Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:23]>ClCCl>[O:23]1[CH2:3][CH:2]1[CH2:1][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])=[CH:9][CH:10]=1
Reactant: C=CCOc1ccc(N2C(=O)C=CC2=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1C=CC(=O)N1c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-(4-Allyloxyphenyl)maleimide (175 g, 76.4 mole) and 3-chloroperoxybenzoic acid (262 g, 70-75%, Across) were dissolved in 2.0 l of dichloromethane. After stirring for 72 h at room temperature, the reaction mixture was concentrated under reduced pressure to a slurry. Ether (2.0 l) was added to the slurry and stirred for 0.5 h at room temperature. The product was filtered off, washed with ether, and dried in an oven.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.CO[CH:12]=[C:13]=[CH2:14].[Cl-].[NH4+]>CCOCC.OC(C1C=CC(NS(C)(=O)=O)=CC=1)CN1C=CN=C1>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:14][C:13]#[CH:12])=[CH:4][CH:5]=1
Reactant: Clc1ccc(Br)cc1
Reactant: C=C=COC
Agent: CS(=O)(=O)Nc1ccc(C(O)Cn2ccnc2)cc1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: C#CCc1ccc(Cl)cc1

Procedure:
In a flask containing 59 g (2.43 mole) magnesium turnings in 500 ml anhydrous ether under an atmosphere of nitrogen, and slowly a solution of 465 g (2.43 mole) of 4-bromochlorobenzene in 1 liter 4 anhydrous ether. With caution, once the Grignard has started maintain slow reflux until all 4-bromochlorobenzene has been added. Stir an additional hour and then add this Grignard (maintain slow reflux) to a suspension of 170 g (2.43 mole) methoxyallene and 69 g of cuprous bromide in 300 ml anhydrous ether under N2. When addition is complete, stir another 10 minutes and then add saturated ammonium chloride. Decant off the ether solution wash the solid residue with ether (3×50 ml). Combine the ether extracts and wash with 1N HCl, saturated aqueous sodium bicarbonate, water and dry over magnesium sulfate. Evaporate off the ether and distill the residue in vacuo to obtain the title compound (99-105 mmHg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]([NH:18]C(=O)OC(C)(C)C)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=1)[NH2:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl (pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)carbamate (1.83 g, 5.19 mmol) in DCM (12 mL) was added TFA (3.86 mL, 51.9 mmol). The resulting mixture was then stirred at rt for 1 h. The mixture was then concentrated and dried to give the title compound as a yellow oil which was used without further purification in the amide coupling step.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(Cl)(Cl)Cl.CO>C(Cl)Cl>[C:16]([N:5]1[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
4-Hydroxypiperidine (10.8 g, 107 mmol) and Et3N (17 mL, 123 mmol) in 80 mL of CH2Cl2 was cooled in an ice bath whereupon benzyl chloroformate (16.3 mL, 114 mmol) was added. After stirring 1.5 h at R.T. the mixture was subjected to standard work-up conditions to give 13.9 g (55%) of N-Cbz-piperidine after chromatography (CHCl3 /MeOH; 10:1). [1H]-NMR(CDCl3) consistent with structure.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[CH3:18][C:19]([NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>O1CCOCC1.O.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:36][C:19]([NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: CC(C)(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 16.3 %

