Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C(CCl)N(c1ccccc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CSc1ccc(F)cc1)N(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-fluorothiophenol (0.13 mL, 1.2 mmol) in tetrahydrofuran (4 ml) was added aqueous 15% sodium hydroxide. 2-Chloro-N-cyclohexyl-N-phenylacetamide (320 mg, 1.3 mmol) was added, and the solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue purified on a preparatory plate using 20% ethyl acetate/hexanes to furnish 2-(4-fluorophenylthio)-N-cyclohexyl-N-phenylacetamide as a white solid. (M+1)=343.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](C)([C:14](OCC)=O)[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[Li+:20].[OH-]>CO.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:14])[C:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[Li+:20]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Cl)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)[O-])c1ccc(Cl)nn1

Procedure:
A solution of diethyl 2-(6-chloropyridazin-3-yl)-2-methylmalonate (19.8 g, 69.1 mmol) and LiOH (3.31 g, 138 mmol) in MeOH:Water (3:1, 200 mL) was stirred at 25° C. for 3 hrs. MeOH was removed from the reaction via rotary evaporation, and the resulting residue was reconstituted in H2O (300 mL). The aqueous mixture was washed with Et2O (3×100 mL) and then lyophilized to dryness to provide lithium 2-(6-chloropyridazin-3-yl)propanoate 48B in quantitative yield. The material was used without further work-up. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (3 H, d, J=7.33 Hz) 3.63 (1 H, q, J=7.24 Hz) 7.71 (2 H, s). ESI-MS:m/z 187.0 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38]([OH:40])[CH:39]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38]([OH:40])[CH:39]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: COc1ccc(CCN)cc1O
Product: COc1ccc(CCNc2nccc(-c3cccc(CN(CCCN)S(C)(=O)=O)c3)n2)cc1O

Procedure:
Intermediate 4 from above was coupled with 5-(2-Amino-ethyl)-2-methoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 486. 1H NMR (Varian 300 MHz, CDCl3-CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 8.0 (d, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.2 (m, 1H) 6.8 (s, 1H) 6.6 (s, 2H) 4.5 (s, 2H) 3.8 (m, 2H) 3.7 (s, 3H) 3.3 (m, 2H), 2.9 (m, 7H) 1.8 (m, 2H).
Reaction SMILES: Br[C:2]1C=C[C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[NH:37]1C=CC(C(=O)C)=C1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][NH:37][CH:5]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1cc[nH]c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc[nH]c4)ccc3c1)n2C1CCCCC1
Yield: 8 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(1H-pyrrol-3-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (10 mg, 8% yield).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([N:31]3C(=O)C4=CC=CC=C4C3=O)[CH:28]=[C:29]([Cl:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CN>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:26]=[C:27]([NH2:31])[CH:28]=[C:29]([Cl:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: CN
Solvent: CCO
Product: CCCc1nc2c(Cl)cc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.05 g of methyl 4'-[(2-n-propyl-4-chloro-6-phthalimido-1H -benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate are dissolved in 125 ml of ethanol and mixed with 5 ml of a 40% aqueous methylamine solution. The reaction mixture is stirred for 3 hours at ambient temperature and then stirred into saline solution. After extracting 3 times with ethyl acetate the combined organic phases are dried over sodium sulphate and evaporated down. The residue is stirred with petroleum ether/ether (1:4) for 24 hours, the solids formed are suction filtered and dried.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20].COCCOC>O>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@@:8]2([C:17]3[C:5](=[CH:4][CH:3]=[C:2]([C:25]4[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:20])[CH:18]=3)[CH2:6][CH2:7]2)[N:9]=1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(CC3)N=C(N)OCC2(F)F)c1
Yield: 10 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 3-cyanophenylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (10% yield) as an off-white solid. MS (ISP): m/z=340.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([O:30][CH3:31])=[N:23][C:24]([CH3:29])=[N:25][C:26]=1[O:27][CH3:28])=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[N:23][C:22]=1[O:30][CH3:31]
Reactant: COc1nc(C)nc(OC)c1N=C=S
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(OC)nc(C)nc2OC)c1NCCCO
Temperature: 70 °C
Reaction time: 72 h
Yield: 12 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (2.00 g, 7.73 mmol) and 5-isothiocyanato-4,6-dimethoxy-2-methylpyrimidine (4.89 g, 23.2 mmol) in tetrahydrofuran (25 mL) was stirred at 70° C. for 3 days. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 40-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-{[(4,6-dimethoxy-2-methylpyrimidin-5-yl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate (435 mg).
Reaction SMILES: [O:1]([C:8]1[C:13]2[C:14]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[O:1]([C:8]1[C:13]2[C:14]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][NH:16][C:12]=2[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2n[nH]c3ccnc(Oc4ccccc4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Oc2nccc3[nH]nc(NCC4CCNCC4)c23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the compound prepared in Example 435 (0.262 g) in dichloromethane (3 mL) was treated with trifluoroacetic acid (0.6 mL) at room temperature. After stirring at room temperature for 4 hours, the mixture was shaken in dichloromethane and washed with aqueous saturated sodium bicarbonate, dried, and evaporated in vacuo to provide the title compound (0.065 g) with the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:15][C:8]3([CH2:13][CH2:12][N:11](C)[CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:15][C:8]3([CH2:13][CH2:12][N:11]([C:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:25])[CH2:10][CH2:9]3)[C:6]=2[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)SC(c1ccccc1)c1ccc(F)cc12
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1ccccc1)c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.3 g of 6-fluoro-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine] and 0.3 g of phenyl chloroformate in 10 ml of methylene chloride which was previously stirred at ambient temperature for 16 hours is sequentially quenched with water, washed with 10% sodium hydroxide and dried. The reaction mixture is concentrated under vacuum leaving a viscous oil which crystallized with standing. The solid product is recrystallized from an ether-pentane mixture to give prisms, m.p. 156°-158° C. of 6-fluoro-1,3-dihydro-3-phenyl-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=3)[N:5]3[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]3[CH:3]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Product: COc1ccc(-c2cc3nc(C)cn3c(NCCNc3ccc([N+](=O)[O-])c(N)n3)n2)cc1OC

