Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1nc(CCCOc1ccccc1)n2CCCCNC(=O)N1CCOCC1
Yield: 31.1 %

Procedure:
Using the general method of Example 143 except that pyridine was used in place of chloroform, 1-(4-aminobutyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.25 g, 3.2 mmol) was reacted with 4-morpholinecarbonyl chloride (0.41 mL, 3.5 mmol) to provide 0.50 g of N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}morpholine-4-carboxamide as a light brown solid, m.p. 71.5-72.1° C. Analysis: Calculated for C28H34N6O3.0.5 H2O: % C, 65.73; % H, 6.90; % N, 16.43. Found: % C, 65.43; % H, 6.90; % N, 16.29.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][S:9](=[O:12])(=[O:11])[O:10][C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][S:9](=[O:12])(=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OS(=O)(=O)N2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)OS(=O)(=O)N2

Procedure:
A solution of 6-nitro-3H-benzo[1,2,3]oxathiazole 2,2-dioxide (example 5) (8.1 g, 37 mmol) in methanol (250 ml) is hydrogenated at atmospheric pressure in the presence of Pd—C. The catalyst is then filtered off, the clear solution is treated with methanolic HCl (1 N) and the solvent is distilled off under reduced pressure. The residue is dissolved in ethanol and the product crystallizes after addition of diethyl ether.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]([C:35]5[CH:39]=[N:38][S:37][N:36]=5)C(OC(C)(C)C)=O)[O:23][C:22]4=[O:40])=[CH:17][C:16]=3[F:41])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.N.C(OCC)C>FC(F)(F)C(O)=O.O>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:35]4[CH:39]=[N:38][S:37][N:36]=4)[O:23][C:22]3=[O:40])=[CH:17][C:16]=2[F:41])=[CH:11][CH2:10]1)=[O:8]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CN(c2ccc(C3=CCN(C(=O)[C@@H]4COC(C)(C)O4)CC3)c(F)c2)C(=O)O1)c1cnsn1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: O=C([C@@H](O)CO)N1CC=C(c2ccc(N3C[C@H](CNc4cnsn4)OC3=O)cc2F)CC1
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
A solution of 3-(4(1-(2,2-dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)-5(R)-(N-(t-butoxycarbonyl)-1,2,5-thiadiazol-3-ylamino-methyl)oxazolidin-2-one (580 mg, 0.96 mM) in trifluoroacetic acid (2 ml) was warmed at 60° for 2 minutes and then kept at ambient temperature for 10 minutes. A solution of trifluoroacetic acid in water (10 ml, 1:1) was added and the mixture kept for 30 minutes. More trifluoroacetic acid (2 ml) was added and after a further 90 minutes, excess aqueous ammonia was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water, sodium bicarbonate solution and brine and dried (sodium sulfate). Solvent was evaporated and the residue purified on a silica Mega Bond Elut® column, eluting with dichloromethane and then 4% methanol in dichloromethane to give an oil which solidified on trituration with diethyl ether to give the title product (203 mg, 46%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:16]2([OH:19])[CH2:15][CH2:14][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:18][CH2:17]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(C2(O)CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared as a white solid from 4-bromotoluene (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][CH:35]([F:46])[O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[F:34][CH:35]([F:46])[O:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:42])=[CH:44][CH:45]=1
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(OC(F)F)cc4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 4-difluoromethoxy benzoic acid (0.45 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL) and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford 4-difluoromethoxy-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide as a yellow solid (0.63 g, 64%): mp, 155-157° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.2 min. (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.50-2.65 (m, 2H), 2.85-2.92 (m, 1H), 4.95 (d, J=5.8 Hz, 2H), 5.16-5.21 (dd, J=5, 12 Hz, 1H), 7.28-7.30 (m, 2H), 7.36 (t, J=73.5 Hz, 1H), 7.72-7.86 (m, 3H), 7.98-8.02 (m, 2H), 9.18 (t, J=5.8 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.34, 48.86, 112.61, 116.03, 117.97, 119.45, 121.87, 127.13, 129.45, 130.55, 131.52, 133.05, 134.79, 139.22, 153.30, 165.60, 166.95, 167.52, 169.81, 172.74. Anal Calcd for C22H17F2N3O6: C, 57.77; H, 3.75; N, 9.19; F, 8.31. Found: C, 57.67; H, 3.59; N, 9.01; F, 8.22.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][O:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][O:17][CH2:16][CH2:15][N:14]2[S:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(NC(=O)C2COCCN2)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)C2COCCN2S(=O)(=O)c2ccc(Cl)cc2)no1