Procedure:
A mixture of 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) (4.28 g, 13.9 mmol), benzyl (2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)carbamate (CB7) (6.12 g, 15.0 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.390 g, 1.40 mmol), palladium(II) acetate (0.150 g, 0.680 mmol), and cesium fluoride (4.34 g, 28.6 mmol) in dioxane/water (4:1, 90 mL) was heated at 70° C. overnight. The reaction was cooled and diluted with brine and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a clear oil (1.16 g, 15%): 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.44-7.32 (m, 7H), 7.19 (d, J=8.2 Hz, 2H), 5.12 (s, 2H), 4.56 (s, 1H), 3.05 (s, 2H), 1.33 (s, 6H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 511 ([M+H]+).
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][S:8]([C:11]1[N:12]=[C:13]([C:17]2[N:18]([CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[N:19]=[C:20]3[C:25]=2[C:24](=[O:26])[N:23]([CH3:27])[C:22](=[O:28])[N:21]3[CH2:29][CH:30]([CH3:32])[CH3:31])[N:14]([CH3:16])[CH:15]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:44]I>CN(C=O)C>[C:3]([N:7]([CH3:44])[S:8]([C:11]1[N:12]=[C:13]([C:17]2[N:18]([CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=3)[N:19]=[C:20]3[C:25]=2[C:24](=[O:26])[N:23]([CH3:27])[C:22](=[O:28])[N:21]3[CH2:29][CH:30]([CH3:32])[CH3:31])[N:14]([CH3:16])[CH:15]=1)(=[O:9])=[O:10])([CH3:5])([CH3:6])[CH3:4]
Reactant: CI
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(S(=O)(=O)NC(C)(C)C)cn3C)n(Cc3cccc4ccccc34)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nc(S(=O)(=O)N(C)C(C)(C)C)cn3C)n(Cc3cccc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaH (10 mg, 0.25 mmol) was added to a solution of the compound of Example 164 (84 mg, 0.14 mmol) and CH3I (100 μL) in 2 mL DMF. After warming to room temperature and stirring for 16 h, solvent was removed and the residue was partitioned between water and EtOAc. The EtOAc was separated and washed with brine. Drying and removal of solvent gave an oil that was purified by preparative reverse phase HPLC (45%-75% gradient of CH3CN-water with 0.1% TFA).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[OH-].[NH4+:12]>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][NH2:12])[CH:6]=1
Reactant: [NH4+]
Reactant: ClCCOc1cccnc1
Agent: [OH-]
Solvent: CO
Product: NCCOc1cccnc1
Temperature: 125 °C
Yield: 36.2 %

Procedure:
The 2-chloro-1-(3-pyridyloxy)ethane (1.23 g, 7.80 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 125° C. (oil bath temperature) for 42 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was diluted with saturated NaCl solution (15 mL) and basified to pH 12 with 10% NaOH solution (5 mL). The mixture was extracted with chloroform (4×50 mL). The combined light-yellow chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.390 g (36.2%) of a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:28]4[CH2:27][CH2:26][O:25][CH2:30][CH2:29]4)=[CH:38][CH:37]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Product: O=c1c2cnc(Nc3ccc(CN4CCOCC4)cc3)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 1E (0.060 g, 0.167 mmol) and 4-(morpholinomethyl)aniline (0.051 g, 0.267 mmol) was heated in a capped vial at 90° C. for 1 hour. The crude material was purified by HPLC (see protocol in Example 1F). The TFA salt was treated with saturated aqueous NaHCO3 and extracted into ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with methanol/ethyl acetate (5:95 to 10:90) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 2.56-2.39 (m, 4H), 3.54 (s, 2H), 3.73-3.67 (m, 4H), 7.05 (d, J=1.9 Hz, 1H), 7.43-7.36 (m, 2H), 7.61-7.52 (m, 3H), 7.70-7.67 (m, 1H), 7.80-7.73 (m, 2H), 7.86 (s, 1H), 9.15 (s, 1H). MS (ESI+) m/z 488.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>O.C(O)(=O)C.[Fe]>[NH2:22][C:18]1[CH:17]=[C:16]([CH2:15][NH:14][C:12]([C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Br:1])[CH:11]=2)=[O:13])[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc1Br
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)NCc2cccc(N)c2)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
Iron powder (135 mg, 2.4 mmol) was added to a suspension of 2-bromo-4-[[[(3-nitrophenyl)methyl]amino]carbonyl]benzoic acid, methyl ester (Example 16; 125 mg, 3.18 mmol) in water (530 μL) and acetic acid (111 μL) at 25° C. The reaction was heated to reflux for 30 min and then cooled to 25° C. The suspension was diluted with water (20 mL), stirred for 15 min, and filtered through Celite. The filter cake was washed well with water (100 mL). The filtrate was extracted with ethyl acetate (50 mL) followed by ethyl acetate containing 2% methanol (50 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated. The residue was diluted with 10% methanol in dichloromethane and stirred with Celite. After 1 h, the suspension was filtered and washed well with 10% methanol in dichloromethane. Concentration of the filtrate afforded 4-[[[(3-aminophenyl)methyl]amino]carbonyl]-2-bromobenzoic acid, methyl ester (100 mg, 87%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[S:10][CH2:11][CH2:12][C:13]([OH:15])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]2[S:10][CH2:11][CH2:12][C:13](=[O:15])[C:4]=2[CH:5]=1
Reactant: COc1ccc(SCCC(=O)O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c2c(c1)C(=O)CCS2

