Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=2[CH3:21])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(I)CC>>[CH2:15]([C:12]1[N:13]([CH3:14])[C:9]([C:7](=[O:8])[C:6]2[CH:22]=[CH:23][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[C:10]([CH3:21])[CH:11]=1)[CH3:16].[CH2:12]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH3:10]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C#N)cc2)n1C
Solvent: CCCI
Product: CCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc(C#N)cc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 93), using an equivalent quantity of n-propyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[CH:18]=[O:19]>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][C:10]=1[CH:18]=[O:19]
Reactant: O=Cc1cc(B(O)O)ccc1F
Reactant: Brc1ccccn1
Product: O=Cc1cc(-c2ccccn2)ccc1F
Yield: 64 %

Procedure:
General Procedure G using 2-bromopyridin and 4-fluoro-3-formylbenzeneboronic acid gave the title compound as colourless crystals in 64% yield.
Reaction SMILES: C([O:3][C:4]([CH:6]1[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.O.O.[OH-].[Li+]>C1COCC1.CO>[C:23]([O:22][C:20]([N:18]([CH3:19])[CH:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][CH:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:14]=1)=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: CCOC(=O)C1Oc2ccc(CC(C)N(C)C(=O)OC(C)(C)C)cc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)O2)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 21 mg (0.06 mmol) of 1D in 0.5 mL of THF, 0.5 mL of methanol, and 1 mL of water was added 50 mg (1.19 mmol) of lithium hydroxide monohydrate as solid. The reaction mixture was allowed to stir at room temperature for 2.5 hours and concentrated to dryness. To the residue, 10 mL of water was added, and pH of the resulting mixture was adjusted to 2 using phosphoric acid. This was extracted with 3×35 mL of ethyl acetate. Organic layers were combined, dried (anhydrous Na2SO4) and concentrated to dryness to give 10 mg (0.029 mmol, 53%) of 1M (M+Na, 360).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+]([O-])([O-])=O.[C:35]([C:43]1[CH:44]=[C:45]([NH:49][C:50]([NH2:52])=[NH2+:51])[CH:46]=[CH:47][CH:48]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O.O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:52]=[C:50]([NH:49][C:45]5[CH:44]=[C:43]([C:35]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[O:42])[CH:48]=[CH:47][CH:46]=5)[N:51]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=[NH2+])Nc1cccc(C(=O)c2ccccc2)c1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3cccc(C(=O)c4ccccc4)c3)n2)cc1
Temperature: 140 °C
Yield: 62 %

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (100 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added N-(3-benzoylphenyl)guanidinium nitrat (223 mg, 0.74 mmol) and potassium carbonate (102 mg, 0.74 mmol). The suspension was heated at 140° C. (bath temperature) for 18 hours. The mixture was cooled to room temperature, ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) provided [3-({4-[7-(Cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}amino)phenyl](phenyl)methanone (90 mg, 76%) as a yellow solid. 1H NMR (CDCl3): δ 8.10 (d, 1 H), 8.04 (s, 1 H), 7.95 (d, 1 H), 7.81 (d, 2 H), 7.64 (d, 1 H), 7.57 (d, 2 H), 7.53-7.38 (m, 6 H), 7.22 (t, 1 H), 6.98 (d, 2 H), 6.53 (d, 1 H), 6.04-5.99 (m, 2 H); 4.00 (m, 1 H), 3.86 (s, 3 H), 2.12 (m, 2 H), 1.81-1.67 (m, 6 H); MS m/z 581 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]([F:28])([F:27])[CH2:12][O:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=1[O:25][CH3:26]>ClCCl.C(O)(=O)C.O>[CH2:21]([O:20][C:18](=[O:19])[C:17]1[C:23]([N+:6]([O-:9])=[O:7])=[CH:24][C:14]([O:13][CH2:12][C:11]([F:10])([F:27])[F:28])=[C:15]([O:25][CH3:26])[CH:16]=1)[CH3:22]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCC(F)(F)F)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC)c(OCC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 52.9 %

