Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:63]2[CH2:62][CH2:61][CH:60]([S:59][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[Br:52])[CH2:65][CH2:64]2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: Brc1ccccc1SC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCC(Sc2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.15 g, 0.00059 mole) in DMF (4 mL) was added DIPEA (0.226 g, 0.00176 mole), HOBt (0.095 g, 0.00071 mole) and EDCI.HCl (0.134 g, 0.00071 mole). After 2 minutes 4-(2-bromo-phenylsulfanyl)-piperidine hydrochloride (0.21 g, 0.00071 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) afforded 0.153 g (51%) of N-biphenyl-4-yl-3-[4-(2-bromo-phenylsulfanyl)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 509.08 (M+1)+, 87.3%, 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 7.82-7.6 (m, 6H), 7.48-7.36 (m, 3H), 7.36-7.28 (m, 1H), 7.22-7.12 (m, 1H), 5.6-5.2 (d, 1H), 4.25 (d, 1H), 3.7 (m, 1H), 3.55 (s, 2H), 2.95 (m, 1H), 2.0 (m, 2H), 1.7-1.5 (m, 1H), 1.5-1.35 (m, 1H).
Reaction SMILES: S(Cl)(Cl)=O.CC1C(C)=CC=CC=1C(O)=O.CC1C(C)=CC=CC=1C(Cl)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[CH3:49][C:50]1[C:55]([CH3:56])=[CH:54][CH:53]=[CH:52][C:51]=1[C:57]([N:59]=[C:60]=[S:61])=[O:58]>C1(C)C=CC=CC=1.C(O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:60]([NH:59][C:57](=[O:58])[C:51]2[CH:52]=[CH:53][CH:54]=[C:55]([CH3:56])[C:50]=2[CH3:49])=[S:61])=[CH:44][CH:43]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1C
Agent: Cc1cccc(C(=O)Cl)c1C
Agent: Cc1cccc(C(=O)O)c1C
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,3-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,3-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,3-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml), and a solution of 2,3-dimethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (81 mg, yield 98%).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:13])[CH:11]=[N:12][C:2]=1[O:22][C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=1)[CH3:8]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1ccc(Cl)c(Cl)c1

Procedure:
Ethyl 2-chloro-5-fluoronicotinate (5.09 g, 25 mmol see reference J. Med. Chem., 1993, 36(18) 267-88) and 3,4-dichlorophenol (6.11 g, 37.5 mmol) were dissolved in 1,4-dioxane and the solution was purged with argon. Anhydrous caesium carbonate (12.21 g, 37.5 mmol) was added and the mixture was heated under reflux for 17 hours. The reaction mixture was partitioned between water (300 ml) and ethyl acetate (300 ml). The aqueous layer was acidified to pH 3 by addition of 2M hydrochloric acid and the phases were separated. The aqueous layer was extracted with ethyl acetate (2-fold 100 ml) and the combined organic solutions were dried over magnesium sulphate and concentrated in-vacuo to give a red oil. The material isolated was redissolved in ethyl acetate and was washed with 5% potassium carbonate solution (2-fold 200 ml), 0.5 M sodium hydroxide solution (2-fold 200 ml) and saturated sodium hydrogen carbonate solution (100 ml). The organic phase was dried over magnesium sulphate and concentrated in-vacuo. The residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (4:96) to give 2-(3,4-dichloro-phenoxy)-5-fluoro-nicotinic acid ethyl ester as a colourless oil that crystallised on standing (4.95 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.Cl.[NH2:11][OH:12].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[N:11][OH:12])[NH2:9])[CH:5]=[N:4][CH:3]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1cncc(Br)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of 3-bromo-5-cyanopyridine (1.0 eq), hydroxylamine hydrochloride (1.5 eq.), K2CO3 (2.1 eq) in ethanol (0.1 M) was stirred at 80° C. for 3 days. The mixture was concentrated, diluted with EtOAc and aqueous NaHCO3. The title compound was isolated by filtration as beige solid.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[CH:32]>C(O)C>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][N:18]([CH2:32][C:31]#[CH:30])[CH2:19][CH2:20][CH:21]=2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCNC2)c(O)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCN1CCC=C(c2ccc(C(C)(C)CCCCCC)cc2O)C1

