Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[CH:41]([N:44]([CH2:48][C:49]([OH:51])=O)[CH:45]([CH3:47])[CH3:46])([CH3:43])[CH3:42]>>[CH:45]([N:44]([CH:41]([CH3:42])[CH3:43])[CH2:48][C:49]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:51])([CH3:46])[CH3:47]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)N(CC(=O)O)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN(C(C)C)C(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using diisopropylamino-acetic acid as the reacting carboxylic acid. LCMS: m/e 671.7 (M+H)+, 4.99 min (method 3). 1H NMR (599 MHz, <DMSO_CDCl3>) δ=8.45-8.37 (m, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.69-7.65 (m, 1H), 7.24-7.20 (m, 2H), 5.31-5.24 (m, 1H), 4.79-4.73 (m, 1H), 4.67-4.62 (m, 1H), 3.95 (br. s., 2H), 3.66 (d, J=5.9 Hz, 3H), 2.94 (s, 1H), 2.78 (s, 1H), 2.74 (br. s., 1H), 2.63 (d, J=13.5 Hz, 1H), 2.30 (t, J=9.1 Hz, 1H), 2.13 (dd, J=6.2, 16.7 Hz, 1H), 2.07-1.98 (m, 1H), 1.75 (br. s., 1H), 1.72 (s, 4H), 1.69-1.61 (m, 1H), 1.52-1.41 (m, 8H), 1.36-1.33 (m, 3H), 1.33-1.31 (m, 2H), 1.30-1.28 (m, 3H), 1.28-1.25 (m, 3H), 1.09 (s, 6H), 1.01 (s, 6H), 0.93 (br. s., 6H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([O:16][CH2:17][CH3:18])[CH2:15][CH2:14]2)=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:16][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:8][C:9]=2[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH3:18]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)(C)C)CC1
Temperature: 95 °C

Procedure:
Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-tert-butyl-phenyl 1,1,1-trifluoromethansulfonate (Intermediate 110, 260.0 mg, 0.71 mmol) in triethylamine (4 mL) and DMF (6 mL) was sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (40.0 mg, 0.06 mmol). The resulting reaction mixture was heated to 95° C. for 18 hours. The title compound, 215.0 mg (96%), was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[CH3:21][CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1>>[CH3:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])(=[O:13])=[O:12])[CH2:23]1
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Reactant: CC1CNCCN1
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(N3CCNC(C)C3)cccc21
Yield: 38 %

Procedure:
The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and 3-methylpiperazine according to Method 1 to give 110 mg (38%) of a white solid: 1HNMR (CD3OD) δ 7.92-6.82 (m, 9H), 3.64-3.39 (m, 5H), 3.12-3.03 (m, 1H), 2.92-2.83 (m, 1H), 2.47 (s, 3H), 1.40 (d, J=7 Hz, 3H); MS (ESI) 370.0 (M+H)+; Purity (HPLC) 94%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].C[C:16]1[C:24](C)(C)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:27][C:28]([OH:30])=[O:29])[CH:22]=2)[N:17]=1.[Br-:31].[Na+].C(OCC)(=O)C>S1(CCCC1)(=O)=O>[Br-:31].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][N+:17]1[C:18]2[C:23](=[CH:22][C:21]([CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=2)[CH2:24][CH:16]=1)([O-:3])=[O:2]
Reactant: CC1=Nc2ccc(CC(=O)O)cc2C1(C)C
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: O=C(O)Cc1ccc2c(c1)CC=[N+]2Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 54 %

Procedure:
3,5-Dinitrobenzyl chloride (12.46 g, 57.5 mmol) was added to a solution of 2,3,3-trimethyl-3H-indol-5-yl-acetic acid (2.5 g, 11.5 mmol) with sodium bromide (5.92 g, 57.5 mmol) in sulfolan (10 ml). The reaction was heated at 100° C. for 20 hrs, then cooled to room temperature. The crude reaction mixture was added dropwise to an excess of ethyl acetate and the dark brown solid was filtered OFF and dissolved in dimethylsulfoxide before purification by reverse phase chromatography. The product was isolated as beige solid (54% yield). 1H NMR (d6-DMSO): δH: 8.75 (s, 1H), 8.45 (s, 2H), 7.15 (s, 1H), 6.95 (d, 1H), 6.70 (d, 2H), 5.10 (s, 2H), 3.95 (s, 2H), 3.45 (s, 3H), 1.40 (s, 6H). MALDI-TOF, m/z=398 (M+=398 for C20H20N3O6).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([NH:26][CH2:25][CH2:23][OH:24])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(C)cccc3c21
Reactant: NCCO
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(C)cccc3c21
Temperature: 150 °C