Procedure:
To a solution of morpholine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (55 mg; 0.19 mmol) in anhydrous DMF (1 mL) is added 4-chlorobenzenesulfonyl chloride (40.1 mg; 0.19 mmol) and N,N-diisopropylethylamine (0.089 mL; 0.513 mmol). The reaction mixture is left stirring at room temperature for 18 hours in the presence of catalytic amount of 4-dimethylaminopyridine. After this time, the reaction mixture is diluted with ethyl acetate and washed with eater 3 times, then brine, dried over Na2SO4, filtered and concentrated in vacuo. Recrystallization from hot methanol provides the title compound, m/z 428 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>ClCCl.O>[O:9]=[C:5]1[N:4]([CH2:3][CH2:2][O:1][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:8][CH2:7][O:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OCCN1CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCN1CCOC1=O
Reaction time: 3 h
Yield: 40.7 %

Procedure:
To a mixture of 3-(2-hydroxy-ethyl)-oxazolidin-2-one (1.00 g, 7.63 mmol) and Hunigs base (2.92 mL, 16.8 mmol) in dichloromethane (19 mL) at 0° C. was added mesyl chloride (0.650 mL, 8.40 mmol) slowly via syringe. The mixture was stir cold for three hours, diluted with 10 mL of water and 25 mL of dichloromethane. The layers were separated and the organic layer was washed with aqueous NaHCO3 (3×30 mL) followed by water (1×15 mL). The organic layer was then dried (Na2SO4), filtered, and concentrate under reduced pressure to provide 650 mg of methanesulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester as a light brown oil. In a separate flask 6-nitroindazole (318 mg, 1.95 mmol) was treated with potassium carbonate (538 mg 3.9 mmol) in DMF (10 mL) for 30 minutes, afer which methanesulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester (490 mg 2.34 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (210 mg, 39% yield). 1H NMR (300 MHz, DMSO-d6) ppm 3.49 (m, 2H), 3.62 (t, J=5.76, 2H), 4.13 (m, 2H), 4.76 (t, J=5.76, 2H), 7.97–8.03 (m, 2H), 8.33 (m, 1H), 8.83 (m, 1H); MS (DCI/NH3) m/z 277 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5]([C:10]#[C:11][CH:12]([CH3:14])[CH3:13])[CH:4]=1.CC([O-])(C)C.[K+]>CN1CCCC1=O>[CH:12]([C:11]1[NH:9][C:6]2=[CH:7][N:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[CH:10]=1)([CH3:14])[CH3:13]
Reactant: COc1cc(C#CC(C)C)c(N)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2cc(C(C)C)[nH]c2cn1
Temperature: 140 °C

Procedure:
To a solution of 6-methoxy-4-(3-methylbut-1-ynyl)pyridin-3-amine (Compound 4, 588 mg, 3.1 mmol) in N-methylpyrrolidone (10 ml) was added KOtBu (0.87 g, 7.8 mmol) at room temperature. The mixture was heated to 140° C. for 0.5 h and cooled to room temperature, quenched with H2O, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as light brown syrup.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([CH2:20][C:11]2[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:14]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:10]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O

Procedure:
Following the procedure of Example 1(10), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a slightly yellow oil (yield: 97.5%).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1([CH3:27])[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:20])[CH:11]=2)[C@H:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.Cl>C1COCC1.CO>[CH3:3][C:4]1([CH3:27])[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:20])[CH:11]=2)[C@H:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)ccc1C(=O)O
Temperature: 50 °C
Yield: 91.9 %

