Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCl.[C:3]([NH2:7])(=[O:6])C=C.[C:8]([Cl:13])(=O)[C:9](Cl)=[O:10].[CH:14]([Cl:17])(Cl)Cl>>[Cl:13][CH:8]([CH2:14][Cl:17])[C:9]([N:7]=[C:3]=[O:6])=[O:10]
Reactant: ClC(Cl)Cl
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CC(N)=O
Agent: ClCl
Product: O=C=NC(=O)C(Cl)CCl
Yield: 72 %

Procedure:
99 g (1.40 moles) of chlorine were passed into a solution of 100 g (1.41 moles) of acrylamide in 1,000 ml of chloroform while stirring at about 0° to 5° C. The mixture was then stirred for a further 3 hours at about 20° C, after which 270 g (2.13 moles) of oxalyl chloride was added dropwise, while continuing the stirring. The solution was then heated to the boil under reflux, until the evolution of gas had ceased. Fractional distillation of the reaction solution gave 172 g (72% theory) of 2,3-dichloro-propionyl isocyanate of boiling point 38 to 41° C/1.0 mm Hg. ##STR76##
Reaction SMILES: [CH2:1]([C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[C:10](=[O:29])[CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([O:26]CC)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[C:10](=[O:29])[CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([OH:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccccc1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1Cc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Dissolve 3-[(2-benzylphenacyl)amino]-2-carbethoxy-4,6-dichloroindole (100 mg, 0.214 mmol) in tetrahydrofuran (7 mL) and water (7 mL). Add lithium hydroxide monohydrate (25.2 mg, 6 mmol) and stir overnight. Stir at 40° C. for 2 hours, dilute with water (10 mL) and ethyl acetate (25 mL). Acidify with 1N hydrochloric acid while stirring. Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ether/hexane) to give the title compound (89 mg, 95%); mp 234°-235° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CCN(CC)CC.CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a DMF (780 mL) suspension of tert-butyl 4-aminopiperidine-1-carboxylate (78.0 g) and 3-methoxybenzoic acid (65.2 g), Et3N (130 mL), HOBt.H2O (71.7 g) and EDC.HCl (82.8 g) were added and the mixture was stirred at room temperature for 12 hours. H2O (1.56 L) was added and the mixture was stirred in a water bath for 1.5 hours. The precipitation was filtrated to obtain tert-butyl 4-[(3-methoxybenzoyl)amino]piperidine-1-carboxylate (126 g, a colorless solid substance). To an EtOAc (900 mL) suspension of the compound obtained in the above process, 4 M HCl/EtOAc solution (900 mL) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and thereafter, CHCl3 (2.00 L) and 2 M aqueous NaOH solution (1.00 L) were added to the residue and the mixture was stirred for 15 minutes. A water layer was separated from an organic layer and thereafter extracted twice with CHCl3 (800 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain 3-methoxy-N-piperidin-4-ylbenzamide (87.8 g, a light yellow solid).
Reaction SMILES: Cl[Mg][CH2:3][CH:4]([CH3:6])[CH3:5].[C:7](#N)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:16]COCC>>[CH3:5][CH:4]([CH3:6])[CH2:3][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:16]
Reactant: N#Cc1ccccc1
Reactant: CCOCC
Reactant: CC(C)C[Mg]Cl
Agent: Cl
Product: C=C(CC(C)C)c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Chloro-(2-methylpropyl)magnesium (150 ml, 0.300 mol, from Aldrich) was added over 20 minutes to a solution of benzonitrile (10.21 ml, 0.100 mol, from Aldrich) in ether (150 ml), stirring under argon at room temperature. The solution was allowed to stir under argon at room temperature for 18 hours. The reaction mixture was then cooled to 0° C. and 1.2N HCl (125 ml) was added. The aqueous layer was extracted with ether (twice), and the organic layers were combined and washed with brine and dried over MgSO4, filtered and concentrated to a yellow oil. The oil was purified by flash chromatography on Merck silica gel in 2% EtOAc in hexane. Fractions containing the product were combined and concentrated to afford the title compound as a yellow oil (13.305 gm, 83%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](C2C=CC=CC=2C(OCC)=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[O-:22][CH2:23][CH3:24].[Na+].[C:26](#[N:28])C.C1(C)C=CC=CC=1>O>[C:26]([CH2:24][C:23]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=1)=[O:22])#[N:28]
Reactant: CC[O-]
Reactant: CC#N
Reactant: C=CCOc1ccc(-c2ccccc2C(=O)OCC)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOc1ccc(C(=O)CC#N)cc1

