-dimethylethyl ester (36 g) was obtained and used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[CH:16][CH:17]=1)[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.1 %

Procedure:
A solution of [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester (2.0 g, 6.7 mmol), potassium carbonate (1.0 g, 7.3 mmol), sodium iodide (0.4 g, 2.7 mmol), and DMF (10 mL) was stirred for 30 minutes. A solution of ethyl bromoacetate (0.8 mL, 7.4 mmol) in DMF (10 mL) was added dropwise to the reaction. The reaction was further stirred at room temperature for 3 days, and then poured into water (200 mL). The product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 1:5 ethyl acetate/hexanes, v/v) to provide the desired product 33 (2.3 g, 89%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.34 (t, 3H), 1.57 (m, 4H), 2.56 (t, 2H), 3.20 (q, 2H), 4.25 (q, 2H), 4.59 (s, 2H), 5.10 (s, 2H), 6.85 (d, 2H), 7.06 (d, 2H), 7.38 (m, 5H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([CH3:17])[C:11](=[O:18])[C:10]=1[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].[O-:32][C:33]#[N:34].[K+].FC(F)(F)C(O)=O>O>[C:33](=[O:32])([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]([C:10]1[C:11](=[O:18])[C:12]([CH3:17])=[C:13]([CH3:16])[C:14](=[O:15])[C:9]=1[CH3:8])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:34]
Reactant: N#C[O-]
Reactant: CC1=C(C)C(=O)C(C(CCCCCO)c2ccccc2)=C(C)C1=O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C)C(=O)C(C(CCCCCOC(N)=O)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
Toluene (10 ml) was added to 1.20 g (3.68 mmole) of 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-phenylhexanol and 0.90 g (3.68×3 mmole) of potassium cyanate, followed by stirring at room temperature, and 1.38 g (3.68×3.3 mmole) of trifluoroacetic acid was added to the mixture over the 5-minutes period. 5 Minutes later, the reaction temperature was raised to 40° C., and stirring was effected at 35° to 40° C. for 3 hours. After water was added, the insoluble matter was filtered out, and isopropyl ether was added to the filtrate to effect extraction. The organic layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was chromatographed on a silica gel column to elute with isopropyl ether to give 0.79 g (58%, recrystallized from isopropyl ether) of 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-phenylhexyl carbamate. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound No. 59 was prepared.
Reaction SMILES: C=CC1C=CC=CC=1.[F:9]C1C=CC(C=C)=CC=1.[C:18]1([C@H:24]2[CH2:26][C@H:25]2[CH2:27][OH:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:9][C:21]1[CH:22]=[CH:23][C:18]([CH:24]2[CH2:26][CH:25]2[CH:27]=[O:28])=[CH:19][CH:20]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: OC[C@@H]1C[C@@H]1c1ccccc1
Solvent: C=Cc1ccccc1
Product: O=CC1CC1c1ccc(F)cc1

Procedure:
Instead of styrene, 4-fluorostyrene (10.0 g) was used and treated by the same techniques as in Reference Example 23-1(1) and (2) as well as Reference Example 19-1 to give the titled compound as a colorless oil (4.48 g).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.O[CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:20]([NH:21][C:22](=[O:45])[CH2:23][CH:24]([NH:31][S:32]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)(=[O:34])=[O:33])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][S:18](=[O:47])(=[O:46])[N:17]([CH3:48])[C:16]=2[CH:49]=1.[CH3:50][N:51]1CCOC[CH2:52]1.N(C)C.S([O-])(=O)(=O)C>C(Cl)Cl.C1COCC1>[CH3:50][N:51]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:20]([NH:21][C:22](=[O:45])[CH2:23][CH:24]([NH:31][S:32]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)(=[O:33])=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][S:18](=[O:47])(=[O:46])[N:17]([CH3:48])[C:16]=2[CH:49]=1)[CH3:52]
Reactant: CN1c2cc(CO)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O
Reactant: CN1CCOCC1