Procedure:
A solution of 21.1 g 3-[(2-methyl-4-methoxyphenyl)thio]propanoic acid and 160 g polyphosphoric ester in 150 ml CHCl3 is refluxed for 45 min. To the cooled reaction mixture is added 200 ml 0.5 N NaOH. The organic phase is separated and the aqueous phase is extracted with 100 ml CHCl3. The combined organic extracts are dried over Na2SO4, filtered, concentrated under reduced pressure and flash chromatrographed with ethyl acetate/hexane (8:92) to yield 6-methoxy-8-methyl-2H-[1]benzothiopyran-4-one.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O[CH:27](N(C)C)[N:28]([CH3:30])[CH3:29])(C)(C)C>>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:13]2[CH2:18][CH2:17][CH2:16][C:15](=[CH:27][N:28]([CH3:30])[CH3:29])[C:14]2=[O:19])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCC1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C)C=C1CCCC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O

Procedure:
2-(3,5-Bis-trifluoromethyl-phenyl)-cyclohexanone (155, 0.5 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (184 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 366.1 [(M+H)+].
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)([O:10][CH3:11])=[O:9].S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O.O>[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:33])=[CH:30][CH:29]=1)([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1

Procedure:
A solution of 19.0 g. of methanesulfonamide in 150 ml. of dry dimethylacetamide is added dropwise during 15 minutes to a stirred and cooled (water bath) suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide. The mixture is then stirred and heated at 60°-80° C. for 2 hours. In the meantime, a mixture of 36.2 g. of p-(15-carbomethoxypentadecylamino)benzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated to an oil which is coevaporated twice with added dioxane to remove excess thionyl chloride. To the resulting oily residue p-(15-carbomethoxypentadecylamino)benzoyl chloride hydrochloride is added, in one portion, the previously prepared mixture of sodium methanesulfonamide in dimethylacetamide. The mixture becomes very hot and is cooled briefly in a water bath and then is stirred at room temperature for 30 minutes. The mixture is filtered through a bed of diatomaceous earth and the filtrate is poured into 2 l. of water. The resulting suspension is coagulated by the addition of 250 ml. of saturated sodium chloride solution and the mixture is filtered. The product is washed with water, partially air dried and then crystallized from 1.5 l. of ethanol. The product is recrystallized from p-dioxane and dried at 65° C. to yield the title compound as tan crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>>[ClH:21].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Agent: Cl
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccc(Cl)cc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(11.5 mg, 33%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and 4-chlorophenylsulfonyl chloride (22.5 mg, 0.11 mmol). HRMS-FAB+ for C21H18ClF3N2O2S.HCl, calculated MH+ (--HCl): 455.08078; found: 455.08266.
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=O)[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)C(C)C)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[C:46]1([SH:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(#N)C.C(OCC)(=O)C.C1C=CC=CC=1>[C:46]1([S:52][C:3]2[CH2:4][CH:5]3[N:1]([C:7](=[O:8])[CH2:6]3)[C:2]=2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Reactant: Sc1ccccc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)N12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
An ice-cold solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (13 mg, 0.05 mmol) in anhydrous acetonitrile is treated with N,N-diisopropylethylamine (10.4 μl, 0.06 mmol) and diphenyl chlorophosphate (10.9 μl, 0.053 mmol) and the resulting solution is stirred in the cold and under a nitrogen atmosphere for 90 mins. More N,N-diisopropylethylamine (8.7 μl, 0.05 mmol) and thiophenol (5.1 μl, 0.05 mmol) are added and the reaction mixture is stirred in the cold for 2 hours. The resulting mixture is combined with a second similar run, diluted with ethyl acetate to 10 ml volume, washed with water, 1M pH3 phosphate buffer, 5% aqueous sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated under vacuum to an oil (34 mg). This material is purified on a 0.25 mm×20×20 silica gel GF plate using 3:1 toluene-ethyl acetate as developing solvent. The UV visible band at Rf 0.55 is removed and eluted with ethyl acetate. Evaporation of the solvent leaves a residue which is lyophilized from benzene to provide benzyl 3-phenylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (17 mg) as an amorphous, white powder.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([CH2:22][CH:23]=[CH2:24])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:22]([N:17]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:20][N:19]([CH2:2][C:3]2[N:4]=[CH:5][NH:6][C:7]=2[CH3:8])[C:18]1=[O:21])[CH:23]=[CH2:24]
Reactant: Cc1[nH]cnc1CO
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(Cc2nc[nH]c2C)c1=O
Temperature: 25 °C