Procedure:
Concentrated sulphuric acid (64 ml) and concentrated nitric acid (10.0 ml, 0.152 mol) were added cautiously, over 1 hour, to a two-phase system containing a stirred solution of ethyl 4-(2,2,2-trifluoroethoxy)-3-methoxybenzoate (35.3 g, 0.127 mol) in dichloromethane (340 ml), acetic acid (173 ml) and water (40 ml) at 5° C. The reaction was allowed to warm to ambient temperature over 60 hours (with vigorous mechanical stirring), the aqueous phase was separated, and the organic phase washed with water (6×250 ml). The organic phase was concentrated to a total volume of ˜200 ml, isohexane (150 ml) was added and the solid which precipitated was collected by suction filtration. Drying of the solid in vacuo yielded ethyl-3-methoxy-4-(2,2,2-trifluoroethoxy)-6-nitrobenzoate (21.7 g, 52% yield) as a yellow solid. The mother liquors contained a mixture of product (28%) and starting material (72%) which was recycled in a latter reaction:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH3:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.Cl[C:14]1C=CC(C(O)=O)=N[CH:19]=1.BrC(CC)C>>[CH:11]([C:4]1[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH2:14][CH3:19])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CCc1cc(Cl)cnc1C(=O)O
Solvent: CCC(C)Br
Product: CCC(C)c1cc(Cl)cnc1C(=O)O

Procedure:
The (RS)-3-sec-butyl-5-chloro-pyridine-2-carboxylic acid was prepared in analogy to the preparation of 5-chloro-3-ethyl-pyridine-2-carboxylic acid by treatment of 5-chloropyridine-2-carboxylic acid with 2-bromo-butane. The (RS)-3-sec-butyl-5-chloro-pyridine-2-carboxylic acid was obtained as a white solid (yield: 6% of theory). Mass (calculated) C10H12ClNO2 [213.66]; (found) [M+H]+=213, [M+2-H]+=215.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[NH:6][C:7]1[C:12]([CH2:13][NH:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1.[O-:22][CH2:23]C.[Na+].C(=O)(OCC)OCC>O1CCOCC1>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:6]2[C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][N:14]([CH2:15][CH3:16])[C:23]2=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: CC[O-]
Reactant: CCNCc1cccnc1Nc1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: C1COCCO1
Product: CCN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Yield: 96.5 %

Procedure:
To a mixture of 2.0 g of 2-(m-trifluoromethylanilino)-3-ethylaminomethylpyridine, 1.0 g of sodium ethoxide and 30 ml of dioxane was added dropwise 2.4 g of diethyl carbonate, and the mixture was heated under reflux for 5 hours. After the reaction was complete, the dioxane was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was recrystallized from ether to yield 2.1 g of 1-(m-trifluoromethylphenyl)-3-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 155° - 157° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Cl.Cl[CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[S:22]1[C:18]([CH2:17][O:3][CH:4]2[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]2)=[CH:19][N:20]=[CH:21]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: ClCc1cncs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCc2cncs2)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 292 mg, 7.30 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (602 mg, 3.47 mmol) in dimethylformamide (8 mL) at room temperature. The reaction mixture was stirred for 30 minutes prior to the addition of a solution of 5-(chloromethyl)thiazole hydrochloride (1.18 g, 6.85 mmol) and diisopropylethylamine (2.42 mL, 13.89 mmol) in dimethylformamide (3 mL) at 0° C. The reaction mixture was then heated up to 80° C. and stirred overnight. Since the LCMS monitoring still indicated the presence of starting material, an additional portion of sodium hydride (60% in oil, 139 mg, 3.47 mmol) was added. The reaction mixture was then stirred again at 80° C. After 17 hours stirring at 80° C., the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a solution of sodium hydroxide (5×50 mL) and with brine (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using petroelum ether/dichloromethane/ethyl acetate (7/0/3 to 2/0/8, then 0:5:5 to 0/2/8) as eluent. A second purification was performed on silica gel, using petroelum dichloromethane/acetone (9/1 to 8/2) as eluent. The title product was obtained as a yellow oil (150 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6](C3CCNCC3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.BrCCCN1C2C=CC=CC=2N=N1>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: BrCCCn1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccc(Cl)cc2[nH]1
Reaction time: 8 h