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2c(c1)N(C)S(=O)(=O)CC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Methanesulfonic anhydride (100 mg, 0.55 mmol) was added to a THF (5 mL) solution of N-(7-hydroxymethyl-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazin-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step D) (200 mg, 0.345 mmol) and N-methylmorpholine (0.11 mL, 0.55 mmol). After 30 min stirring, Me2NH (1.73 mL, 3.45 mmol, 2.0 M in THF) was added to this freshly prepared mesylate solution. After stirring overnight, the mixture was diluted with CH2Cl2 (30 mL), washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica (0-5% MeOH in CH2Cl2) provided the title compound. MS (+ESI, m/z): 607 (M+H)+.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[N:22]/[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)/N=C/c1ccccc1Cl
Reactant: C[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A quantity of 16 ml (295.41 mmol) of nitromethane was admixed with 436 μl (2.50 mmol) of N,N-diisopropylethylamine and the yellow solution was stirred at RT for 1 h. Then 2.0 g (8.34 mmol) of the compound from Example 111A were added and the mixture was stirred overnight at RT. All of the volatile constituents were removed on a rotary evaporator. The residue was dissolved in 9 ml of isopropanol in the heat of boiling, and the solution was then cooled to 0° C. The white solid precipitated was filtered off with suction and washed with a little cold isopropanol. Drying in an HV gave 1.18 g (47% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[O-]S([O-])(=O)=O.[Mg+2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=O>C(Cl)(Cl)Cl>[CH3:27][O:26][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:23]=1[O:24][CH3:25])[CH:19]=[N:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(CN)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: COc1cc(C=NCC(OC)OC)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
Aminoacetaldehyde dimethylacetal (20.0 mL, 19.5 g, 0.185 mol) was dissolved in chloroform (80 mL) and MgSO4 (15 g) was added. Then 3,4,5-trimethoxybenzaldehyde (10c, 10.03 g, 0.05112 mol) was also added and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with chloroform (70 mL), washed with water (4×150 mL), brine (150 mL), dried (Na2SO4), and concentrated to provide the pure imine as a colorless oil (14.47 g, 100%). 1H NMR (300 MHz CDCl3) 8.10 (s, 1H), 6.91 (s, 2H), 4.58 (t, J=5.4 Hz, 1H), 3.81 (s, 6H), 3.79 (s, 3H), 3.69 (s, J1=5.4 Hz, J2=1.2 Hz, 2H), 3.33 (s, 6H).
Reaction SMILES: [N+](C1C=CSC=1C1C=CC(Cl)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)([O-])=O>>[NH2:16][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccsc1-c1ccc(C(F)(F)F)cc1
Agent: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Product: Nc1ccsc1-c1ccc(C(F)(F)F)cc1
Yield: 70 %

Procedure:
The same procedures as described in Example 3 were carried out except that 3-nitro-2-(4-chlorophenyl)thiophene was replaced by 3-nitro-2-(4-trifluoromethylphenyl)thiophene. The yield was 70%. 1 H-NMR(CDCl3, δ value):4.00(2H, brs), 6.67(1H, d, J=5.1), 7.18(1H, d, J=5.1), 7.64(1H, s)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:21])[CH:12]=[C:13]([SH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.II.C(N(CC)CC)C>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[C:11](=[O:21])[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:20]1
Reactant: O=C(C=C(S)c1ccccc1)Nc1nc2ccccc2s1
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1cc(-c2ccccc2)sn1-c1nc2ccccc2s1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