Procedure:
A mixture of 1.0 g. (3.33 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-1,2,5,6-tetrahydropyridine, 539 mg. (3.90 mmoles) of anhydrous potassium carbonate and 395 mg. (3.32 mmoles) of 1-bromo-2-propyne in 23 ml. of ethanol is heated at reflux for 20 hours. The reaction mixture is evaporated and dissolved in 100 ml. of saturated sodium bicarbonate and 200 ml. of dichloromethane. The organic extract is washed with two 150 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is crystallized from pentane to yield 161 mg. of the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])=[C:2]=[O:3].[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH2:25])[CH2:19][CH2:18]1>C1C=CC=CC=1>[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][NH:25][C:2]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=2[C:13]([F:14])([F:15])[F:16])=[O:3])[CH2:19][CH2:18]1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: NCCN1CCOCC1
Solvent: c1ccccc1
Product: O=C(NCCN1CCOCC1)Nc1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
To a solution of 1-isocyanato-4-nitro-2-(trifluoromethyl)benzene (339 μL, 2.21 mmol, 1.0 equiv) in benzene (3.0 mL), was added 2-morpholinoethanamine (316 mg, 2.43 mmol, 1.0 equiv). The resulting precipitant was filtered and washed with hexanes to provide 1-(2-morpholinoethyl)-3-(4-nitro-2-(trifluoromethyl)phenyl)urea, which was advanced without further purification. MS (MH+) 363; Calculated for C14H17F3N4O4: 362.1
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][CH:29]([CH3:32])[CH2:30][NH2:31]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:31][CH2:30][CH:29]([CH3:32])[CH3:28])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: CC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)CNCC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), 2-methylpropan-1-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 2), 274 (38), 86 (bp), 70 (8), 57 (8).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[S:13][C:12]([C:14](=[O:18])[CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[Cl-]>C(O)=O.CCN(CC)CC>[CH:1]1([CH2:7][O:8][C:9]2[S:13][C:12]([C@H:14]([OH:18])[CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CCC(=O)c1ccc(OCC2CCCCC2)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: N#CC[C@@H](O)c1ccc(OCC2CCCCC2)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(1R,2R)—RuCl(TsDPEN)(p-cymene) (6.3 mg, 0.01 mmol) was added to a degassed solution of 3-(5-(cyclohexylmethoxy)thiophen-2-yl)-3-oxopropanenitrile (4) (0.27 g, 1.03 mmol) in HCOOH:Et3N (1:1, 4.0 M in EtOH) and the reaction mixture was stirred at room temperature for 24 hrs. Aqueous NH4Cl (25%) was added and the mixture was extracted twice with MTBE. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography gave (R)-3-(5-(cyclohexylmethoxy)thiophen-2-yl)-3-hydroxypropanenitrile as an off-white solid which was used directly in the next step. Yield (0.21 g, 77%); 1H NMR (400 MHz, CD3OD) δ 6.64-6.78 (m, 1H), 6.02-6.10 (m, 1H), 4.99-5.09 (m, 1H), 3.79-3.88 (m, 2H), 2.79-2.91 (m, 2H), 1.62-1.90 (m, 6H), 1.12-1.39 (m, 3H), 0.98-1.12 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-])=O)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]>C(O)C.O=[Pt]=O>[NH2:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[OH:17])[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)=[O:21]
Reactant: Cc1ccc(NC(=O)c2ccc(O)c([N+](=O)[O-])c2)cc1C
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(O)c(N)c2)cc1C

Procedure:
A solution of N-(3,4-dimethyl-phenyl)-4-hydroxy-3-nitrobenzamide (700 mg) in ethanol (50 mL) was hydrogenated over PtO2 at 40 psi for 3 h. The catalyst was filtered through Celite and the filtrate evaporated to give 3-amino-N-(3,4-dimethylphenyl)-4-hydroxy-benzamide as an off-white solid, mp=220-223° C.; MS (m/z) 255 (M−1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)=[O:18])C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][CH:19]2[C:17]([OH:18])=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[N:4]=1
Reactant: ClCc1cccc(SCC2CC2)n1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SCC3CC3)n2)c(Cl)c1
Yield: 89 %