Procedure:
100 mg (0.89 mmol) of 4-hydroxymethyl-5-methyl-1H-imidazole, 252 mg (1.07 mmol) of the compound from Example 12A and 370 mg (2.68 mmol) of potassium carbonate were dissolved in 4.5 ml of DMF and 4.5 ml of water, and the mixture was stirred in a microwave oven at 200° C. for 75 min. After cooling to RT, for work-up, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: first cyclohexane/ethyl acetate 1:1, then dichloromethane/methanol 10:1). This gave 153 mg (52% of theory) of the target compound in a purity of 73%.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]([CH2:19][CH2:20][C:21]#N)[CH3:18])[N:4]=1.[NH3:23]>C(Cl)Cl.[Ni]>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]([CH3:18])[CH2:19][CH:20]([NH2:23])[CH3:21])[N:4]=1
Reactant: N
Reactant: COc1cc2nc(N(C)CCC#N)nc(N)c2cc1OC
Agent: [Ni]
Agent: Cl
Solvent: ClCCl
Product: COc1cc2nc(N(C)CC(C)N)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25 gms, 0.77 moles of N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride, 25 gms of Raney-Nickel and 500 ml of 9.8% methanolic ammonia solution were charged in an autoclave. The reaction mixture was hydrogenated at 70° C. under a pressure of 5 kg/cm2 (70 psi) for 2 hours. The reaction mass was cooled to room temperature, filtered on hyflo bed and washed with 200 ml methanol. The solvent was distilled under reduced pressure. The residue obtained was stirred in 50 ml methylene chloride and concentrated under reduced pressure at 40° C. The residue was dissolved in 200 ml isopropanol and acidified to pH 1-2 with isopropanolic HCl. The N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl propylenediamine hydrochloride obtained was isolated by filtration and dried under suction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Mg].[C:10]([C:12](=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2([CH:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1cccc(I)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C1(c2cccc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-chloro-3-iodobenzene (14.1 g, 59.28 mmol) in diethyl ether (12 ml) was added dropwise to a mixture of magnesium turnings (1.59 g, 65.4 mmol) in diethyl ether (50 ml) at room temperature. When the Grignard reaction was complete, the resulting organomagnesium reagent was added dropwise to a stirred mixture of compound 16a (5.0 g, 17 mmol) and cuprous iodide (800 mg, 4.2 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. The reaction mixture was stirred 1 hour at 0° C. and then quenched with saturated ammonium chloride solution. Ethyl acetate (500 ml) was added and the mixture was washed successively with saturated ammonium chloride, water and brine. The organic layer was dried and concentrated and the resulting crude material was purified by column chromatography on silica gel eluting with 4:1 hexane:ethyl acetate. This afforded tert-butyl 4-(3-chlorophenyl)-4-(1-cyano-2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (16b) as an oil (5.2 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.37-7.26 (m, 4H), 3.99 (br.q, 2H, J=6 Hz), 3.91 (br m, 2H), 3.58 (s, 1H), 2.88 (br.m, 2H), 2.52 (ddd, 2H, J=6, 4, 3 Hz), 2.04 (m, 2H), 1.43 (s, 9H), and 1.06 (t, 3H, J=6 Hz). ES-LCMS m/z 429 (M+Na+).