Procedure:
1-(2-methylphenyl)-4-chloro-6-methylpyrrolo [3,2-c]quinoline (306 mg, 1.0 mmol) was dissolved in 10 ml of ethanolamine in a pressure tube and heated at 150° C. for 3 hours. After removal of the reaction solvent under reduced pressure and diluted in 20 ml of methylene chloride, the residue was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 236 mg of desired compound as solid in 72% of yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][OH:23])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([O:23][CH2:22][CH2:21][C:5]2[CH:6]=[C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:33])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCC)c(CCO)c1)OC(C)C
Product: CCOc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(Cl)cc1

Procedure:
Using ethyl 3-[4-ethoxy-3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([CH:29]2[NH:34][C:33](=[O:35])[CH2:32][O:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:34]1[C:33](=[O:35])[CH2:32][O:31][CH2:30][C@H:29]1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Reactant: O=C1COCC(C2CCCCC2)N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)COC[C@H]1C1CCCCC1
Temperature: 110 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
A heavy wall flask was charged with trans-cyclohexane diamine (623 mg, 5.5 mmol, 0.5 equiv), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (4.27 g, 14.2 mmol, 1.3 equiv), K2CO3 (3.02 g, 21.8 mmol, 2.0 equiv), CuI (1.04 g, 5.5 mmol, 0.5 equiv), 5-cyclohexyl-morpholin-3-one (2.0 g, 10.9 mmol, 1.0 equiv) and 1,4-dioxane (10.0 mL). The mixture was flushed with N2 and stirred at 110° C. for 48 hours. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel, EtOAc/heptane 50% to give product 2.8 g (yield 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:24])[CH:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(Br)ccc2n1
Product: Clc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(Br)ccc2n1
Yield: 60 %

Procedure:
Prepared using general procedure 3; 6-Bromo-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (1.94 g, 5.05 mmol) and 30 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 1.209 g of material (3.00 mmol, 60%). 1H NMR (300 MHz, DMSO): 9.69(s, 1H), 8.71(s, 1H), 7.91(d, 1H, J=8.88 Hz), 7.78(d, 1H, J=8.88 Hz), 7.69(d, 1H, J=8.88 Hz), 7.68(s, 1H), 7.44(dd, 1H, J=8.68, 2.22 Hz), 6.91(m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[C:6](SC)[S:7][CH3:8])[CH3:2].[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([S:7][CH3:8])=[N:21][N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]=1[NH2:12])=[O:13])[CH3:2]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Solvent: CCO
Product: CCOC(=O)c1c(SC)nn(-c2ccccc2)c1N

Procedure:
To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester (5.00 g, 23.0 mmol) in dry ethanol (100 mL) is added phenylhydrazine (2.28 mL, 23.0 mmol). The reaction mixture is heated to reflux for 2 h before removal of the solvent. The resulting solid is recrystallized from EtOH (20 mL) to provide 5-amino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid product; HPLC-MS calculated for C13H15N3O2S (M+H+) 278.1, found 278.1.
Reaction SMILES: CC1(C)[O:7][C:6]2[C:8]([O:12][CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9][CH:10]=[CH:11][C:5]=2[C:4](=[O:26])C1.[OH-].[K+].[OH:30]S([O-])(=O)=O.[K+]>CS(C)=O>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[CH2:13][O:12][C:8]1[C:6]([OH:7])=[C:5]([CH:11]=[CH:10][CH:9]=1)[C:4]([OH:30])=[O:26])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=S(=O)([O-])O
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cccc2c1OC(C)(C)CC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1COc1cccc(C(=O)O)c1O
Temperature: 60 °C
Yield: 93 %