A mixture of 0.250 g (0.800 mmol) N-(2-benzothiazolyl)-3-mercapto-3-phenylpropenamide and 10 mL methylene chloride was stirred at room temperature. Added was 0.203 g (0.800 mmol) iodine dissolved in 10 mL methylene chloride and the mixture stirred 5 mins. Added next was 0.5 mL (excess) triethylamine and the mixture stirred for one hour. Solvent was evaporated and the residue dissolved in ethyl acetate and washed with water. The organic layer was dried, filtered and solvent was evaporated. The resulting solid was recrystallized from absolute ethanol to provide 0.090 g (0.290 mmol, 36%) N-(2-benzothiazolyl)-5-phenyl-4-isothiazolin-3-one as a very pale, yellow solid, mp=201°-202° C. NMR (CDCl3 /TMS): 6.6 (s, 1H)7.3-7.95 (m, 9H). IR (Nujol): 1680. High resolution mass spectrum: Calculated; 311.031282. Measured; 311.030775. Anal. calcd. for C16H10N2OS2 : C 61.91, H 3.25, N 9.03, S 20.66; Found C 61.82, H 3.14, N 8.97, S 20.55.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Cl.[CH3:22][O:23][C:24]1[C:25]([CH2:32]Cl)=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[C:25]([CH2:32][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccnc(CCl)c1OC
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: Cl
Product: COc1ccnc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1OC
Yield: 26 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione and 3,4-dimethoxy-2-chloromethylpyridine hydrochloride. Yield: 26%. MS M+H calculated 360.2. Found 360.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.0 μM.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]4[CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.C1COCC1.O.[OH-].[Li+]>CO>[CH2:34]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]1[NH:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCCCC4Cc4ccccc4)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC1CCCCC1Cc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 1-{4′-[4-(2-benzyl-cyclohexylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.130 g, 0.24 mmol) in 2:1:1 THF:H2O:MeOH was added lithium hydroxide (0.050 g, 1.19 mmol), and the reaction was stirred at 70° C. for 2 hours. After acidic workup, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].Cl.[CH2:6]([O:8][C:9](=[O:12])[CH2:10][NH2:11])[CH3:7]>C(O)=O>[CH2:6]([O:8][C:9](=[O:12])[CH2:10][NH:11][CH:1]=[O:2])[CH3:7]
Reactant: O=C[O-]
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: CCOC(=O)CNC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A hot solution of sodium formate (150 g) in formic acid (200 mL) was added to a hot solution of glycine ethyl ester hydrochloride (228.7 g; 1.64 mol) in hot formic acid (250 mL). This was allowed to stir at room temperature for 1 hour (sodium chloride separated). Small portions of acetic anhydride (450 g) were added to the well-stirred suspension as an exothermic reaction ensued. The suspension was stirred overnight, the solid was filtered and the filtrate was distilled in vacuo to remove excess reagents. The residue was filtered and then distilled to give N-formylglycine ethyl ester (182 g; 85%) as a colorless liquid having a bp 105°-100° C. under vacuum.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:15]3[CH:16]=[C:17]4[O:25][CH2:24][O:23][C:18]4=[CH:19][C:20]=3[C:21](=[O:22])[C:13]=2[C:12]2[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([O:26][CH3:27])[CH:11]=2)[C:6]1=[O:30].[H-].[Na+].[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>CN(C=O)C.O>[NH:33]1[CH:37]=[CH:36][C:35]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:15]4[CH:16]=[C:17]5[O:25][CH2:24][O:23][C:18]5=[CH:19][C:20]=4[C:21](=[O:22])[C:13]=3[C:12]3[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([O:26][CH3:27])[CH:11]=3)[C:6]2=[O:30])=[N:34]1
Reactant: c1cn[nH]c1
Reactant: COc1cc2c3c(n(CCCBr)c(=O)c2cc1OC)-c1cc2c(cc1C3=O)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c3c(n(CCCc4cc[nH]n4)c(=O)c2cc1OC)-c1cc2c(cc1C3=O)OCO2
Temperature: 60 °C
Yield: 57.6 %

Procedure:
