Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:7]1[CH:6]=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH:10]=[CH:9][C:8]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:17])=[O:16]
Reactant: CCC(=O)c1ccc(NC(C)=O)cc1
Reactant: O=[N+]([O-])O
Product: CCC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: -20 °C

Procedure:
To 140 ml of nitric acid are added portionwise, while maintaining the temperature at −20° C., 37.8 g (198 mM) of N-(4-propanoylphenyl)acetamide. The reaction medium is then poured into a water/ice mixture. The solid that precipitates out is filtered off and washed with water to give, after drying, 37.6 g of N-(2-nitro-4-propanoylphenyl)acetamide in the form of a pale yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[CH:9][C:8]=1[C:19]#[N:20].[OH-:21].[Na+]>>[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[CH:9][C:8]=1[C:19]([NH2:20])=[O:21]
Reactant: Cc1ccccc1-n1ncc(C#N)c1N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccccc1-n1ncc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
300 ml of 96% strength sulphuric acid are cautiously added to 40.0 g (201.8 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carbonitrile (Example 9A) while cooling in ice. The mixture is then heated to 40° C. and stirred for 2 hours at this temperature. After cooling, it is poured into 2 l of ice-water and cautiously neutralized with 50% strength sodium hydroxide solution. After extraction with ethyl acetate three times (2 l each time) the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate, and the solvent is distilled off under reduced pressure. 36.0 g (82% of theory) of product (purity >90%) are obtained and are employed without further purification in subsequent reactions.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:20]([C:22]1([OH:26])[CH2:25][O:24][CH2:23]1)#[CH:21]>>[F:19][C:3]1[C:2]([C:21]#[C:20][C:22]2([OH:26])[CH2:25][O:24][CH2:23]2)=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC1(O)COC1
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)COC3)c(F)cc1OCC2
Yield: 83 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-ethynyloxetan-3-ol to give the titled compound as a light brown solid (140 mg, 83%).
Reaction SMILES: [CH2:1]([N:3]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=O)[CH:7]=[CH:6][N:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:53][CH2:54][C:55]1[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>CN(C=O)C.O.C(Cl)Cl>[CH3:61][C:60]1[CH:59]=[C:58]([CH3:62])[NH:57][C:56](=[O:63])[C:55]=1[CH2:54][NH:53][C:11]([C:8]1[CH:7]=[CH:6][N:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:9]=1[CH3:10])=[O:13]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1nccc(C(=O)O)c1C)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(c1nccc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
A stirred solution of 2-[ethyl(oxan-4-yl)amino]-3-methylpyridine-4-carboxylic acid (20 mg, 0.08 mmol) in dry DMF (1.0 ml) at 0° C. under nitrogen, was treated with HATU (37 mg, 0.1 mmol) and DIPEA (26 μl, 0.15 mmol) dropwise. The resulting solution was stirred for 10 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 15 mg, 0.09 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then stirred at room temperature for 18.5 hours. The reaction mixture was cooled to 0° C. and retreated with HATU (120 mg, 0.31 mmol) and DIPEA (84 μl, 0.48 mmol). After stirring for 10 minutes, 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 49 mg, 0.29 mmol) was added. The reaction mixture was stirred for 1 hour at 0° C. and was then lifted out of the ice bath stirred at room temperature for 48 hours. The reaction mixture was diluted with water (20 ml) and CH2Cl2 (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×15 ml). The combined organic phases were washed with water (2×25 ml), brine (2×25 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-40% MeOH:CH2Cl2 and 0-25% MeOH (containing 10% NH4OH):CH2Cl2) to give 6.7 mg (22% Yield) of the title compound as an off white solid. LC-MS 100%, m/z=399.1; 1H NMR (250 MHz, DMSO) δ 11.49 (s, 1H), 8.32 (t, J=4.9 Hz, 1H), 8.14 (d, J=4.9 Hz, 1H), 6.84 (d, J=4.9 Hz, 1H), 5.86 (s, 1H), 4.26 (d, J=4.7 Hz, 2H), 3.84 (dd, J=10.3, 3.5 Hz, 2H), 3.21 (dt, J=13.6, 4.6 Hz, 5H), 2.19 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 1.62 (dt, J=21.1, 6.6 Hz, 4H), 0.80 (t, J=6.9 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([S:30]([CH2:33][CH2:34]Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][S:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:31])=[O:32])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=S(=O)(CCCl)Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCS(=O)(=O)Cc2ccccc2)CC1