Procedure:
A mixture of 41.25 g. (200 mmoles) of ethyl 4-[(2-propenyl)oxy]phenylbenzoate, 15.0 g. (220 mmoles of sodium ethoxide and 13 ml. (240 mmoles) of acetonitrile in 85 ml. of dry toluene was mechanically stirred under a nitrogen atmosphere at 108° C. for 24 hours. The reaction mixture was cooled and diluted with 600 ml. of water. After all of the solid had dissolved, the mixture was washed with two 100 ml. portions of ethyl ether. The aqueous phase was then acidified to pH 5-6 with concentrated aqueous hydrochloric acid (required about 15 ml.). The precipitate which formed was collected by suction filtration, washed with water and air dried. This solid was sufficiently pure to carry directly into the next step. If desired, an analytically pure sample could be obtained by crystallization from an ethyl acetate/hexane mixture. 1H NMR (CDCl3, δ) 7.90 [d, 2H, J=9 Hz, phenyl-H(2]), 6.99 (d, 2H, J=9 Hz, phenyl-H(3)), 6.05 (m, 1H, vinyl CH), 5.43 (d, 1H, J=17 Hz, vinyl CH2), 5.35 (d, 1H, J=11 Hz, vinyl CH2), 4.63 (d, 2H, J=5 Hz, OCH2), 4,02 (s, 2H, CH2CN).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+](C1C=CC([O:24][C:25]([N:27]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([F:40])([F:39])[F:38])=[CH:34][CH:35]=3)[C@@H:30]([NH:41][C:42]3[CH:47]=[CH:46][C:45]([N:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)=[CH:44][N:43]=3)[CH2:29][C@H:28]2[CH2:54][CH3:55])=O)=CC=1)([O-])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:7]([CH3:11])([CH3:10])[CH2:8][O:9][C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([C:37]([F:40])([F:38])[F:39])=[CH:34][CH:35]=2)[C@@H:30]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:44][N:43]=2)[CH2:29][C@H:28]1[CH2:54][CH3:55])=[O:24])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Reactant: CC[C@@H]1C[C@H](Nc2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](Nc2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
3-Hydroxy-2,2-dimethyl-propionic acid tert-butyl ester (137 mg) and sodium hydride (60%; 32 mg) were added to a solution of the compound obtained in Example 9 (1) (300 mg) dissolved in tetrahydrofuran (5 ml) and stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aq. solution and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate=7:3→2:3) to give the titled compound (227 mg). MS (m/z):607 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1)=[O:6].[N:17]1(C(N)=O)[CH2:21]CC[CH2:18]1>>[CH3:18][N:17]([CH3:21])[C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1ccc(C(=O)CCCCl)cc1
Reactant: NC(=O)N1CCCC1
Product: CN(C)C(=O)Cc1ccc(C(=O)CCCCl)cc1