Procedure:
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (36 mg, 0.17 mmol) obtained in Step D of Preparation Example 20 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (45 mg, 0.18 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (59 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:23]=[C:22](B(O)O)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:22]2[C:16]3[CH2:17][C:18]([CH3:20])([CH3:21])[O:19][C:15]=3[CH:14]=[C:13]([Cl:12])[CH:23]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: CC1(C)Cc2c(cc(Cl)cc2B(O)O)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(Cl)cc3c2CC(C)(C)O3)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.7 grams (0.012 mole) of 6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 mL (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)pyridine.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[C:38]1[N:39]=[N:40][N:41]([C:43]2[CH:50]=[CH:49][C:46](C=O)=[CH:45][CH:44]=2)[CH:42]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CC(N(C)C)=O>[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[C:38]1[N:39]=[N:40][N:41]([C:43]2[CH:44]=[CH:45][C:46]([CH2:20][N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[CH:49][CH:50]=2)[CH:42]=1
Reactant: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCNCC5)cc4)nn3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) was added to a solution of tert-butyl-1-piperazinecarboxylate (1.22 g; 6.59 mmol; 10 eq.) and 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) in DMA (4 mL) and the reaction mixture was stirred overnight at RT. Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) and glacial acetic acid (75.42 μl; 1.32 mmol; 2.00 eq.) then sodium cyanoborohydride (83 mg; 1.32 mmol; 2. eq.) were added to complete the reaction which was quenched with water and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting gum was stirred at RT in a solution of HCl in dioxane (5 mL, 4N) for 2 hours. The reaction mixture was basified to pH=9-10 and extracted with EtOAc. Organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a formic acid salt. It was dissolved in MeOH and passed through a SPE-NH2 cartridge. The fractions containing the desired compound were concentrated to dryness affording a yellow gum, which was twice sonicated in 3 mL of Et2O. The suspension obtained was concentrated then dried overnight under high vacuum to afford the title compound as a beige solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.23 (brs, 1H), 9.25 (s, 1H), 8.14-8.13 (m, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5 Hz, 1.5 Hz, 1H), 3.52 (s, 2H), 2.72-2.69 (m, 4H), 2.487 (s, 3H), 2.32-2.30 (m, 4H). HPLC (Condition A): Rt 2.22 min (purity 95.4%). MS (ESI+): 374.3, MS (ESI−): 372.3.
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5](=O)[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO>[OH:20][N:19]=[C:5]1[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=2[C:2](=[CH2:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6]1
Reactant: C=C1c2ccccc2CC(=O)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C1c2ccccc2CC(=NO)c2ccccc21
Yield: 95.3 %

Procedure:
A mixture of 16.5 g of the oxo-compound from Step C, 6.6 g of hydroxylamine hydrochloride, 8.2 of sodium acetate and 300 ml of methanol was heated under reflux for 5 hours. The solvent was evaporated and the residue was treated with 250 ml of water. The mixture was extracted with 3×150 ml of ether, and the extract was dried, filtered, and evaporated to give 16.8 g of 10-hydroxyimino-5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, m.p. 156°-160° C.
Reaction SMILES: [N:1]1[C:5]2=[CH:6][CH:7]=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:9][C:4]2=[N:3][N:2]=1.[H-].[Na+].[CH3:17][CH2:18][CH2:19]I>CN(C)C=O>[CH2:17]([N:2]1[N:1]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:4]2=[N:3]1)[CH2:18][CH3:19]
Reactant: CCCI
Reactant: COC(=O)CC1=CC=C2N=NN=C2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc2ccc(CC(=O)OC)cc2n1
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution of methyl 5-benzotriazoleacetate (10 g, 0.0523 mol) in N,N-dimethylformamide was added dropwise to a chilled (ice-bath) suspension of sodium hydride (60% dispersion in oil, 2.3 g, 0.0575 mol) in N,N-dimethylformamide. When the addition was complete, the ice-bath was removed and the mixture stirred for 1 hour. N-Propyl iodide (9.78 g, 0.0575 mol) was added dropwise, and once the addition was complete the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto ice/water, and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue was further purified by column chromatography to afford methyl (2-propylbenzotriazol-5-yl)acetate (4.8 g).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[N:17]([CH2:18][CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]=[CH:15][C:14]=1[C:27]([O:29]CC)=O)=[S:11])(=O)C1C=CC=CC=1.C(O)(=O)C>[OH-].[Na+].O>[OH:26][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][N:17]1[C:13]2[NH:12][C:10](=[S:11])[NH:9][C:27](=[O:29])[C:14]=2[CH:15]=[N:16]1
Reactant: CCOC(=O)c1cnn(CC(O)c2ccccc2)c1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=S)[nH]c2c1cnn2CC(O)c1ccccc1
Reaction time: 12 h
Yield: 79.8 %

