Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([S:12][CH2:13][CH:14]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:16])=[O:11])=O)(C)(C)C.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]([S:12][CH2:13][CH:14]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
3-[[2-[N-(t-butyloxycarbonyl)glycylthiomethyl]-3-phenylpropionyl]amino]benzoic acid (compound of Example 165) (0.43 g) is dissolved in trifluoroacetic acid (3 ml), and the mixture is stirrred at room temperature for 30 minutes and adjusted to pH 4.0 with aqueous sodium hydrogen carbonate solution, and then is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and thereto is added dioxane, and the solution is lyophilized to give the title compound (0.22 g). m.p.: 91°-96° C. (amorphous) IR (KBr; cm-1): 1690, 1660
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[CH:19][N:18]=[CH:17]1.[CH2:23]=[O:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]1[CH2:23][OH:24]
Reactant: Cc1cncn1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: C=O
Product: Cc1cnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1, 2',5 -dichloro-2-(5-methylimidazol-1-yl)benzophenone is heated in a bomb to 150° C. with 37% aqueous formaldehyde solution to give 2',5-dichloro-2-[2-(hydroxymethyl)-5-methylimidazol-1-yl]benzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:27]([O-])(=[O:29])C.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([C:14]2[CH:15]=[CH:16][C:17]([CH:27]=[O:29])=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Brc1ccc(CN(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(Cc2ccc(Br)cc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
In an argon atmosphere, N-(4-bromobenzyl)diphenylamine (169 mg, 0.500 mmol) obtained in Example 64 was dissolved in dimethylformamide (1.5 mL), and phosphorus oxychloride (0.116 mL, 1.25 mmol) was added thereto, followed by stirring at 100° C. for 30 minutes. The reaction liquid was cooled to room temperature, poured into saturated sodium acetate aqueous solution, and was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=4/1) to give 4-[N-(4-bromobenzyl)-N-phenylamino]-benzaldehyde (159 mg, 87%).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:15][N:13]([CH:12]=[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:8]#[N:9])[CH3:14]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 25.0 g of pivaloyl acetonitrile in 50 ml of N,N-dimethylformamide dimethyl acetal was stirred at room temperature for 8 hours under argon and then the solvent was evaporated and n-hexane was added with stirring. The product was collected by filtration to give 34.6 g of 2-[(dimethylamino)methylene]-4,4-dimethyl-3-oxopentanenitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][O:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(F)c(F)c2)cc1

Procedure:
Combine 3,4-difluorobenzeneboronic acid (1.0 g, 5.2 mmol), methyl-4-bromobenzoate (0.241 g, 1.73 mmol), Pd(OAc)2 (0.019 g, 0.086 mmol), tetrabutylammonium bromide (0.111 g, 0.345 mmol), and potassium phosphate (0.733 g, 3.454 mmol). Purge the reaction vessel with argon and add anhydrous DMF (20 mL) to the reaction mixture. Heat the sealed reaction vessel to 120° C. with stirring until completion. Cool the reaction to room temperature, dilute with ethyl acetate, and filter through a short plug of celite with additional ethyl acetate. Wash organics with water, dry over MgSO4, filter, and evaporate. Purification by flash column chromatography yields 3′,4′-difluorobiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in dioxane (45 mL) and add an equal volume of 1 M aqueous NaOH. Heat the reaction vessel to 60° C. with stirring until completion. Remove the solvent by evaporation. Dissolve the residue in dichloromethane and wash with 1N aqueous hydrochloric acid. Dry the organics over MgSO4, filter and evaporate to yield 0.048 g (12%) of the title compound. MS (ES): m/z 235 (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].O.[BrH:24].N([O-])=O.[Na+]>O1CCCC1>[Br:24][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1[nH]c2c(Br)cccc2c1S(=O)(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (26 mg, 0.080 mmol, 1.0 equiv) was dissolved in 2 mL of a 1:1 solution of tetrahydrofuran:water to which 0.2 mL of concentrated aqueous HBr was added and the mixture was cooled to 0° C. NaNO2 (28 mg, 0.40 mmol, 5.0 equiv) was added in one portion, followed by CuBr (57 mg, 0.40 mmol, 5.0 equiv) 25 minutes later. The reaction was warmed to ambient temperature and stirred for 72 hours. The reaction mixture was partitioned between dichloromethane and water and extracted three times with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 388.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[C:18]([N+:29]([O-])=O)[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[NH2:29][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][C:23]1=[O:28])[C:15]([NH:14][C@H:9]([C:7]1[NH:6][C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)[CH2:10][CH2:11][S:12][CH3:13])=[O:32]