Procedure:
[4-(4-Chloro-butyryl)-phenyl]-acetic acid, pyrroldineamide;
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[S:16]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17]1>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:21](/[C:18]2[CH:19]=[CH:20][S:16][CH:17]=2)\[C:22]#[N:23])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: N#CCc1ccsc1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3ccsc3)cc2c1
Yield: 83.7 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (222 mg) was condensed with 3-thiopheneacetonitrile (123 mg) through Method B (production step 3), to thereby yield the target product (yield: 273 mg, 83%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][C:42]([C:54]([F:57])([F:56])[F:55])=[N:41]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:44]4[N:40]([CH3:39])[N:41]=[C:42]([C:54]([F:57])([F:56])[F:55])[CH:43]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: Cn1nc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(C(F)(F)F)nn3C)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 45 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (58 mg, 0.21 mmol), sodium carbonate (22 mg, 0.21 mmols), and bis(triphenylphosphine)palladium(II) dichloride (6 mg, 0.01 mmol) in 1,2-dimethoxyethane (2.0 ml) and water (0.50 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane diethyl ether) to give 38 mg (45% yield, 66% purity) of the title compound.
Reaction SMILES: FC(F)(F)S([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=O)=O.[N:40]1C2C=CC=CC=2N[CH:41]=1>[C-]#N.[Zn+2].[C-]#N.CN(C)C=O>[NH:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25]([C:41]#[N:40])[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: O=C(c1ccc2c(c1)ncn2S(=O)(=O)C(F)(F)F)N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21
Reactant: c1ccc2[nH]cnc2c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound is also obtained as follows: A flask charged with a stir bar, zinc cyanide (0.32 g), trifluoromethanesulfonic acid cis-1-(1-trifluoromethanesulfonyl-1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment at N-1 or N-3 of the benzimidazole, 1.08 g), and N,N-dimethylformamide (5 mL) is sparged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.31 g) is then added and the resulting mixture is heated to 100° C. and stirred at this temperature for 2 h. After cooling to room temperature, 1-hydroxybenzotriazole hydrate (0.45 g) and water (1.5 mL) are added and stirring is continued at room temperature for 3 h. Ethyl acetate, little methanol, and saturated aqueous Na2CO3 solution are added and the mixture is filtered over Celite. The aqueous phase of the filtrate is separated and neutralized with 2 M aqueous citric acid and extracted with ethyl acetate. The organic phases are combined and washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 96:4-90:10) to give the title compound as a solid. Yield: 0.42 g (68% of theory).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>CN(C)C=O>[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2[nH]cc(I)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (140 mg, 3.5 mmol) was added to an ice-cold solution of 2-chloro-7-iodo-5H-pyrrolo[2,3-b]pyrazine (5) (820mg, 2.9mmol) in dimethylformamide (7 ml) under nitrogen. After 30 minutes tosyl chloride (570mg, 3mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with water (15 ml). An off white solid was filtered off and dried in vacuo (950 mg, 75%). MS(ES+) 434.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:10])[CH3:9].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:11]=[N+:12]=[N-:13])(=[O:10])[CH3:9]
Reactant: CC(=O)OCCCCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCCN=[N+]=[N-]
Temperature: 80 °C

Procedure:
To a 500 mL flask was added 5.0 g (32.8 mmol, 1.0 eq) of 5-chloropentylacetate and dissolved in 100 mL of DMF. Next, 2.6 g (40 mmol, 1.2 eq) of sodium azide was added by a glass pipette. A water condenser was placed onto the flask and the reaction heated to 80° C. for 16 hrs with stirring. The reaction was then cooled to room temperature and quenched with 300 mL of water to dissolve the sodium salts. The aqueous solution was extracted with diethyl ether 3×100 mL. The organic layers were combined and dried with MgSO4. The solution was filtered and concentrated under vacuum with no external heat, resulting in 5-azido-1-pentylacetate (4.46), which was carried onto the next step (described in Example 20) without further purification. 1H NMR (500 mHz, DCM): δ: d 4.08 (t, J=6.0 Hz, 2H), 3.33 (t, J=6.2 Hz, 2H), 2.06 (s, 3H), 1.66-1.47 (m, 6H)13C NMR (100 MHz, DCM): δ: 171.37, 64.58, 51.89, 29.02, 28.71, 23.73, 21.27
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.ClS(O)(=O)=O.O>C(Cl)Cl>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.5 h