Procedure:
tert-butyl-2-(2, 2-dimethyl-4-oxo-4,4-benzo[1,3]dioxin-8-yloxymethyl)pyrrolidine-1-carboxylate 47 (1.65 g, 4.54 mmol) was dissolved in DMSO (9.5 mL) and then 49% aqueous KOH (1.5 mL) was added to the solution to form a basic reaction mixture. This basic reaction mixture was heated at 60° C. for 40 min. After cooling to room temperature and addition of 0.5 M aqueous KHSO4 (100 mL) gave an acidic suspension. The suspension was extracted with ether (4×250 mL) and the combined extracts were washed with brine (2×50 mL) and dried (Na2SO4). Evaporation of the ether gave 1.26 g (93%) of 3-(1-tert-butoxycarbonyl pyrrolidin-2-ylmethoxy)-2-hydroxy benzoic acid 48 as a brown solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[Br:12][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: Nc1ncccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)cc1C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 3-trifluoromethyl-pyridin-2-ylamine (Fluorochem Ltd., Derbyshire, United Kingdom, 5.37 g, 32.8 mmol) in 100 ml of dry CH3CN under argon were added N-bromosuccinimide (6.45 g, 36.2 mmol) in 4 equal portions over a period of 1 h at 0-5° C. The cooling bath was removed and stirring was continued for 3 h. The solvent was evaporated under vacuum, then the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated to give the title compound as a orange oil. (M+H=239; 241).
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH2:28][C:29]1[C:32](=[O:33])[C:31](=[O:34])[C:30]=1OCC>CO>[ClH:1].[NH2:28][C:29]1[C:32](=[O:33])[C:31](=[O:34])[C:30]=1[NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reactant: CCOc1c(N)c(=O)c1=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(N)=Nc1nc(-c2cccc(CNc3c(N)c(=O)c3=O)n2)cs1
Yield: 73.5 %

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g), triethylamine (1.8 ml) and 1-amino-2-ethoxy-1-cyclobutene-3,4-dione (0.65 g) in methanol (30 ml) was heated under reflux for 7 hours. The solvent was removed by concentration in vacuo. To the residue was added a mixture of water and ethyl acetate, and the mixture was adjusted to pH 1.0 with 6N-hydrochloric acid. The isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from an aqueous N,N-dimethylformamide to give 4-[6-(1-amino-3,4-dioxo-1-cyclobuten-2-yl)aminomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole hydrochloride (1.17 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[S:28]([O:1][CH:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1)([CH3:27])(=[O:30])=[O:29]
Reactant: OC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.2 g of 2-hydroxy-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a mixture of 16.8 ml of pyridine and methane sulphonylchloride, after which the mixture is stirred for 2 hours at 0° C and then another 2 hours at room temperature. After that the mixture is poured out into water and then extracted with ether. The ether layers are dried and evaporated to dryness.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[C:17]([OH:23])=[C:16]([CH2:24][CH2:25][CH3:26])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:27])[CH:3]=1.Br[CH:29]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:30]([CH:29]([CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[O:23][C:17]1[C:16]([CH2:24][CH2:25][CH3:26])=[CH:15][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:27])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:19][C:18]=1[CH2:20][CH2:21][CH3:22])([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(CCc1ccccc1)C(=O)OCC
Temperature: 60 °C
Yield: 63.6 %

Procedure:
To a stirred solution of 0.150 g (0.41 mmol) of 5,7-dimethyl-2-ethyl -3-[4-hydroxy-3,5-dipropylphenyl]methyl-3H-imidazol[4,5-β]pyridine (Step G of Example 13) and 0.127 g (0.49 mmol) of ethyl α-bromo-4-phenylbutanoate in 2 mL anhydrous DMF was added 0.290 g (0.82 mmol) cesium carbonate and the reaction mixture was stirred and heated at 60° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with methylene chloride, filtered, and evaporated in vacuo. The residue was then purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 0.145 g (64%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=2[F:17].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:41])[C@@H:38](Cl)[CH3:39]>O>[CH3:35][O:36][C:37](=[O:41])[C@H:38]([O:16][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]2[C:13]=1[C:14]([CH3:15])=[C:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=1[Cl:1])[C:6](=[O:18])[NH:7]2)[CH3:39]
Reactant: Cc1c(Cc2ccc(Cl)cc2Cl)c(=O)[nH]c2c(F)ccc(O)c12
Reactant: COC(=O)[C@H](C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](C)Oc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.30 g), N,N-dimethylformamide (4.0 mL), potassium carbonate (0.13 g) and (S)-2-chloropropionic acid methyl ester (0.11 g) was stirred at 45° C. for 3 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 6:4 by volume) to afford title compound as a pale peach solid, 0.17 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:29](=[O:31])=[O:30]>CCOCC>[C:1]([O:5][C:6]([NH:7][C:8]1[C:13]([C:29]([OH:31])=[O:30])=[CH:12][C:11]([Cl:14])=[N:10][CH:9]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Temperature: 0 °C
Yield: 35 %