Procedure:
A solution of 6 (4.38 g, 10 mmol) in 2 M NaOH (40 mL) was refluxed for 10 min and successively diluted with H2O (40 mL). The solution was acidified with glacial acetic acid. Standing in a refrigerator for 12 h, a solid crystallized, and was filtered and recrystallized from absolute ethanol to give 7 (2.3 g, 80%) as a white solid; mp 264-265° C. 1H NMR: δ 4.15-4.30 and 4.55-4.72 (2m, 2H, CH2N), 4.85-5.00 (m, 1H, CHO), 5.66 (br s, 1H, OH, disappears with D2O), 7.20-7.51 (m, 5H Ar), 8.02 (s, 1H, H-3), 12.20 (s, 1H, NH, disappears with D2O), 13.40 (s, 1H, NH, disappears with D2O). IR cm−1: 3362 (NH), 3142-2773 (OH), 1681 (CO). Anal. (C13H12N4O2S) C, H, N, S.
Reaction SMILES: O=C1NC(C(NCC2C=CN=C(OCCCC3N=CNN=3)C=2)=O)=NC2SC=C(COCC3C=CC(C(OCC)=O)=CC=3)C1=2.[CH3:44][C:45]1[C:53]2[C:52](=[O:54])[NH:51][C:50]([C:55]([NH:57][CH2:58][C:59]3[CH:60]=[C:61]([CH:71]=[CH:72][CH:73]=3)[O:62][CH2:63][CH2:64][CH2:65][C:66]([O:68]CC)=[O:67])=[O:56])=[N:49][C:48]=2[S:47][CH:46]=1>>[CH3:44][C:45]1[C:53]2[C:52](=[O:54])[NH:51][C:50]([C:55]([NH:57][CH2:58][C:59]3[CH:60]=[C:61]([CH:71]=[CH:72][CH:73]=3)[O:62][CH2:63][CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:56])=[N:49][C:48]=2[S:47][CH:46]=1
Reactant: CCOC(=O)CCCOc1cccc(CNC(=O)c2nc3scc(C)c3c(=O)[nH]2)c1
Agent: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Product: Cc1csc2nc(C(=O)NCc3cccc(OCCCC(=O)O)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 42 and using, instead of ethyl 4-[({[4-oxo-2-({[(2-{[3-(1H-1,2,4-triazol-3-yl)propyl]oxy}pyridin-4-yl)methyl]amino}carbonyl)-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]methyl}oxy)methyl]benzoate, ethyl 4-[3-({[(5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)carbonyl]amino}methyl)phenoxy]butanoate obtained in Reference Example 122, the title compound was obtained as a white powder (465.7 mg, 91%).
Reaction SMILES: [C:1]1(=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:15])[CH:3]=[CH:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.O1CCOCC1.C(Cl)(Cl)Cl.CS(C)=O.CN(C=O)C>[OH:15][C:4]1[C:5]2[C:14](=[CH:13][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:1]([OH:16])=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=O)c2cc3ccccc3cc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Oc1ccc(O)c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a 250 ml-round-bottom flask, was added 2 g (MW 208; 0.0096 mol) of 1,4-anthracenedione (4). To it a solution of 6.6816 g (MW 174; 0.0384 mol) of sodium hydrosulfite in 50 mL of distilled water and 50 mL of 1,4-dioxane were added. The resulting mixture was stirred at room temperature for 2-3 hours. The reaction progress is checked with TLC (using CH2Cl2:hexanes:ether 1:1:0.2 as the eluant). The mixture was transferred to a 500-mL beaker slowly, cooled over an ice-water bath, and added 100 mL of distilled water. Dark green solids precipitated. The beaker was covered with aluminum foil, and placed in the refrigerator for 1 h. The solid was filtered through a glass fritted funnel and the product was washed with 30 mL of distilled water twice. The solid product was dried under vacuum to give 1.754 g (87% yield), mp 167-169° C.; 1H NMR (CDCl3 contains a small amount of p-dioxane) d 8.7 (m, 2H, C 9,10 Hs), 8.05 (m, 2H, C 5,8 Hs), 7.5 (s, 2H, C 6,7 Hs), 6.6 (s, 2H, C 2,3 Hs). The diol is insoluble in chloroform but soluble in DMSO and DMF.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=O)[C:13](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].C=C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:12][CH2:13][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2ccc(Br)cc2C1
Temperature: 25 °C

Procedure:
A solution of 3-bromophenylacetic acid (10.4 g, 48.4 mmol) in oxalyl chloride (50 mL, 0.57 mol) was stirred at ambient temperature for 5 min then at reflux for 5 h. The oxalyl chloride was removed in vacuo and the residue was dissolved in anhydrous CH2Cl2 (100 mL). This solution was added dropwise to a rapidly stirred, ice-cooled solution of AlCl3 (23.2 g, 174.2 mmol) in CH2Cl2 (500 mL). A stream of ethylene gas was blown into the vortex of the stirred solution during the addition and the reaction temperature was kept at <5° C. The reaction mixture was allowed to warm to ambient temperature and then poured onto ice and stirred vigorously. The organic portion was removed and the aqueous layer extracted with CH2Cl2 (2×200 mL). The combined CH2Cl2 fractions were passed through a 2″ pad of silica and concentrated to give a thick, red oil. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 75:25 to provide the title compound as a pale yellow solid. MS: m/z=226 (M+1).