Procedure:
9α-Hydroxyandrostenedione (10.00 g.) is dissolved in methylene chloride (100 ml.) and cooled to 0°-5°. Chlorosulfonic acid (5 ml.) is added dropwise and the mixture stirred to 0.5 hour at 0°-5°. Water (50 ml.) is added dropwise while the temperature rises to 23°. The mixture is stirred for 5 minutes and the phases separated. The organic phase is washed with an aqueous sodium bicarbonate solution (10%, 25 ml.) and water (50 ml.) containing 10 ml. of a saturated sodium chloride solution. Each of the aqueous washes is back extracted with the same methylene chloride (25 ml.) which is then added to the organic phase. The organic phase is concentrated to approximately 50 ml. Heptane (100 ml.) is added and the mixture concentrated to approximately 50 ml. with the temperature reaching a maximum of about 35°. The mixture is cooled to 0°-5°, Stirred 0.5 hour, the solids are collected by filtration, under vacuum at 55° to give androsta-4,9(11)-diene-3,17-dione, 8.95 g. (89.5% weight yield, 95.0% chemical yield). GC (Example 1) shows 99% androsta-4,9(11)-diene-3,17-dione.
Reaction SMILES: Br[CH2:2][C:3](O)=[O:4].[NH:6]1[C:11]2=[N:12][C:13]([CH2:16][CH2:17][CH2:18][NH2:19])=[CH:14][CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7]1.[CH:20]1([CH2:31][C:32]([O:34]C)=[O:33])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][NH:22][CH2:21]1>>[NH:6]1[C:11]2=[N:12][C:13]([CH2:16][CH2:17][CH2:18][NH:19][C:3]([CH2:2][N:22]3[CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH:20]([CH2:31][C:32]([OH:34])=[O:33])[CH2:21]3)=[O:4])=[CH:14][CH:15]=[C:10]2[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)CBr
Reactant: NCCCc1ccc2c(n1)NCCC2
Reactant: COC(=O)CC1CNCCc2ccccc21
Product: O=C(O)CC1CN(CC(=O)NCCCc2ccc3c(n2)NCCC3)CCc2ccccc21

Procedure:
2-(3-{[N-(3-(1,2,3,4-tetrahydropyridino[2,3-b]pyridin-7-yl)propyl)carbamoyl]methyl}-1H,2H,4H,5H-benzo[d]azepinyl)acetic acid was prepared from bromoacetic acid, 3-(1,2,3,4-tetrahydropyridino[2,3,b]pyridin-7-yl)propylamine and methyl 2-(1H,2H,3H,4H,5H-benzo[d]azepin-1-yl)acetate according to the procedure of Example 27. EI-MS m/z 437 (M+H)+; 1H NMR (400 MHz; CDCl3): 9.61 (1H, br), 8.39 (1H, br), 7.15 (5H, m), 6.31 (1H, d, J=7.25 Hz), 3.64 (2H, m), 3.34 (6H, m), 2.99 (4H, m), 2.71 (4H, m), 1.93 (5H, m), 0.86 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][N:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:36][C:37]1[C:45]2[C:44]([N:46]3[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]3)=[N:43][CH:42]=[N:41][C:40]=2[NH:39][CH:38]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:52][CH:49]2[CH2:48][CH2:47][N:46]([C:44]3[N:43]=[CH:42][NH:41][C:40]4=[N:39][CH:38]=[C:37]([CH3:36])[C:45]=34)[CH2:51][CH2:50]2)=[O:11])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: COc1cc(C(=O)O)ccn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(c3nc[nH]c4ncc(C)c3-4)CC2)ccn1
Reaction time: 0.17 h