Reactant: CSCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c([N+](=O)[O-])c1)c1nc2cc(Cl)ccc2[nH]1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(N)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
65 mg (0.13 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide dissolved in 2 ml of ethyl acetate are combined with 143 mg (0.63 mmol) tin (II)chloride-dihydrate and 130 mg (1.55 mmol) sodium hydrogen carbonate and refluxed for 2 hours. The reaction solution is combined with ice water, stirred for 10 minutes and then the precipitate formed is filtered off. After drying for 3 days the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0->91:9).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:9][O:8][C:5]1[N:4]=[CH:3][C:2]([NH:1][C:18](=[O:19])[CH2:17][Cl:16])=[CH:7][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(N)cn1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)CCl)cn1
Reaction time: 0.25 h

Procedure:
A solution of 3-amino-6-methoxypyridine (25.0 grams) in absolute ether (160 ml) was charged into a glass reaction flask equipped with a mechanical stirrer, dropping funnel and thermometer. The solution was cooled to a temperature of about 0° C and pyridine (18.1 ml) was added thereto. A solution of chloroacetyl chloride (17.0 ml) in ether (40 ml) was then slowly added to the flask with stirring over a period of about 15 minutes resulting in the formation of a precipitate. The temperature of the reaction mixture was kept between about 0° to 5° C during the addition of the chloroacetyl chloride. After completion of the addition stirring was continued for a period of about 30 minutes. The solid precipitate which had formed was then recovered by filtration and was washed with aqueous sodium bicarbonate and then with water. The washed product was then dried to yield the desired product N-(6-methoxy-3-pyridyl)-α-chloroacetamide as a white solid having a melting point of 117° to 118° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]([CH3:16])[CH:6]=[CH:5]2.[Se](=O)=[O:18]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:13]([CH3:14])[CH3:15])[N:8]=[C:7]([CH:16]=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)c(OC(C)C)cc2n1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1cc2nc(C=O)ccc2cc1F

Procedure:
To 6-fluoro-7-isopropoxy-2-methylquinoline (270 mg, 1.23 mmol) in dioxane/water (5 mL/0.05 mL) was added selenium dioxide (164 mg, 1.48 mmol) and the reaction was heated to reflux for 2 hours. After cooling and concentrating, the residue was purified by chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-7-isopropoxyquinoline-2-carbaldehyde as a solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH2:20])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]3[N:42]([CH3:43])[N:41]=[N:40][N:39]=3)[CH:33]=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:19][CH2:18][O:17][CH2:16][C@H:15]3[NH:20][C:30]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[N:42]([CH3:43])[N:41]=[N:40][N:39]=4)[CH:33]=3)=[O:29])[CH2:8]2)=[CH:21][CH:22]=1
Reactant: N[C@@H]1COCC[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CC#N
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2COCC[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine (44 mg, 143 μmol) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (47 mg, 158 μmol) were dissolved in acetonitrile (1 mL) and the mixture was stirred at room temperature. After 24 h , the mixture was concentrated, dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated. The residue was purified by reverse phase high pressure liquid chromatography (C18, 10-100% acetonitrile in water, containing 0.05% trifluoroacetic acid), then by flash column chromatography (5% methanol in dichloromethane, containing 0.5% ammonium hydroxide) to provide the product as a glass (16 mg, 23%). 1H NMR (300 mHz, CD3OD) δ7.95 (s, 1H), 7.52 (m, 2H), 7.43 (m, 1H), 7.05 (m, 2H), 6.86 (m, 2H), 4.19 (s, 3H), 3.94 (dd, J=10.7, 4.4 Hz, 1H), 3.87 (bd, 1H), 3.50 (td, J=9.9, 4.4 Hz, 1H), 3.39 (m, 1H), 3.09 (t, J=10.2 Hz, 1H), 2.93 (bd, 1H), 2.85 (bd, 1H), 2.56 (dd, J=12.8, 5.2 Hz, 1H), 2.45 (m, 2H), 2.30 (dd, J=12.4, 6.6 Hz, 1H), 2.04 (bt, 1H), 1.9-1.5 (7H), 1.40 (m, 1H), 0.95 (m, 1H), ESI MS: (M+H)+=508.3 (100%).
