Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[F:16][C:17]([F:29])([F:28])[S:18]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[F:28][C:17]([F:16])([F:29])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([NH:25][C:11](=[O:12])[C:6]2[C:7](=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]=2[Cl:13])[C:8]([OH:10])=[O:9])=[CH:26][CH:27]=1)(=[O:19])=[O:20]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Product: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
14 g (0.05 mol) of tetrachlorophthalic anhydride and 11 g (0.05 mol) of 4-trifluoromethylsulphonylaniline were heated to 200° C. and the mixture was kept at this temperature for 2 hours. It was then cooled and the reaction product was precipitated by adding ice-water. The product was then filtered off, washed with 50 ml of methanol and then stirred with 10% strength sodium hydroxide solution until it had dissolved. The impurities were filtered off and aqueous dilute hydrochloric acid was added to the filtrate. The crystals thereby obtained were filtered off and dried at 50° C. 14 g (that is to say 56% of theory) of N-(4-trifluoromethylsulphonylphenyl)-tetrachlorophthalamic acid of melting point 92°-97° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@H:4]([OH:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:12]I>C(#N)C.[Ag]=O>[CH3:1][O:2][C:3](=[O:11])[C@H:4]([O:10][CH3:12])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CI
Reactant: COC(=O)C[C@@H](O)C(=O)OC
Agent: O=[Ag]
Solvent: CC#N
Product: COC(=O)C[C@@H](OC)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
The above (R)-2-hydroxysuccinic acid dimethyl ester was re-dissolved in methyl iodide (100 mL), freshly prepared silver oxide (30.2 g) was added and the mixture was stirred for 24 hours at room temperature. The reaction mixture was diluted with acetonitrile (200 mL), and filtered through celite to remove silver salts and excess silver hydroxide. The filtrate was taken to dryness to leave (R)-2-methoxysuccinic acid dimethyl ester as an oil (23.2 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)[N:3]=1.[C:24]([O-:27])(O)=[O:25].[Na+]>C1COCC1.O>[C:8]1([CH2:6][O:27][C:24](=[O:25])[NH:23][C@@H:19]2[CH2:20][CH2:21][CH2:22][N:17]([C:4]3[CH:5]=[C:6]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:18]2)[CH:15]=[CH:14][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@@H](N)C3)nc(N)n2)cc1F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(N3CCC[C@@H](NC(=O)OCc4ccccc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-{2-amino-6-[(3R)-3-amino-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (125 mg, 0.324 mmol) in THF (4 mL) and saturated NaHCO3 (2 mL) was added phenylmethyl chloridocarbonate (0.055 mL, 0.389 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL), then extracted with EtOAc (3×10 mL). The organic was combined, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated to afford the crude title compound (155 mg) as a yellow oil. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[C:32]([Cl:34])[CH:33]=1>CO.C(Cl)Cl>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[O:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[O:19])=[CH:16][CH:17]=3)=[CH:4][C:3]1=2
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(Oc3cc(Cl)cc(Cl)c3)CCN4)cc2)CC1
Yield: 82 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (20 mg) was reacted with 3,5-dichlorophenol (27.7 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (82% yield). LCMS: m/z=497.12 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.13 (m, 1H), 2.24-2.35 (m, 1H), 2.33 (s, 3H), 2.35-2.60 (m, 4H), 3.40-3.66 (m, 4H), 3.70-3.92 (m, 2H), 5.30 (bs, 1H), 5.37 (t, J=3.3 Hz, 1H), 6.93 (d, J=1.6 Hz, 2H), 7.02 (dd, J=1.6 and 1.6 Hz, 1H), 7.44-7.51 (m, 4H), 7.60 (d, J=2.1 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]O)=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.CS([Cl:42])(=O)=O>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Cl:42])=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CO)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g {4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-methanol and 1.84 ml triethylamine were dissolved in 150 ml dichloromethane. To this ice cooled solution were added 0.82 ml methanesulfonylchloride. The cooling bath was removed and the reaction mixture was stirred at room temperature additional three hours. The reaction mixture was washed three times with 50 ml saturated NaHCO3 solution dried over MgSO4 and the solvent was removed in vacuo to provide 3.1 g 4-Butyl-5-(3-chloro-4-chloromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazole as crude material. This material was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[CH:11]([CH3:13])[CH3:12]>>[CH2:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccsc1
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccsc1

Procedure:
Following General Procedure BI above, and using 3-thiopheneacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C[C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9].[CH2:10]1[CH2:14]O[CH2:12][CH2:11]1>O.C(O)(=O)C.C=O>[N:4]1([CH2:3][CH2:2][CH:6]2[CH2:5][CH2:7][CH2:7][C:5]3[NH:4][C:3]([CH:8]=[O:9])=[CH:2][C:6]2=3)[CH2:14][CH2:10][CH2:11][CH2:12]1
Reactant: C1CCOC1
Reactant: Cc1cc(C)c(C=O)[nH]1
Agent: C=O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cc2c([nH]1)CCCC2CCN1CCCC1
Temperature: 95 °C