Procedure:
A mixture of 5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 3.7 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed with water-separator. Then there are added 4.8 parts of 1-(3-bromopropyl)-1H-benzotriazole and stirring is continued overnight at reflux temperature. The reaction mixture is cooled, water is added and the undissolved product is filtered off and set aside. The organic phase is separated from the filtrate, dried, filtered and evaporated. The residue is combined with the undissolved product (see above) and purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 2 parts (25%) of 1-{1-[3-H-benzotriazol-1-yl)propyl]-4-piperidinyl}-5-chloro-1,3-dihydro-2H-benzimidazol-2-one; mp. 203.4° C.
Reaction SMILES: Br[C:2]1[N:6]=[C:5](/[C:7](/[CH3:20])=[CH:8]/[C:9]2[N:19]=[C:12]3[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[N:4]([CH3:21])[N:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:17][C:16]1[N:11]2[N:10]=[C:9](/[CH:8]=[C:7](/[C:5]3[N:4]([CH3:21])[N:3]=[C:2]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[N:6]=3)\[CH3:20])[N:19]=[C:12]2[C:13]([CH3:18])=[N:14][CH:15]=1
Reactant: C1CCNC1
Reactant: C/C(=C\c1nc2c(C)ncc(C)n2n1)c1nc(Br)nn1C
Product: C/C(=C\c1nc2c(C)ncc(C)n2n1)c1nc(N2CCCC2)nn1C
Yield: 25 %

Procedure:
Was prepared in the same manner as described in Example 87a) using (E)-2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)prop-1-enyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (448 mg, 1.29 mmol, Eq: 1.00) instead of 2-[(E)-2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine and pyrrolidine (183 mg, 213 μl, 2.57 mmol, Eq: 2) instead of pyrrolidin-2-one affording 5,8-dimethyl-2-[(E)-2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-propenyl]-[1,2,4]triazolo[1,5-a]pyrazine (109 mg, 41.1%) as a white solid. MS: m/z=339.5 (M+H+)
Reaction SMILES: C(O[C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:5])C.[H-].[Na+].[C:13](#[N:15])[CH3:14].CO>C1(C)C=CC=CC=1>[O:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]([CH2:14][C:13]#[N:15])=[O:5]
Reactant: CCOC(=O)c1ccco1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCC(=O)c1ccco1
Yield: 75.9 %

Procedure:
63.05 grams (0.5 mole) of furan-2-carboxylic acid ethyl ester and 30.0 grams (1 mole) of sodium hydride (80 weight % suspension in white oil) were reacted with 41 grams (1 mole) of acetonitrile in 500 ml of toluene with the addition of 1 ml of methanol at 90° C. After 3 hours reaction time the toluene was distilled off, the residue stirred with 500 ml of water, acidified with hydrochloric acid to pH 1.5 and the precipitated product filtered off with suction and recrystallized from methanol. There were obtained 51.3 grams (76% of theory) of 2-furanoylacetonitrile having a melting point of 74°-75° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:25])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].O.[OH-].[Li+]>O1CCCC1.O.CO>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C:5]([CH3:25])([C:3]([OH:4])=[O:2])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (1.62 g, 4.52 mmol) in tetrahydrofuran/water/methanol (50 mL, 5:1:1) at 0° C. was added lithium hydroxide hydrate (2.2 g, 52.3 mmol). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The reaction mixture was heated at 40° C. for 19 h then cooled to room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and water and the mixture was acidified to pH 5 with hydrochloric acid (1 M). The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residue was dissolved in toluene and the solvent was evaporated to give 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester as a yellow oil (1.47 g, 95%). LCMS (m/z) 343.1 [M−H], Tr=2.36 min. To a solution of 3-methyl-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester (1.37 g, 4.0 mmol) in dichloromethane (30 mL) at 0° C. was added (R)-1-(7-bromo-quinolin-2-yl)-ethylamine hydrochloride (1.30 g, 4.5 mmol) and N,N-diisopropylethylamine (2.8 mL, 16.0 mmol) followed by (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (1.81 g, 4.76 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 20:1 to 0:1 to afford the title compound (929 mg, 40%) as a yellow foam and as a mixture of diastereoisomers. LCMS (m/z) 577.3, 579.2 [M+H], Tr=3.72 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with 1-methylpiperazine to give (2S)-1-(tert-butoxycarbonyl)-2-(4-methylpiperazin-1-ylcarbonyl)pyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.7–2.05 (m, 4H), 2.1–2.25 (m, 1H), 2.32 (s, 3H), 2.35–2.5 (m, 4H), 2.6–2.7 (m, 1H), 2.8–2.9 (m, 1H), 3.3–3.7 (m, 8H), 4.15 (br s, 1H); Mass Spectrum: M+H+ 242.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:17][O:15][C:14]([C:12]1[S:13][C:9]([CH2:8][CH2:7][CH2:6][CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=C(O)c1ccc(CCCC2OCCO2)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(CCCC2OCCO2)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.4 %