Yield: 88.6 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.50 g) as a starting compound, 2-benzylsulfonylethyl chloride (1.21 g) and potassium carbonate (1.54 g) were reacted and treated in the same manner as in Example 199 to give 1.72 g of 4-amino-5-chloro-2-methoxy-N-((1-(2-benzylsulfonylethyl)piperidin-4-yl)methyl)-benzamide,
Reaction SMILES: [H-].[Na+].[N:3]([CH2:6][C@H:7]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[N+:4]=[N-:5].[CH3:25]I>CN(C=O)C>[N:3]([CH2:6][C@H:7]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[N+:4]=[N-:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H](CN=[N+]=[N-])COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CN=[N+]=[N-])COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.7 %

Procedure:
To a solution NaH (0.29 g, 7.35 mmol) in DMF (10 mL) was added a solution of (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-ylcarbamate (1.5 g, 4.9 mmol) in DMF (10.0 mL). The mixture was stirred at RT for 30 min followed by addition of MeI (1.0 mL, 9.8 mmol). The resulting mixture was stirred for another 2 h. LCMS indicated the completion of the reaction. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-yl(methyl)carbamate (1.8 g, crude), which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:19]Br)=[O:5])[CH3:2].CN(C)C=[O:24]>[Cl-].[Na+].O.FC(F)(F)C([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:19][OH:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1CBr
Reactant: CN(C)C=O
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30.7 g of crude 4-Bromomethyl-2-(4-methoxy-phenyl)-oxazole-5-carboxylic acid ethyl ester were dissolved in 170 ml dry dimethylformamide. 29.95 g Silver trifluoroacetate were added and the mixture was stirred at room temperature overnight. 100 ml brine was added and the mixture was stirred for one hour. The reaction mixture was filtered through a pad of celite, the solvent removed in vacuo and the resulting residue dissolved in 200 ml ethanol. The mixture was heated to reflux for three hours. Then the solvent was removed in vacuo and the residue dissolved in water and extracted five times with ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with n-heptane:ethyl acetate=5:1=>ethylacetate) to obtain 17.8 g 4-hydroxymethyl-2-(4-methoxy-phenyl)-oxazole-5-carboxylic acid ethyl ester as a solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)(=[O:16])=[O:15])=[CH:8][C:7]=1[CH3:34].COC1C(SCC2C=CC(C3C=CC(C(F)(F)F)=CC=3)=CC=2)=CC(C)=C(C=1)OCC(O)=O.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH3:13][O:12][C:10]1[C:9]([S:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)(=[O:16])=[O:15])=[CH:8][C:7]([CH3:34])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:35])=[O:2]
Reactant: COC(=O)COc1cc(OC)c(S(=O)(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(OCC(=O)O)c(C)cc1S(=O)(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h

Procedure:
Preparation of [5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfonyl)-phenoxy]-acetic acid methyl ester (compound 50A) Example 4 (200 mg) was dissolved in 5 ml dichloromethane. Excess m-chloroperbenzoic acid (300 mg) was added and the reaction was allowed to stir 3 h. The solvent was removed under vacuum and the crude product was purified by MPLC. MS m/z 509 (M+1). Step 2. Preparation of [5-Methoxy-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethanesulfonyl)-phenoxy]-acetic acid (compound 50) The title compound was prepared in the manner analogous to Example 1 using 50A. 400 MHz 1H NMR (DMSO-d6) δ 13.13 (br(s), 1H), 7.85 (d, 2H, J=8.1 Hz), 7.77 (d, 2H, J=8.3 Hz), 7.66 (d, 2H, J=8.6 Hz), 7.3 (m, 3H), 6.76 (s, 1H), 4.89 (s, 2H), 4.67 (s, 2H), 3.96 (s, 3H), 2.04 (s, 3H). MS m/z 495 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(=S)=S>[Br:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(O)c1
Solvent: S=C=S
