Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=c1c2ccc(O)c(Cl)c2oc2cccc(F)c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(=O)c3c(F)cccc3oc2c1Cl
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 2.6 g of 4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 2.8 g of potassium carbonate, 3.3 g of ethyl bromoacetate and 40 ml of N,N-dimethylformamide (DMF) was stirred at 60°-70° C. for 4 hours. After cooling the mixture, water was added thereto and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 3.4 g of ethyl 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetate. A mixture of this ester (3.3 g), sodium hydroxide (1.9 g) and water (100 ml) was refluxed for 30 minutes. After cooling, the mixture was rendered acidic with concentrated hydrochloric acid and the resulting crystal was recovered by filtration and dried. Recrystallization from DMF gave 2.5 g of 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[C:15]([F:18])[C:14]([F:19])=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[C:15]([F:18])[C:14]([F:19])=[CH:13]3)[C:34]([NH:33][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:35])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc2nn(-c3cccc(Cl)c3)c(Nc3cccc(Cl)c3)c2cc1F
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2cc(F)c(F)cc2nn1-c1cccc(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(3-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as white solid. MS: m/e=515.4 [M+H+].
Reaction SMILES: [C:1]([O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([CH3:21])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[CH2:28]([O:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][C:12]=1[CH3:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(OC(=O)c2ccccc2)c2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OC(=O)c2ccccc2)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
10.8 g (0.039 mol) of 4-benzoyloxy-2-methylnaphthol was dissolved in 100 ml of acetone, and to this was added 5.5 g (0.04 mol) of anhydrous potassium carbonate, and, while stirring at room temperature, 7.7 g (0.045 mol) of benzyl bromide was added dropwise over 30 minutes, and following completion of the addition, stirring was continued for 20 hours at room temperature. Then, inorganic salt was filtered out and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water, and the solvent evaporated under reduced pressure. n-Hexane was added to the residue to cause crystallization. Recrystallization from ethyl acetate-n-hexane gave 11.9 g of white crystals, m.p. 179-180° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[O:21]=[C:10]1[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:3][CH:4]=2)=[CH:14][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][NH:11]1
Reactant: C1CCNCC1
Reactant: O=C(Nc1cc(-c2ccncc2)c[nH]c1=O)c1ccc(Br)cc1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(-c2ccncc2)c[nH]c1=O)c1ccc(N2CCCCC2)cc1
Temperature: 160 °C
Yield: 43 %

Procedure:
4-Bromo-N-(1,2-dihydro-2-oxo-5-(pyridin-4-yl)pyridin-3-yl)benzamide (30 mg, 0.081 mmol) I-20 was placed in a microwave tube equipped with a stirrer bar. NMP (0.75 mL) was added, followed by piperidine (1.5 mL). The reaction vessel was heated at 160° C. for 2 hours in a microwave. After cooling, the solvent and excess piperidine were removed in vacuo. The crude compound was recrystallized from methanol to give the title compound as a white solid (13 mg, 43% yield). MS (ES+) m/e=375. 1H NMR (DMSO-d6) δH 1.54-1.65 (6H, m), 3.30-3.38 (4H, m), 7.02 (2H, d), 7.61 (2H, d), 7.72-7.80 (1H, m), 7.78 (2H, d), 8.59 (2H, d), 8.77 (1H, d), 9.13 (1H, s), 12.58 (1H, bs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11](OC)=[C:10](OC)[CH:9]=1)=[O:7].[C:23]1(OC)[C:24](=CC=[CH:29][CH:30]=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C1C2C(=CC=CC=2)C=CC=1C(Cl)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]2[C:10](=[CH:24][CH:23]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)naphthalene was prepared analogously to 3,4,3',4'-tetramethoxybenzophenone using veratrole (2.6 mL, 20 mmol), aluminum chloride (2.9 g, 22 mmol) and 2-naphthoyl chloride (3.9 g, 20 mmol) with a reaction time of 4 hours at reflux. The crude product was purified by flash column chromatography (silica gel, 2.5% ethyl acetate/methylene chloride) to afford 4.52 g (77%) of the product as a white solid: mp 120-121.5° C.; 1H NMR (CDCl3) δ 8.24 (s, 1H), 8.03-7.84 (m, 4H), 7.68-7.40 (m, 4H), 7.00-6.87 (m, 1H), 3.97 (s, 3H), 3.95 (s, 3H); 13C NMR (CDCl3) δ 195.5, 153.0, 149.0, 135.5, 134.9, 132.2, 131.0, 130.4, 129.2, 128.1, 128.0, 127.8, 126.7, 125.9, 125.4, 112.2, 109.8, 56.1, 56.0; Anal. Calcd for C19H16O3. Theoretical: C, 78.06; H, 5.52. Found: C, 77.73; H, 5.69.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:24][OH:25])[OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>>[C:1]([O:20][CH2:21][CH:22]([CH2:24][OH:25])[OH:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:26]([O-:31])(=[O:32])[CH2:27][CH2:28][C:29]([O-:19])=[O:30]
Reactant: O=C1CCC(=O)O1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Product: O=C([O-])CCC(=O)[O-]
Temperature: 140 °C
Reaction time: 3 h