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][C@H:14]2[C@:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=3[F:26])([CH2:13]2)[CH2:11]1)(C)C>C1COCC1>[F:26][C:17]1[CH:18]=[C:19]([C:22]([F:25])([F:23])[F:24])[CH:20]=[CH:21][C:16]=1[C@:12]12[CH2:13][C@H:14]1[CH2:15][N:10]([CH2:9][CH2:8][CH2:7][OH:6])[CH2:11]2
Reactant: CC(C)(C)[Si](C)(C)OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2F)C1
Solvent: C1CCOC1
Product: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To (1S,5R)-3-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (135 mg, 0.3 mmol) HCl (1N, 2 mL) was added followed by THF (2 mL) and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was concentrated under vacuum and the solid was washed with Et2O (3×10 ml), dissolved in MeOH (2 mL) and eluted through SCX cartridge (eluent: NH3, 0.5 M in MeOH) to give 86 mg of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14].[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][N:9]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
0.62 g (25.88 mmol) of sodium hydride was added in portions at 60° C. to a suspension of 3.9 g (23.5 mmol) of 3-methylxanthine in 85 ml of dimethylformamide, and the mixture was stirred at this temperature for 1.5 hours and heated to 90° C. 6.6 g (23.67 mmol) of trityl chloride in 30 ml of dimethylformamide were then added and the mixture was stirred at 90° C. for 3 hours. The solid was then filtered off hot with suction and the filtrate was concentrated under reduced pressure, the residue was taken up in 1 N sodium hydroxide solution, the mixture was heated to 80° C. and the solid was filtered off with suction. The filtrate was brought to pH 4-5 using 2 N hydrochloric acid. The precipitate formed in this way was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19/0.2). Yield:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH2:23][C:24]([O:26]CC)=[O:25])=[N:15]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([CH2:23][C:24]([OH:26])=[O:25])=[N:15]3)=[CH:11][CH:10]=2)=[O:7])=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc12
Yield: 96.6 %

Procedure:
Ethyl 2-[1-[4-(4-chlorobenzamido)benzyl]-1H-indazol-3-yl]acetate (159 mg, 0.355 mmol) was dissolved in tetrahydrofuran (10 mL). In an ice bath, 10 mL aqueous solution dissolving lithium hydroxide monohydrate (42 mg, 1.0 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated. It was filtered, and dried to obtain a white solid 144 mg, at a yield of 96.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[OH:11].C(Cl)(=O)C([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)c1ccc(Cl)c(O)c1
Temperature: 60 °C

Procedure:
An amount of 1 g (5.57 mmol) of 4-chloro-3-hydroxy benzoic acid is added 10 ml (115.8 mmol) of oxalyl chloride and refluxed at 60° C. till the solid had gone into solution. After cooling, the mixture is evaporated to dryness to give 4-chloro-3-hydroxy-benzoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CO.ClCCl>[CH2:22]([NH:1][CH2:2][CH2:3][C:4]1[N:8]([C@@H:9]2[CH2:18][C:17]3[C:12](=[C:13]([F:20])[CH:14]=[C:15]([F:19])[CH:16]=3)[O:11][CH2:10]2)[C:7](=[S:21])[NH:6][CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: NCCc1c[nH]c(=S)n1[C@H]1COc2c(F)cc(F)cc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Fc1cc(F)c2c(c1)C[C@@H](n1c(CCNCc3ccccc3)c[nH]c1=S)CO2
Temperature: 22.5 °C
Reaction time: 40 h
Yield: 50.9 %

Procedure:
To (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (2.36 g, 7.58 mmol) in a mixture of Methanol (15.00 ml) and Dichloromethane (15 ml) was added BENZALDEHYDE (0.845 ml, 8.34 mmol). To the resulting clear solution SODIUM CYANOBOROHYDRIDE (0.702 g, 10.61 mmol) was added in portions at 20-25° C. to avoid intensive foaming and the solution was stirred at 20-25° C. for 40 h. The solution was quenched at 20-25° C. with 1N HCl (12 ml), neutralised with 3N NaOH (12 ml), the mixture was extracted with DCM (100 ml). The organic phase was washed with brine, dried (MgSO4), evaporated to dryness. The residue was purified on a column with EA-MeOH 9:1 as eluent, fractions collected, concentrated to approx 20 ml, cooled in ice. The precipitate collected, washed with Ethyl Acetate-Petroleum Ether 1:1, dried on air to give (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione (1.55 g, 3.86 mmol, 50.9% yield).