Product: Cc1cc(C)c(Br)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 3,5-dimethylphenol (15.0 g, 123 mmol) in carbon disulfide (330 mL) was slowly added N-bromosuccinimide (21.9 g, 123 mmol) in several batches with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the precipitated crystals were filtered and then were washed with ethyl acetate-hexane (10:1). The solution was concentrated, and the residue was purified by silica gel chromatography (ethyl acetate:hexane=1:9) to obtain 16.3 g (yield 66%) of the title compound. Oily matter.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[NH2:27][CH2:28][C@@H:29]([OH:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:27][CH2:28][C@H:29]([OH:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: NC[C@@H](O)CN1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(CCCNC[C@H](O)CN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 45 °C
Yield: 45.6 %

Procedure:
5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (1.13 g, 2.9 mmol) was dissolved in 5.6 ml of dichloromethane under stirring, and added with (R)-1-amino-3-morpholin-4-yl-propan-2-ol 78c (0.93 g, 5.8 mmol) to the solution at room temperature. Upon the completion of the addition, the reaction mixture was heated to 45° C. for 14 hours in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction was stopped. The reaction solution was added with 15 ml of saturated brine, extracted with dichloromethane (20 ml×3), the combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (S)-5-[3-(2-hydroxy-3-morpholin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 78d (600 mg, yield 72.5%) as a yellow oil.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20](=[O:25])[CH:19]=[C:18]2[NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][C:20](=[O:25])[CH:19]=[C:18]2[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:3])[CH2:29][CH2:28]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: CC(Br)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc2ncccc2c1)N1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a solution of 6-(1-bromoethyl)-quinoline (0.44 g, 1.86 mmol) and 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.35 g, 1.24 mmol) in DMF (10 mL) was added K2CO3 (0.26 g, 1.86 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, and was then treated with H2O (100 mL) to provide 0.52 g (96%) of a white precipitate after filtration. MS (ESI(+)Q1MS) m/z 435 (M+H)+; 1H NMR (300 MHz, DMSO) δ ppm 8.82-8.88 (m, 1H), 8.30-8.37 (m, 2H), 7.97-8.02 (m, 1H), 7.76-7.89 (m, 2H), 7.58-7.64 (m, 1H), 7.47-7.55 (m, 1H), 7.22-7.34 (m, 2H), 5.23 (s, 1H), 3.76 (dt, 1H), 3.37-3.52 (m, 1H), 2.96-3.04 (m, 1H), 2.80-2.89 (m, 1H), 2.09-2.21 (m, 2H), 1.82-1.98 (m, 2H), 1.50-1.71 (m, 2H), 1.40 (d, 3H). The pure racemic mixture was separated into enantiomers by prep HPLC chiral chromatography using a CHIRALPAK AD column: 7.5/7.5/85 MeOH/EtOH/Hexane. Enantiomers had retention times of 4.1 and 6.3 minutes. The optical rotations of the enantiomers were [α]D (90:10 CH2Cl2:MeOH, 25° C.)=+19.2 and −14.7, respectively.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:12][CH2:11][CH2:10][S:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:2]=[O:1]
Reactant: OCCSc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc(SCCO)c1

Procedure:
Manganese dioxide (1.36 g) was added to a solution of 2-(3-(hydroxymethyl)phenylthio)ethanol (example 65, step b) (0.29 g) in DCM (10 mL). The resulting mixture was heated at reflux for 4 h, cooled and filtered through Celite. The filter pad was washed with DCM (3×20 mL). The filtrate and washing were combined and evaporated to give the subtitled compound as a yellow gum. Yield 0.2 g.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][CH2:53][C:54]([CH3:60])([CH3:59])[C:55]([O:57]C)=[O:56])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[C:35]([O:34][C:32]([N:9]1[CH2:10][CH2:11][C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:24]([Cl:31])=[CH:25][C:26]([CH3:30])=[CH:27][C:28]=3[Cl:29])=[CH:15][CH:14]=2)[C@@H:7]([C:5]([N:4]([CH2:39][C:40]2[CH:41]=[C:42]([CH:43]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:45]=2)[O:51][CH2:52][CH2:53][C:54]([CH3:59])([CH3:60])[C:55]([OH:57])=[O:56])[CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:8]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCC(C)(C)C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCC(C)(C)C(=O)O)c1
Temperature: 100 °C

Procedure:
To a solution of tert-Butyl (3R,4S)-3-({cyclopropyl[3-(4-methoxy-3,3-dimethyl-4-oxobutoxy)-5-(3-methoxypropyl)-benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-piperidine-1-carboxylate (1 eq.) from Example 21/Step 2 in ethanol was added 1 N aqueous NaOH (3 eq.). The reaction was heated to 100° C. for 10 min in a microwave reactor (Biotage). After cooling to rt, the reaction was concentrated in vacuo to removed the ethanol solvent. The resulting solution was acidified with 1 N HCl and extracted with ethyl acetate. The combined organic extracted were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[C:6]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=O)[CH:7]=1>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]3[CH2:19][CH2:20][C:21]4[C:26]3=[C:25]([CH:24]=[CH:23][CH:22]=4)[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[N:8][C:6]=2[CH:7]=1
Reactant: CN1CCN(C(=O)Nc2cc(Cl)ccc2N2CCc3ccccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cc(Cl)ccc3N3CCc4cccc2c43)CC1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A stirred solution of 6.30 g (0.017 mole) of N-[5-chloro-2-(2,3-dihydro-1H-indol-1-yl)-phenyl]-4-methyl-1piperazinecarboxamide of Example 4b in 100 ml of phosphorus oxychloride was refluxed for 6 hours under nitrogen, then cooled to room temperature. The excess phosphorus oxychloride was removed at aspirator pressure with gentle warming. The residue was chilled in an ice-bath (with exclusion of moisture) and then treated first with 250 ml of ice-cold 2N-NaOH, then with 250 ml of dichloromethane. The mixture was stirred vigorously until all the material passed into solution. The organic phase was separated, washed four times with water, dried over Na2SO4 and concentrated in vacuo to 5.7 g (95%) of a semi-crystalline material. Recrystallization from acetone afforded 2.20 g (37% overall yield) of 9-chloro-6-(4-methyl-1-piperazinyl)-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine, m.p. 154°-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH2:15][C:16](=O)[CH2:17][CH3:18]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:16]([CH2:17][CH3:18])[CH2:15][CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(=O)CC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCC(CC)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from 3-pentanone and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: O[CH:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([OH:15])[C:5]=2[C:4](=O)[O:3]1.O.[NH2:18][NH2:19]>CS(C)=O>[OH:15][C:6]1[C:5]2[C:4](=[O:3])[NH:18][N:19]=[CH:2][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=C1OC(O)c2c1c(O)nc1ccccc21
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]ncc2c1c(O)nc1ccccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
0.54 g (0.0025 mol) of (RS)-1,4-dihydroxy-1,3-dihydrofuro[3,4-c]quinolin-3-one was dissolved in 5 ml of dimethyl sulphoxide while gassing with argon. 0.125 g (0.0025 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 4 days. The suspension obtained was suction filtered and rinsed with ethyl acetate. Yield: 0.28 g (53%) of 5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as yellow crystals; m.p. >350° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[S:27][CH:28]=[CH:29][C:30]=1B(O)O>>[Cl:25][C:26]1[S:27][CH:28]=[CH:29][C:30]=1[C:5]1[CH:6]=[CH:7][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:24]
Reactant: OB(O)c1ccsc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccsc1Cl
Yield: 45 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-chlorothiophene-3-boronic acid (available from Combi-Blocks Inc.; 65 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(2-chloro-thiophen-3-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (42 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.44-8.56 (m, 2H), 8.33 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.45-7.61 (m, 2H), 7.08 (d, J=5.5 Hz, 1H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[OH-].[K+].CS(C)=O.[C:24]([O:32][CH2:33][CH2:34]Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:24]([O:32][CH2:33][CH2:34][O:16][N:15]=[CH:14][C:5]1[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Reactant: O=C(OCCCl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCCOC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime and 0.3 g (0.0054 mole) of powdery potassium hydroxide were added to 20 ml of dimethyl sulfoxide, and the resulting mixture was stirred for 30 minutes. To this solution was added 0.8 g (0.0043 mole) of 2-chloroethyl benzoate, and reaction was carried out at from 40° to 50° C. for 3 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.3 g of the desired compound.