Procedure:
To a solution of 5-(3-[1,3-dioxolan-2-yl]propyl)-2-thiophene carboxylic acid (58.0 g, 239 mmol) in 300 mL of dimethylformamide was added potassium carbonate (41.4 g, 299 mmol) followed by methyl iodide (51.0 g, 359 mmol). The slurry was stirred at ambient temperature for 17 hours and then poured into 600 mL of water. The resulting suspension was extracted twice with 500 mL of t-butylmethylether and the combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated by rotory evaporation to afford 57.84 g (94.3%) of the title compound which was of sufficient purity for use in Preparation 3. IR (CHCl3, cm−1) 3021, 1707, 1541, 1463, 1296, 1101. 1H NMR (300 MHz, CDCl3) d 1.75 (m, 4H), 2.84 (t, J=7.4 Hz, 2H), 3.81 (s, 3H), 3.82 (m, 2H), 3.92 (m, 2H), 4.84 (t, J=4.3 Hz, 1H), 6.76 (d, J=3.9 Hz, 1H), 7.58 (d, J=3.7 Hz, 1H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C@@H:10]([NH:12][CH3:13])[C@H:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:21]([Cl:29])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[ClH:29].[CH:1]1([N:7]2[CH2:8][C@@H:9]([OH:14])[C@H:10]([N:12]([CH3:13])[C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN[C@@H]1CN(C2CCCCC2)C[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1)[C@@H]1CN(C2CCCCC2)C[C@H]1O
Product: Cl

Procedure:
A solution of trans-1-cyclohexyl-4-methylamino-3-pyrrolidinol (19.8 g) in 200 ml of methylene chloride was cooled to 5° C. and 20 g of powdered, anhydrous potassium carbonate was added. The mixture was stirred and cooled while 14.1 g of benzoyl chloride in 100 ml of methylene chloride was added dropwise. The mixture was allowed to come to room temperature and stirred for 24 hr., then heated at reflux for 5 hrs. The mixture was cooled and extracted with water. The methylene chloride was evaporated and the residue was converted to the hydrochloride and recrystallized twice from isopropyl alcohol, m.p. 184°-186.5° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:18](=[O:21])[NH:19][N:20]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1C)([CH3:4])([CH3:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][NH2:31])[CH:24]=1.[CH2:32]1COCC1>>[C:1]([C:5]1[N:6]=[C:7]([NH:31][CH2:30][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:8]2[N:9]([C:18](=[O:21])[NH:19][N:20]=2)[C:10]=1[C:11]1[CH:16]=[C:15]([CH3:32])[CH:14]=[CH:13][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccccc1-c1c(C(C)(C)C)nc(Cl)c2n[nH]c(=O)n12
Reactant: NCCc1cccnc1
Reactant: C1CCOC1
Product: Cc1cccc(-c2c(C(C)(C)C)nc(NCCc3cccnc3)c3n[nH]c(=O)n23)c1

Procedure:
A solution of 31 mg of the product of Step A and 120 mg of 2-pyridin-3-yl-ethylamine in THF (3.0 mL) was heated at reflux for 16 h. The solvent was removed and the residue was purified by silica gel chromatography to afford the title compound as a light yellow solid. MS (M+H+)=403.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18](Cl)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:22]#[N:23])[CH:3]=1.[F:24][C:25]1[C:30]([OH:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([O:31][C:30]4[C:29]([F:32])=[C:28]([F:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=4[F:24])(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:22]#[N:23])[CH:3]=1
Reactant: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Cl)ccc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (480 mg, 1.30 mmol) in DCM (5 mL) was added pentafluorophenol (240 mg, 1.30 mmol) at 0° C. Triethylamine (0.27 mL, 1.95 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with DCM (3 mL) and concentrated under reduced pressure. The crude mass was purified by combi flash column chromatography (12 g column; elution: 7% ethyl acetate in hexane) to provide perfluorophenyl 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (370 mg, 54.9%) as clear liquid. 1H NMR (400 MHz, DMSO) δ 8.22 (d, J=2.5 Hz, 1H), 7.96 (dd, J=8.7, 2.5 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.31 (dd, J=8.7, 2.3 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 4.41 (s, 2H), 3.86 (s, 2H); LCMS (ESI) m/z; 516.02 (M+H).