Procedure:
In analogy to the procedure described for Example 7, 57 mg (39% of theory) of the product are obtained starting from 120 mg (0.32 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 31A) by coupling with 69 mg (0.38 mmol) of (3,4-dimethoxyphenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.Br[CH:10]([CH2:13][C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15])[CH:11]=O>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]2[C:10]([CH2:13][C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15])=[CH:11][N:1]=[C:2]2[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(C)(CC(Br)C=O)[N+](=O)[O-]
Product: Cc1ccn2c(CC(C)(C)[N+](=O)[O-])cnc2c1
Yield: 63.4 %

Procedure:
2-Amino-4-methylpyridine (2.2 g, 20.3 mmol) and 2-bromo-4-methyl-4-nitropentanal (20.3 mmol) are reacted as described in Amine 7 to give 3.0 g of 7-methyl-3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridine (63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][CH:8]([C:19]([O:21][CH3:22])=[O:20])[C:7](=O)[C:6]=2[CH:24]=1.[BH4-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:24]=1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)c2ccc(Br)cc2C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
In THF (150 ml) was dissolved methyl 7-bromo-1-(t-butoxycarbonyl)-1,2,3,4-tetrahydro-1-benzazepin-5-one-4-carboxylate (7.2 g). To the solution was added sodium borohydride (0.7 g) at −40° C., and then was added dropwise methanol (15 ml). The mixture was stirred at −15° C. for 1 hour. To the mixture was added 1M citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in THF (150 ml), and to the solution was added triethylamine (7.5 ml). To the mixture was added dropwise, under ice-cooling, methanesulfonyl chloride (2.1 ml). Under nitrogen atmosphere, the mixture was stirred at room temperature for 1.5 hours, and to the mixture was added dropwise DBU (13.5 ml) at room temperature. The mixture was stirred at 90° C. for 10 minutes, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (5.18 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:21].C(=O)(O)[O-].[Na+].O>ClCCl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2oc(-c3cccc(F)c3)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1cccc(-c2nc3cc(CCl)ccc3o2)c1
Reaction time: 2 h

Procedure:
Compound 69B was suspended in 100 ml dichloromethane. SOCl2 was added and allowed to stir for 2 h. 20 ml Saturated sodium bicarbonate was added followed by 20 ml water and stirred for 5 minutes. The dichloromethane layer was seperated and dried over anhydrous sodium sulfate. The dichloromethane solution was filtered through silica and eluted with dichloromethane until clear. Concentration of the filtrate gave a pink solid. MS m/z 262 (M+1).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][N:5]=[C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[N:15][OH:16].[CH2:17]1[O:19][CH2:18]1.C(O)(=O)C>O>[CH3:3][O:4][N:5]=[C:6]([C:7]1[O:19][CH2:18][CH2:17][O:16][N:15]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: C1CO1
Reactant: CON=C1C(=NO)Oc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CON=C(C1=NOCCO1)c1ccccc1O
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
At 20° C., 19.8 g (0.3 mol) of potassium hydroxide pellets are added to a suspension of 38.4 g (0.2 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime in 400 ml of water and the mixture was stirred for 30 minutes, on which a solution forms. At 20° C., 17.6 g (0.4 mol) of ethylene oxide are introduced over a period of 75 minutes, and the mixture is stirred at 20° C. overnight, on which a precipitate forms. The mixture is then stirred at 60° C. for 11 hours, on which the precipitate redissolves. The solution is cooled and acidified to pH 5-6 with glacial acetic acid. The crystalline product is filtered off with suction, washed with 300 ml of water a little at a time and dried at 45° C. in a vacuum drying cabinet. 19.6 g (39.3% of theory) of (5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime are obtained.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:36]([NH:40][NH2:41])(=[O:39])[CH2:37][CH3:38]>O1CCCC1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:41][NH:40][C:36](=[O:39])[CH2:37][CH3:38])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCC(=O)NN
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of the carboxylic acid of Example 9 or 16 (6b, 354 mg, 1.28 mmol) in tetrahydrofuran (10 mL) were added triethylamine (0.216 mL) and isobutyl chloroformate (208 μl) under ice-cooling, followed by agitating at 0° C. for 15 minutes. To the reaction solution were added a solution of propionohydrazide (161 mg, prepared following a procedure analogous to Reference Example 3 and Reference Example 6) in tetrahydrofuran (3 mL) at 0° C., followed by stirring at room temperature for 1 hour, and then concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1) to afford 425 mg of the title compound (yield 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=1[OH:26])[CH3:14])[CH:7]=[CH:6]2.Cl[CH2:28][O:29][CH:30]=[O:31]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=1[O:26][C:30]([O:29][CH3:28])=[O:31])[CH3:14])[CH:7]=[CH:6]2
Reactant: O=COCCl
Reactant: COc1ccc2cc(C(C)c3sc(-c4ccccc4)nc3O)ccc2c1
Solvent: c1ccncc1
Product: COC(=O)Oc1nc(-c2ccccc2)sc1C(C)c1ccc2cc(OC)ccc2c1