Procedure:
A mixture of 2-(methyloxy)-4-pyridinecarboxylic acid (40 mg, 0.261 mmol), EDC (80 mg, 0.418 mmol), HOBt (64.1 mg, 0.418 mmol) and DIPEA (0.114 mL, 0.654 mmol) in DCM (1 mL) was prestirred for 10 minutes before adding 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (70 mg) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between DCM (4 mL) and 2M NaOH (4 mL) and the organic phase dried (phase separator) before it was concentrated in vacuo. The crude material was then purified by MDAP. After concentrating the product-containing fractions in vacuo the mixture was triturated with Et2O and filtered to give the title compound E23 as white solid (16 mg), 1H NMR (d6-DMSO) δ 11.54 (1H, s), 8.59 (1H, d), 8.28 (1H, d), 8.22 (1H, s), 7.36 (1H, d), 7.21 (1H, s), 7.07 (1H, s), 4.14-3.99 (3H, m), 3.89 (3H, s), 3.05 (2H, t), 2.36 (3H, s), 1.94 (2H, d), 1.73 (2H, ddd), MS(ES+) 367 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:41]/[C:42](/[CH3:49])=[CH:43]\[C:44]([O:46][CH2:47][CH3:48])=[O:45]>C(O)(C)C>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:1]2[C:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:42]([CH3:49])[NH:41][C:13]([CH3:15])=[C:12]2[C:11]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)[CH2:22][CH2:21]2)=[O:16])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccc(C)cc2)c2ccc(C)cc2)CC1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: COc1cccc(C=O)c1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccc(C)cc3)c3ccc(C)cc3)CC2)C1c1cccc(OC)c1
Yield: 42.2 %

Procedure:
A mixture of m-anisaldehyde, 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl acetoacetate and ethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl ethyl 4-(3-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a colorless powder, m.p. 75°-78° C. (sintering). Yield 42.2%. IR(Nujol)cm-1 : 3330, 1690. NMR(CDCl3) δ: 1.18(3H,t, J=7,--CH2CH3), 2.25(6H,s, ##STR46## 2.27(3H,s, ##STR47## 2.29(3H,s, ##STR48## 3.68(3H,s,--OCH3), 4.05(2H,q,--CH2CH3), 4.09(1H,s,>N--CH<), 4.14(2H,t,J=6,--COOCH2CH2 --), 4.96(1H, s,C(4) --H), 5.62(1H,broad s, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[N:11][C:10]2[C:5](=[C:6]([O:13][Si](C(C)C)(C(C)C)C(C)C)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F-].[Cs+]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:12]=[N:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:13])[C:5]=2[N:4]=1
Reactant: COc1cnc2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc2cccc(O)c2n1
Reaction time: 18 h
Yield: 113.5 %

Procedure:
A solution of (d) (6.95 g, 21 mmol) in tetrahydrofuran/methanol (280 ml/140 ml) was treated with caesium fluoride (4.73 g, 31.4 mmol) and stirred for 18 hours. The mixture was evaporated and the residue partitioned between diethyl ether and dilute aqueous hydrochloric acid. The aqueous phase was further extracted with diethyl ether and the combined extracts dried and evaporated to give an oil (4.2 g).
Reaction SMILES: [OH:1][C@@H:2]([C:7]1[C:8]([I:18])=[C:9]2[CH:16]=[CH:15][N:14]([CH3:17])[C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4].C(O[C:23]([CH3:26])([CH3:25])[CH3:24])(=O)C.C([O-])([O-])=O.[Na+].[Na+]>>[C:23]([O:1][C@@H:2]([C:7]1[C:8]([I:18])=[C:9]2[CH:16]=[CH:15][N:14]([CH3:17])[C:10]2=[N:11][C:12]=1[CH3:13])[C:3]([O:5][CH3:6])=[O:4])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2c(ccn2C)c1I
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2C)c1I
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of (S)-methyl 2-hydroxy-2-(4-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (9.6 g, 26.7 mmol) in tert-butyl acetate (349 ml, 2583 mmol) was treated dropwise with HClO4 (12.37 ml, 144 mmol). After 1 h, the reaction mixture was poured into 2M Na2CO3 and the layers partitioned. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by ISCO (0-60% EtOAc-hexanes) to afford the title compound as a white foam (8.0 g, 71%). 1H NMR (CHLOROFORM-d) δ 7.13 (d, J=3.3 Hz, 1H), 6.30 (d, J=3.3 Hz, 1H), 5.75 (s, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 2.73 (s, 3H), 1.25 (s, 9H). LC/MS (m/z) ES+=416.9 (M+1)+