Procedure:
30.0 gm (84.1 mmoles) of glyceryl monooleate were added to a dry 100 ml, single neck, round bottom flask. A football stir bar was added and a nitrogen inlet adapter was attached. The reaction flask was placed into a room temperature oil bath and a nitrogen blanket was applied. The oil bath temperature was raised to 140° C. Once at 140° C., 8.42 gm (84.1 mmoles) succinic anhydride was added and the temperature was raised to 200° C. Heat tape was wrapped around the outside of the top of the flask and adapter to keep the succinic anhydride from subliming. The reaction was continued for 3 hours at 200° C. The flask was removed from the oil bath and allowed to cool to room temperature. The polymer was a pale yellow, viscous liquid.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[CH2:2]1.[CH3:13][NH2:14]>>[OH:1][C:3]1([CH2:2][NH:14][CH3:13])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1
Reactant: CN
Reactant: COC(=O)N1CCCC2(CO2)C1
Product: CNCC1(O)CCCN(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.3 g (54.3 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of methylamine solution (25% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=2[C:20](O)=[O:21])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:13]3[C:12]=2[C:20](=[O:21])[N:24]([CH:25]2[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]2=[O:27])[C:14]3=[O:16])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 89 %

Procedure:
A mixture of 3-(4-isopropylphenylamino)phthalic acid (0.64 g, 2.1 mmol) and rac-α-aminoglutarimide hydrochloride (0.35 g, 2.1 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 1:1 hexanes-ethyl acetate, eluting 0.74 g of the product, in 89% yield: mp 138-140° C.; 1H NMR (DMSO-d6) δ 1.21 (d, J=6.9 Hz, 6H), 2.04-2.08 (m, 1H), 2.52-2.64 (m, 2H), 2.84-2.94 (m, 2H), 5.13 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.19-7.30 (m, 5H), 7.35 (d, J=8.5 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 8.35 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 23.9, 31.0, 32.9, 48.7, 111.3, 113.0, 119.0, 122.5, 127.2, 132.4, 136.2, 136.9, 143.3, 144.5, 167.1, 168.4, 170.0, 172.8; Anal. calcd for C22H21N3O4: C, 67.51; H, 5.41; N, 10.74. Found: C, 67.27; H, 5.36; N, 10.64.
Reaction SMILES: [Si](Cl)(C(C)(C)C)(C)[CH3:2].[CH3:9][C:10]([Si:13]([CH3:36])([CH3:35])[O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:17](=[CH:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH:22]=[CH:23][C:24]2=[O:34])[CH2:16]1)([CH3:12])[CH3:11].C[Al](C)C.C1(C)C=CC=CC=1.C[Si](Cl)(C)C>CN(C=O)C.O1CCCC1.O>[CH3:12][C:10]([Si:13]([CH3:36])([CH3:35])[O:14][C@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:17](=[CH:18][CH2:19][C@@H:20]3[C@@H:29]2[CH2:28][CH2:27][C@@:25]2([CH3:26])[C@H:21]3[C@@H:22]([CH3:2])[CH2:23][C:24]2=[O:34])[CH2:16]1)([CH3:9])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]32)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: C[Al](C)C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]43C)[C@H]12
Reaction time: 2 h