Procedure:
A mixture of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (20 mmol) in THF (40 mL), water (20 mL), acetic acid (3 mL), formaldehyde (37% wt. % solution in water, 5 mL) and the appropriate amine (30 mL) was heated to reflux (oil bath 90-100° C.) for 6 hours. The reaction was concentrated to a volume of 30 mL, basified with 2N NaOH and extracted with ethyl acetate (2×150 mL) and DCM (4×100 mL). The combined organic layers were concentrated and the residue was purified on a silica gel column to give the desired product
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[C:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCCCc1ccccc1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCCc1ccccc1
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with 3-phenyl-propylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(OS(C)(=O)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.4 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (29.5 g, 0.1 mol) and triethylamine (20.2 g, 0.2 mol) were dissolved in toluene (147.7 g) and then cooled to 0° C. To the mixture was added dropwise methanesulfonyl chloride (13.8 g, 0.12 mol) at 0° C. over 40 min. The mixture was further kept at 0° C. for 25 min. The reaction mass was washed with 5% hydrochloric acid (72.9 g) and 5% aqueous sodium bicarbonate (84.0 g), dried over magnesium sulfate, and then concentrated under reduced pressure with a rotary evaporator. After crystallization from the concentrate mass with n-hexane, precipitated crystals were collected by filtration and dried to give N-Boc-O-methanesulfonyl-L-tyrosine methyl ester 6 (36.0 g, yield 96%) as white crystals.
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25](O)[C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([O:35][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH:33]=3)[NH:28][CH:27]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[N:38]1([CH2:37][CH2:36][O:35][C:32]2[CH:33]=[C:34]3[C:26]([CH2:25][C:22]4[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]5[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=5)=[N:20][CH:21]=4)=[CH:27][NH:28][C:29]3=[N:30][CH:31]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C(O)c2c[nH]c3ncc(OCCN4CCOCC4)cc23)cn1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncc(OCCN5CCOCC5)cc34)cn2)cc1
Yield: 11.1 %

Procedure:
A mixture of (5-{Hydroxy-[5-(2-morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methyl}-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (24, 0.2 g, 0.3 mmol), triethylsilane (4 mL, 0.02 mol), and trifluoroacetic acid (2 mL, 0.02 mol) in acetonitrile (30 mL) was refluxed for 2 hours. After removal of solvent, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a light yellow solid (25, 17 mg, 10%). MS (ESI) [M+H+]+=512.42.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1C=O.C(O[CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:16]([O:15][CH:11]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: O=Cc1nccs1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)c1nccs1
Reaction time: 16 h

Procedure:
A mixture of 2-thiazole carboxaldehyde (25 g, 221 mmol), triethylorthoformate (46 mls, 41 g, 276 mmol) and para-toluenesulphonic acid (1.52 g, 9 mmol) in ethanol (200 ml) was sured for 16 hours under a nitrogen atmosphere at ambient temperature. A further amount of para-toluenesulphonic acid (2 g, 11 mmol) was added and the reaction stirred for another 16 hours. The mixture was treated with sodium bicarbonate to pH 9, stirred for a further 5 minutes and then filtered and the filtrate evaporated to dryness to give 2-(1,1-diethoxymethyl)thiazole as a clear oil, which was used without flirher purification (41 g, 99%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][C:23]1([CH3:37])[C:27]([CH3:29])([CH3:28])[O:26][B:25]([C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=2)[O:24]1>COCCOC>[CH3:28][C:27]1([CH3:29])[C:23]([CH3:22])([CH3:37])[O:24][B:25]([C:30]2[CH:35]=[CH:34][C:33]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=3)=[CH:32][CH:31]=2)[O:26]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: CC1(C)OB(c2ccc(OCCN(CC(F)(F)F)c3ccc(C#N)c(C(F)(F)F)c3)cc2)OC1(C)C

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, using dry DME as the reaction solvent: 1H NMR (400 MHz, CDCl3) δ 7.74 (m, 2H; AA′XX′), 7.67 (d, J=8.9 Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 6.99 (dd, J=8.9, 2.7 Hz, 1H), 6.84 (m, 2H; AA′XX′), 4.24 (t, J=5.2 Hz, 2H; partially overlapping 4.20), 4.20 (q, J=8.5 Hz, 2H; partially overlapping 4.24), 4.00 (t, J=5.1 Hz, 2H), 1.33 (s, 12H).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>ClC(Cl)C>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:19](=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Solvent: CC(Cl)Cl
Product: CC(C)CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 66 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.10 g, 0.42 mmol), isovaleryl chloride (0.051 mL, 0.42 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 0.09 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-yl-3-methylbutanamide. MS (ES) m/z 325.2; HPLC purity 100% at 210-370 nm, 10.8 min.; 99.4% at 252 nm, 10.8 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H28N2O+H+, 325.22744; found (ESI, [M+H]+), 325.2269.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].BrC[CH2:43][CH2:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:43][CH2:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(O)(CC)CCCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 89.5 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (84.3 mg, 0.145 mmol), 6-bromo-3-ethyl-3-hexanol (152 mg, 0.725 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=2:1, developed twice) to give 76.4 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from 6-bromo-3-ethyl-3-hexanol.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N:16]=[C:10]2[C:11](=O)[NH:12][NH:13][CH:14]=[C:9]2[C:8]=1[CH3:17].[OH-].[Na+]>>[Cl:3][C:11]1[N:12]=[N:13][CH:14]=[C:9]2[C:8]([CH3:17])=[C:7]([CH3:6])[NH:16][C:10]=12
Reactant: Cc1nc2c(=O)[nH][nH]cc-2c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]c2c(Cl)nncc2c1C
Temperature: 0 °C