6-(3-Bromo-1-propyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (5y) (0.2113 g, 0.448 mmol) was added to sodium hydride (86.8 mg of a 60% suspension in mineral oil, 2.17 mmol) and pyrazole (0.1749 g, 2.57 mmol) in DMF (50 mL) and the reaction mixture was heated at 60° C. for 4 h. The reaction mixture was diluted with water (200 mL) and extracted with chloroform (200 mL). The organic layer was washed with water (7×200 mL) and concentrated. Benzene was added (2×30 mL) and the mixture was concentrated again. The residue was dissolved in chloroform (4 mL) and diethyl ether (50 mL) was added. The precipitate was washed with diethyl ether (100 mL) and a dark red solid (118.5 mg, 57.6%) was obtained: mp 262-264° C. (dec). IR (film) 3462, 3104, 2918, 1693, 1640, 1557, 1495, 1488, 1430, 1394, 1308, 1284, 1251, 1205, 868, 785, 769 cm−1; 1H NMR (DMSO-d6) δ 7.97 (s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.61 (s, 1H), 6.57 (s, 1H), 6.97 (s, 1H), 6.68 (s, 1H), 6.33 (s, 1H), 6.05 (s, 2H), 4.40 (m, 4H), 4.01 (s, 3H), 3.96 (s, 3H), 2.45 (m, 2H); ESIMS m/z (rel intensity) 460 (MH+, 100). Anal. (C25H21N3O6.0.75H2O) C, H, N.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:14]([C:15](=[O:16])[C:4]=2[CH:3]=1)=[CH:13][C:12]1[NH:17][C:18]2[CH:25]=[CH:24][C:23](C)=[CH:22][C:19]=2[C:20](=[O:21])[C:11]=1[CH:10]=3.N>O>[CH:23]1[CH:22]=[C:19]2[C:20]([C:11]3[C:12]([NH:17][C:18]2=[CH:25][CH:24]=1)=[CH:13][C:14]1[C:15]([C:4]2[C:5]([NH:8][C:9]=1[CH:10]=3)=[CH:6][CH:7]=[CH:2][CH:3]=2)=[O:16])=[O:21]
Reactant: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Agent: N
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Reaction time: 7 h

Procedure:
20 g of C.I. pigment red 122 having an average primary particle diameter of 90 nm (in which the content of metal ions having a valence of at least 2 was 380 ppm), 55 g of the above aqueous dispersion of the pigment derivative (g) and 60 g of deionized water were mixed, aqueous ammonia was added so as to adjust the pH of a mixture liquid to 9.0, and the mixture liquid was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 7 hours, to obtain a water-based pigment dispersion.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Product: COc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 4-methoxybenzoyl chloride as a yellow oil (91%). M+ (ESI): 552. HPLC, Rt: 5.65 min (Purity: 98.5%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=O)[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[O:20])[CH:2]=[CH:1][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc2ccccc2c1
Product: O=C(C=Cc1ccc2ccccc2c1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from commercial 2-acetylnaphthalene and 4-chlorobenzaldehyde, 1-(4-chlorophenyl)-3-(2-naphthalenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5](Cl)=[N:6][N:7]=1.[C:18]([NH:22][S:23]([C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1)(=[O:25])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([NH:22][S:23]([C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:5]2[N:4]3[CH:9]=[CH:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:3]3[C:2]([Cl:1])=[N:7][N:6]=2)[CH:31]=1)(=[O:25])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1nnc(Cl)n2ccc(-c3ccccc3)c12
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)ccn23)c1
Temperature: 100 °C
Yield: 31.9 %

Procedure:
To a solution of 1,4-dichloro-8-phenylpyrrolo[1,2-d][1,2,4]triazine (0.150 g, 0.568 mmol) in 1,4-dioxane (15 mL) and water (4 mL) was added N-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (prepared according to WO 2011/028741) (0.232 g, 0.682 mmol) followed by potassium carbonate (0.235 g, 1.70 mmol) The reaction mixture was purged with N2 for 30 min. Bis(triphenylphosphine)palladium(II) chloride (20.0 mg, 0.0280 mmol) was added to the reaction mixture and heated at 100° C. in a sealed tube for 12 h. The reaction mixture was allowed to cool and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure to give a residue which was suspended in water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography using CombiFlash (REDISEP®, silica gel, 12 g, 30% EtOAc/hexanes) to yield N-(tert-butyl)-5-(1-chloro-8-phenylpyrrolo[1,2-d][1,2,4]triazin-4-yl)pyridine-3-sulfonamide (80.0 mg, 32.0%) as a pale yellow liquid. LCMS Method B-3: retention time 2.07 min, [M+1]=442.0. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.19 (s, 9H), 7.23 (d, J=3.2 Hz, 1H), 7.42-7.55 (m, 5H), 7.90 (d, J=3.2 Hz, 1H), 8.00 (br s, 1H), 8.73 (t, J=2.0 Hz, 1H), 9.17 (d, J=2.0 Hz, 1H), 9.22 (d, J=2.0 Hz, 1H).