Procedure:
Prepare M82 by treating a solution of M81 in DMF with t-butyldimethylsilyl chloride following the procedure described in example 13a. To a solution of 3β-[[(1,1-dimethylethyl)dimethylsilyl]oxy]androst-5,15-dien-17-one (M82) (10.0 g, 24.96 mmol) and cuprous bromide (71.5 mg, 0.5 mmol) dissolved in tetrahydrofuran (100 mL) under a nitrogen atmosphere, add a 2M solution of tri-methylaluminum in toluene (13.8 mL, 27.6 mmol). Add trimethylsilyl chloride (5.88 g, 54 mmol) dropwise to the solution. After 2 hours, add water (5 mL) cautiously. Remove the solids by filtration and wash. Purify the crude product by flash chromatography to give 3β-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-15α-methylandrost-5-en-17-one (N88a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)CCCCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:41][CH2:35][CH2:36][CH2:37][CH3:38])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Cc1cccc(C)n1
Agent: CCCCCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 174 mg, 0.53 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (191 mg, 0.58 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (140 μL, 1.21 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Hexyl-1H-pyrazol-3-ylamine (88 mg, 0.53 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) to afford 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-hexyl-1H-pyrazol-3-yl)-propionamide as a white powder (171 mg, 68%) ESI-LRMS m/e calcd for C24H34ClN3O3S [M+] 479.2, found 480.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (t, J=6.7 Hz, 3H, CH3), 1.08-1.21 (m, 2H, CH2), 1.24-1.37 (m, 6H, 3×CH2), 1.45-1.94 (m, 10H, 5×CH2), 2.09-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.96 (t, J=7.1 Hz, 2H, NCH2), 6.63 (d, J=2.3 Hz, 1H, Ar), 7.24 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.1, Jm=1.8 Hz. 1H, Ar), 7.59 (d, Jm=1.8 Hz, 1H, Ar), 7.82 (s, 1H, NH), 8.09 (d, Jo=8.1 Hz, 1H, Ar).
Reaction SMILES: N[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N([O-])=O.[Na+].[ClH:18]>O.[Cu]Cl>[Br:12][C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([Cl:18])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(C)cc1Br
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Cl)c(C)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of methyl 5-amino-2-bromo-4-methylbenzoate (4.86 g, 20 mmol) in hydrochloric acid (6N, 50 mL) was added sodium nitrite (1.38 g, 20 mmol) carefully at −5° C. After one hour, the obtained mixture was added to a boiling solution of copper(I) chloride (3.96 g, 40 mmol) in water (50 mL) dropwise and the resulting mixture was refluxed with stirring for 2 h. The mixture was cooled to rt and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with PE to give methyl 2-bromo-5-chloro-4-methylbenzoate (3.4 g, yield 64.4%). 1H NMR (400 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.81 (s, 1H), 3.85 (s, 3H), 2.51 (s, 3H) ppm; MS: m/z=265.0 (M+1, ESI+).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21](O)=O.C=O.[OH-].[Na+]>CO>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:11][CH2:12][CH:13]([N:16]([CH2:17][CH2:18][CH2:19][OH:20])[CH3:21])[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCCCNC1CCN(Cc2ccccc2)CC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(CCCO)C1CCN(Cc2ccccc2)CC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
From 47.4 g of 1-benzyl-4-(3-hydroxypropylamino)-piperidine-dihydrochloride the base is liberated, combined with 63 ml of 85% formic acid and 22 ml of 37% formaldehyde solution and stirred for two hours at about 90-100° C. The mixture is left to cool, 37 ml of formic acid and 11 ml of formaldehyde solution are added and it is stirred for another hour at about 100-110° C. It is left to cool, combined with 150 ml of methanol, made alkaline with about 270 ml of 32% sodium hydroxide solution with cooling and stirred for about another 30 minutes at 40-50° C. and then the methanol is distilled off. The residue is extracted with twice 100 ml of methylene chloride, the combined methylene chloride phases are dried, filtered and freed from solvent in vacuo. The residue is taken up in 80 ml Ethanol, acidified with 34 ml of 32% hydrochloric acid, combined with 100 ml of acetone and stirred. As soon as crystals have been precipitated more acetone is added. The precipitate is suction filtered, washed with acetone and dried. 42.8 g of 1-benzyl-4-[-(3-hydroxypropyl)-methylamino]-piperidine-dihydrochloride are obtained in the form of a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:17](OCC)(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].N1CCCCC1.C(OC(C)C)(C)C>>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:1][C:17](=[O:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Temperature: 170 °C
Yield: 79.3 %