Procedure:
45 ml of phosphorus oxychloride were added to 3.35 g (0.021 mole) of 2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-one and the mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction mixture was slowly poured into ice-water and the aqueous mixture was neutralized with an aqueous solution of sodium hydroxide. The precipitated yellow solids were collected by filtration and washed well with water. The solids were dissolved in dichloromethane and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 15:1 mixture of chloroform and methanol as an eluent to give 2.39 g of 7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)[CH3:2].[F:14][C:15]([F:22])([F:21])[C:16](=O)[CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][CH:7]=2)[N:12]=[C:16]([C:15]([F:22])([F:21])[F:14])[CH:17]=1
Reactant: CCOC(=O)c1ccc(NN)cc1
Reactant: N#CCC(=O)C(F)(F)F
Product: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2N)cc1
Yield: 90.6 %

Procedure:
Using the same method as Example QQ, 4-hydrazinobenzoic acid ethyl ester (From Example A82, 3.0 g, 16.6 mmol) and commercially available 1N NH 4,4,4-trifluoro-3-oxobutyronitrile (3.4 g, 24.9 mmol) were combined to afford ethyl 4-[5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoate (4.5 g, 91% yield), which was used to the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:16]#[N:17])[S:6][C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:2].[NH2:18][OH:19]>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:16](=[N:18][OH:19])[NH2:17])[S:6][C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:2]
Reactant: NO
Reactant: CCc1cc(C#N)sc1COC1CCCCO1
Product: CCc1cc(C(N)=NO)sc1COC1CCCCO1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 4-ethyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]thiophene-2-carbonitrile (0.86 g, 3.4 mmol) that was obtained in Example 22 (22c) and a 50% aqueous solution of hydroxylamine (0.5 mL). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3 to 5:5) as the eluent to afford the title compound (0.96 g) in a yield of 98% as a colourless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=3)=[O:21])[N:19]=2)[CH:16]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3,4-dichloroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:32])[CH:20]=[CH:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:32])[CH:20]=[CH:21][C:22]3[CH:31]=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3cnc4ccccc4n3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3cnc4ccccc4n3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of the enone 22-2 (1.0 g, 2.2 mmol) in MeOH (50 mL) at 0° C. was treated with NaBH4 (0.092 g, 2.4 mmol). The ice bath was removed and the solution was stirred at room temperature for 1 hr. The reaction was quenched with water (25 mL)and extracted with EtOAc (3×125 mL). The organics were combined, dried (Na2SO4), concentrated in vacuo, and purified on silica gel (90:5:5 CHCl3:EtOAc:MeOH) to afford 0.26 g of 22-3.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([P:10]([Cl:13])([Cl:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[N+:14](C1C=C(P(=O)(O)O)C=CC=1)([O-:16])=[O:15]>>[N+:14]([C:9]1[CH:8]=[C:7]([P:10]([Cl:12])([Cl:13])=[O:11])[CH:6]=[CH:5][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc(P(=O)(O)O)c1
Reactant: O=[N+]([O-])c1ccc(P(=O)(Cl)Cl)cc1
Product: O=[N+]([O-])c1cccc(P(=O)(Cl)Cl)c1

Procedure:
Prepared according to the procedure described for (4-nitrophenyl)phosphonic dichloride using (3-nitrophenyl)phosphonic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[C:32]([O:40][C:41](=[O:43])[CH3:42])=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[C:32]([O:40][C:41](=[O:43])[CH3:42])=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:35])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCOCC3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 39 %

Procedure:
Morpholine (0.176 g, 2.02 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.581 g, 3.03 mmol) were added to a methylene chloride solution (50 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.380 g, 1.01 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=30:1) to obtain the titled compound (0.175 g, 0.394 mmol, 39%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[C:9]1([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1>>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:8]([C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=2)[C:12]2[CH:11]=[CH:10][C:9]([C:16]3[CH:22]=[CH:21][C:19]([N:20]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[C:9]4[CH:15]=[CH:14][C:12]([NH2:8])=[CH:11][CH:10]=4)=[CH:18][CH:17]=3)=[CH:15][CH:14]=2)=[CH:2][CH:1]=1
Reactant: Nc1ccc(N)cc1
Reactant: Nc1ccc(-c2ccc(N)cc2)cc1
Product: Nc1ccc(N(c2ccc(N)cc2)c2ccc(-c3ccc(N(c4ccc(N)cc4)c4ccc(N)cc4)cc3)cc2)cc1

Procedure:
The same reaction as in Synthesis example 1 was carried out except for changing p-phenylenediamine used in Synthesis example 1 to benzidine to obtain 12 parts of orange tetrakis (p-aminophenyl)benzidine.