Procedure:
A stirred solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (3.28 g, 14.3 mmol) and TMEDA (6.7 mL, 44.4 mmol) in Et2O (100 mL) at −78° C. was treated with n-BuLi (4.3 mL, 10 M, 43 mmol). After stirring the mixture at −78° C. for 2 hours CO2 was bubbled into the reaction and the solution was warmed to 0° C. Water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified and extracted with Et2O. The Et2O layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The residual solid was triturated with Hexane/Et2O to give 25A (1.38 g, 35%) HPLC Rt=2.98 min.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[CH2:13]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([CH:2]([CH3:12])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)=[O:4])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N1CCC(Cc2ccccc2)CC1
Reaction time: 3 h

Procedure:
A solution of 26.48 g (0.107 mol) of 2-bromo-3'-chloropropiophenone in 70 ml of acetonitrile is placed in a 500 ml three-necked round-bottomed flask equipped with a pressure equalizing funnel, a calcium chloride drying tube and a magnetic stirrer, and 37.5 g (0.214 mol) of 4-benzylpiperidine are then added at ambient temperature over a period of about 20 minutes, without stirring. The mixture warms up; it is allowed to return to ambient temperature and, after 3 hours, 4-benzylpiperidine hydrobromide is crystallised by cooling the mixture on ice and triturating it. The crystals are filtered off and washed with acetonitrile (2×10 ml) and the filtrate is diluted with 200 ml of diethyl ether. Further 4-benzylpiperidine hydrobromide precipitates and is filtered off. 100 ml of 3N hydrochloric acid are added to the filtrate and the mixture is stirred. Three phases form. The two lower phases are collected, the upper phase is taken up in a few ml of water and the aqueous phase obtained is combined with the two phases previously separated off. Precipitation occurs. The mixture is cooled on ice, stirred and filtered on a glass frit and the first crop of precipitate is dried in a vacuum oven. The filtrate deposits a second precipitate, which is shown by thin layer chromatography to be the same product as the first crop. A total of 34.06 g of crystals of the hydrochloride, melting at between 189° and 198° C., is thus recovered, which is used as such in the subsequent reduction.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Reactant: OCCCCCCCl
Product: CCCCCCOc1ccc(-c2ncc(OCCCCCCO)cn2)cc1

Procedure:
0.013 mol of 2-(4-hexyloxyphenyl)-5-hydroxypyrimidine and 0.020 mol of 6-chlorohexan-1-ol are employed.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:7][O:8][CH2:9][CH2:10][NH2:11].CCO>CO>[CH3:7][O:8][CH2:9][CH2:10][NH:11][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:6]
Reactant: COCCN
Reactant: C=CC(=O)NC
Solvent: CO
Solvent: CCO
Product: CNC(=O)CCNCCOC
Temperature: 140 °C
Yield: 64.6 %

Procedure:
N-Methylacrylamide (ABCR; 500 mg, 5.87 mmol), 2-Methoxyethylamine (Aldrich; 441 mg, 5.87 mmol), and EtOH (2 mL) were combined and heated in a microwave at 140° C. for 40 minutes. The reaction mixture was cooled and added to a 5 g SCX-2 column pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) then the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated in vacuo to give the title compound as a clear oil (608 mg, 65%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.[NH2:18][C:19](=[O:35])[CH:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>>[NH2:18][C:19](=[O:35])[CH:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)[N:5]=[C:4]3[CH2:15][CH2:16][CH2:17][C:3]=23)=[CH:30][CH:29]=1)[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22]
Reactant: CC(C)OC(=O)C(Cc1ccc(N)cc1)C(N)=O
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Product: CC(C)OC(=O)C(Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(N)=O
Yield: 47.3 %

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.060 g, 0.23 mmol) was reacted with isopropyl 3-amino-2-(4-aminobenzyl)-3-oxopropanoate (0.057 g, 0.23 mmol) to afford the title compound (0.052 g, 47%) as a light yellow solid. MW=477.98. APCI MS m/z 478 [M+H]+.