Procedure:
A mixture of 2-amino-5-chlorobenzophenone (6.93 g), diethyl malonate (7.2 g) and piperidine (0.3 ml) was heated at 170° C. for 4 hours. After cooling, isopropyl ether was added to the mixture to obtain crystals of ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenyl-3-quinolinecarboxylate (7.77 g, 79.3%). The crystals was recrystallized from ethanol to give pale-yellowish needles. mp 223°-224° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:33]([N:35]([CH2:36][CH3:37])[C:15]([CH2:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:30])([F:32])[F:31])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])=[O:16])[CH3:34]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid diethylcarbamoylmethyl-amide (48 mg) was prepared by following General Procedure F using {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetic acid (47 mg), diethylamine (0.2 ml), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 522. 1H NMR (DMSO-d6, 400 MHz): δ 8.45 (t, 1H), 8.08 (s, 1H), 7.90 (m, 2H), 7.78 (br, 1H), 7.66 (br, 1H), 7.48 (d, 1H), 7.34 (d, 1H), 4.13 (d, 2H), 3.66 (s, 3H), 3.38-3.28 (m, 4H), and 1.05 (t, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:15]([O:14][C:12]([NH:19][CH:20]1[CH2:21][CH2:22][N:23]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Yield: 84.9 %

Procedure:
Methyl 6-chloropyridine-3-carboxylate (1.00 g, 5.83 mmol) and 4-(N-Boc-amino)piperidine (2.33 g, 11.7 mmol) were dissolved in DMF (10 mL) and the reaction mixture was heated using a microwave reactor at 100° C. for 50 min. DIPEA (1.22 mL, 6.99 mmol) was added and the reaction mixture was heated using a microwave reactor at 100° C. for 30 min. The reaction mixture was diluted with DCM (50 mL), washed with sat aq NaHCO3 (2×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.66 g, 84.9%) as an off-white solid. LCMS (ES+): 336.1 [MH]+. HPLC: Rt 4.73 min, 98.2% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11]1(Cl)[N:16]=[C:15](Cl)[N:14]=[C:13](Cl)[N:12]=1>[OH-].[Na+].COCCO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][C:11]1[N:16]=[C:15]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=[C:13]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:12]=1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1cc(Cl)cc(Cl)c1Oc1nc(Oc2c(C)cc(Cl)cc2Cl)nc(Oc2c(C)cc(Cl)cc2Cl)n1
Reaction time: 0.05 h

Procedure:
By the same procedure as in Example 1, 60 g of sodium hydroxide is dissolved at 70° C. in 1.8 liters of ethylene glycol monomethyl ether and, by the addition of 265.6 g (1.5 moles) of 2,4-dichloro-6-methylphenol, a phenolate solution is prepared into which 92 g (0.5 mole) of cyanuric acid chloride is stirred at 70° over a period of 3 minutes, causing the temperature of the reaction mixture to rise to 81° C. After half an hour of refluxing, the product is separated as in Example 1.
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[CH2:29]=[C:30]1[CH:47]2[C@:42]([CH3:49])([CH2:43][CH2:44][C:45](=[O:48])[CH2:46]2)[C@@H:41]2[C@H:32]([C@H:33]3[C@@:37]([CH2:39][CH2:40]2)([CH3:38])[C:36](=[O:50])[CH2:35][CH2:34]3)[CH2:31]1>>[CH3:29][C@@H:30]1[CH:47]2[C@:42]([CH3:49])([CH2:43][CH2:44][C:45](=[O:48])[CH2:46]2)[C@@H:41]2[C@H:32]([C@H:33]3[C@@:37]([CH2:39][CH2:40]2)([CH3:38])[C:36](=[O:50])[CH2:35][CH2:34]3)[CH2:31]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Agent: C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 94 %

Procedure:
The title compound II-ai was prepared in 94% yield from 3,3:17,17-bis(ethylendioxy)-6α-methylandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.77-0.75 (21H, m), 1.18 (3H, s), 0.98 (3H, d), 0.90 (3H, s).