Reaction SMILES: [C:1]1([N:7]2[C:16](=[O:17])[C:15]3[C:14]([O:18]C(=O)C)=[C:13]4[C:22]5[C:35]([C:36]([OH:39])=[C:37]([OH:38])[C:12]4=[CH:11][C:10]=3[CH:9]=[N:8]2)=[C:34]([O:40][CH3:41])[C:33]2[C:32](=[O:42])[C:31]3[C:26](=[CH:27][C:28]([O:48]C(=O)C)=[C:29]([CH3:47])[C:30]=3[O:43]C(=O)C)[C:25](=[O:52])[C:24]=2[C:23]=5[O:53]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CN(C)C=O>[C:1]1([N:7]2[C:16](=[O:17])[C:15]3[C:14]([OH:18])=[C:13]4[C:22]5[C:35]([CH:36]([OH:39])[CH:37]([OH:38])[C:12]4=[CH:11][C:10]=3[CH:9]=[N:8]2)=[C:34]([O:40][CH3:41])[C:33]2[C:32](=[O:42])[C:31]3[C:26](=[CH:27][C:28]([OH:48])=[C:29]([CH3:47])[C:30]=3[OH:43])[C:25](=[O:52])[C:24]=2[C:23]=5[OH:53])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c2c(c(OC(C)=O)c3c1c(O)c(O)c1cc4cnn(-c5ccccc5)c(=O)c4c(OC(C)=O)c13)C(=O)c1cc(OC(C)=O)c(C)c(OC(C)=O)c1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1c2c(c(O)c3c1C(O)C(O)c1cc4cnn(-c5ccccc5)c(=O)c4c(O)c1-3)C(=O)c1cc(O)c(C)c(O)c1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 100 mg (0.13 mmol) of the resulting intermediate 2-phenyl-10,12,15,16-tetraacetoxy-6,7-dihydroxy-8-methoxy-11-methyl-9,14-dioxo-9,14-dihydronaphthaceno[1,2-g]phthalazin-1-one in 2 m of N,N-dimethylformamide is mixed, while cooling in ice, with 2 m of 1 M potassium hydroxide solution and stirred at room temperature for 2 h. The product is precipitated as a red solid (60 mg) by acidification with aqueous citric acid. The yield is 77% of theory.
Reaction SMILES: [Li+].[OH-].OO.C([C@@H]1COC(=O)N1[C:18](=[O:45])[C@H:19]([C@H:31]1[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:34](C)(C)[CH2:33][CH2:32]1)[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[C:22]([F:30])[CH:21]=1)C1C=CC=CC=1.[O-:46]S([O-])=O.[Na+].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1.[Cl-].[Na+].O.O>[C:39]([O:38][C:36]([N:35]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:19]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[C:22]([F:30])[CH:21]=1)[C:18]([OH:45])=[O:46])=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(C(F)(F)F)c(F)c2)CCC1(C)C
Reactant: O=S([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: OO
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
To a solution of THF (100 mL), water (50 mL) and 1M LiOH (5.70 mL, 5.70 mmol) cooled to 0° C. was added H2O2 (0.728 mL, 7.13 mmol) and the mixture was agitated for 10 min. A solution of 52 (1.65 g, 2.85 mmol) in THF (20 mL) was added, and the mixture was allowed to warm to RT and agitate overnight. 1M Na2SO3 (20 mL) was added, and the mixture was agitated for 15 minutes. The mixture was acidified with 2M KHSO4, and brine (100 mL) was added. The aqueous phase was separated and extracted twice with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and evaporated. The crude product was purified by SiO2 chromatography (Flash 40L) eluting with 20% EtOAc/hexane containing 1% HOAc to afford 1.0 g (83.6%) of 57 as a solid.