Procedure:
The desired compound is prepared by treatment of the product of Example 5 with chloromethylformate and pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.Cl.[NH:32]1[CH2:36][CH2:35][CH:34]([C:37]#[N:38])[CH2:33]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:32]4[CH2:36][CH2:35][CH:34]([C:37]#[N:38])[CH2:33]4)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: N#CC1CCNC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Agent: Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCC(C#N)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and pyrrolidine-3-carbonitrile hydrochloride. LCMS (M+H)+=526.2/528.1.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:25]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:8][C:7]=2[CH:25]=1
Reactant: COc1ccc2nc(-c3cccc4c3-c3ccccc3C4=O)[nH]c2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.2 %

Procedure:
In a 50-ml three-necked flask under an argon atmosphere, dissolve 700 mg of 4-(6-methoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one, obtained in stage 2 of Example 106, in 10 ml of dichloromethane, then add dropwise 5.35 ml of a 1M solution of boron tribromide in dichloromethane and stir for 20 hours at room temperature. Pour the reaction mixture into 50 ml of water. The precipitate that forms is drained and washed with water then with toluene and finally dried. After purification by silica gel flash chromatography, eluting with a mixture of dichloromethane and methanol (90-10 by volume), we obtain 363 mg of 4-(6-hydroxy-1H-benzimidazol-2-yl)-fluoren-9-one, in the form of a brown powder, with the following characteristics:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C@@H:12]2[CH2:14][O:13]2)=[C:6]([CH:9]=1)C=O.C1C=C(Cl)C=C([C:22]([O:24]O)=[O:23])C=1>C(Cl)Cl>[CH:22]([O:24][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:10][CH2:11][C@@H:12]1[CH2:14][O:13]1)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cc(Br)ccc1OC[C@@H]1CO1
Solvent: ClCCl
Product: O=COc1cc(Br)ccc1OC[C@@H]1CO1

Procedure:
Preparation according to Preparation 2 using 5-bromo-2-[(2S)-oxiran-2-ylmethoxy]benzaldehyde (8.3 g, 32 mmol), DCM (100 ml) and m-CPBA (77%, 10.9 g, 48.6 mmol). The mixture was heated at reflux for 3 h. Crude yield: 8.5 g. MS m/z (rel. intensity, 70 eV) 274 (M+, 10), 273 (M+, 9), 189 (98), 188 (bp), 57 (77).
Reaction SMILES: Cl[CH:2](Cl)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([OH:26])=[C:15]([C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[CH:16]=1>O1CCOCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[O:26][CH:2]([C:3]([OH:5])=[O:4])[O:18][C:17]([CH3:25])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]=2[CH:16]=1
Reactant: COc1ccc(O)c(C(C)(O)c2ccccc2)c1
Reactant: O=C(O)C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(C)(c1ccccc1)OC(C(=O)O)O2
Temperature: 90 °C
Yield: 112.7 %

Procedure:
A solution of 17 g of dichloroacetic acid in 180 ml of dioxane was added dropwise with stirring to a suspension of 14.9 g of sodium hydride as 50% oil suspension, 1.1 g of dibenzo-18-courone-6 and 160 ml of dioxane and then a solution of 21.5 g of the product of Step A in 220 ml of dioxane was added. The reaction mixture was heated at 90° C. for 3 hours, was cooled and was poured into ice. The aqueous phase was washed with 300 ml of ether, was acidified with 30 ml of concentrated hydrochloric acid and was extracted 3 times with 200 ml of ether. The ether phase was washed twice with 100 ml of water and was extracted twice with 250 ml of aqueous 5% sodium bicarbonate solution. The aqueous phase was washed with 100 ml of ether, acidified with 40 ml of concentrated hydrochloric acid and was extracted 3 times with 250 ml of ether. The combined organic phases were washed with water until the water was neutral, dried over magnesium sulfate and evaporated under reduced pressure to obtain 29.8 g of raw 6-methoxy-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of 2 diastereoisomeric racemates).