Procedure:
Lithium hydroxide (0.053 g, 2.210 mmol) was added to a solution of (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoate (0.150 g, 0.442 mmol) in THF (2.5 mL), MeOH (2.50 mL), and water (2.50 mL). The mixture was heated at 50° C. for 16 hours. The reaction mixture was then cooled in an ice bath and adjusted to pH˜2 by the addition of 1 N aqueous HCl solution. Water was added, leading to the formation of a white precipitate. The precipitated material was filtered away and dried to afford (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoic acid (0.132 g, 0.406 mmol, 92% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (s, 3H), 1.63 (s, 3H), 2.44 (s, 3H), 5.51 (s, 1H), 7.18-7.44 (m, 6H), 7.48 (d, J=2.15 Hz, 1H), 7.75 (d, J=8.70 Hz, 1H), 12.57 (br. s., 1H). m/z (ESI) 326 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][NH:6][C:7](=[O:36])[CH:8]([CH3:35])[C:9]([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=[O:10].F[C:42]1C=C(C=C(F)C=1)CNC(=O)C(C)(C)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][NH:6][C:7](=[O:36])[C:8]([CH3:42])([CH3:35])[C:9]([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=[O:10]
Reactant: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Reactant: CC(C)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CC(C)(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1

Procedure:
N-(3,5-Difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoguinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2,2-dimethyl-malonamide. MS: m/e=559.3 (M+H+), was prepared in analogy to N-(3,5-difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-malonamide (example 16) from N-(3,5-difluoro-benzyl)-2,2-dimethyl-malonamic acid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[C:23](O)=[O:24]>>[CH2:2]([O:4][C:5]([C:7]1([NH:13][C:23]([C:15]2[O:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)=[O:24])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CCOC(=O)C1(N)CCCCC1
Agent: Cl
Product: CCOC(=O)C1(NC(=O)c2cc3ccccc3o2)CCCCC1
Yield: 80.3 %

Procedure:
3.11 g (15 mmol) of 1-aminocyclohexanecarboxylic acid ethyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, and 2.43 g (15 mmol) of benzofuran-2-carboxylic acid was used instead of 3-furancarboxylic acid in the process according to Reference Example 15 to obtain 3.80 g (80%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C@@H:4](/[CH:5]=[C:6](/[F:10])\[C:7](=[O:9])[OH:8])[C@H:3]1[C:11]([O:13][C@H:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:30])[C@@H:4](/[CH:5]=[C:6](/[F:10])\[C:7](=[O:8])[O:9][C:2]([CH3:4])([CH3:3])[CH3:1])[C@H:3]1[C:11]([O:13][C@H:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C(/F)C(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 17, (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-hydroxy-propenyl]-cyclopropane-1-carboxylate was reacted to obtain a 61% of yield of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-tert-.butoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+26.5° (c=0.25% in chloroform).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:4]=1.Cl[C:39]1[CH:48]=[CH:47][C:46]2[CH2:45][CH2:44][N:43]3[C:49]4[CH:50]=[CH:51][CH:52]=[C:53]([F:56])[C:54]=4[CH:55]=[C:42]3[C:41]=2[N:40]=1.C([O-])([O-])=O.[Na+].[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:1][CH:2]([F:37])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[C:19]([C:39]4[CH:48]=[CH:47][C:46]5[CH2:45][CH2:44][N:43]6[C:49]7[CH:50]=[CH:51][CH:52]=[C:53]([F:56])[C:54]=7[CH:55]=[C:42]6[C:41]=5[N:40]=4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:4]=1
Reactant: CNC(=O)c1c(-c2ccc(C(F)F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(C(F)F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
To a degassed solution of 2-(4-(difluoromethyl)phenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (120 mg, 0.22 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (64 mg, 0.22 mmol), Na2CO3 (62 mg, 0.45 mmol), in 1,4-dioxane (3 mL) and H2O (0.1 mL) was added Pd2(dba)3 (5 mg) and X-Phos (5 mg) under N2. Then the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to RT and filtered. The filtrate was washed with H2O and dried over Na2SO4. After concentrated, the residue was purified by prep-HPLC to give the product (30 mg, yield: 21%). 1H-NMR (CDCl3, 400 MHz) δ 8.08 (d, J=8.0 Hz, 2H), 8.03 (s, 1H), 7.74˜7.64 (m, 4H), 7.47 (d, J=7.6 Hz, 1H), 7.30 (s, 1H), 7.22˜7.14 (m, 2H), 6.89˜6.81 (m, 1H), 6.81˜6.73 (m, 1H), 6.00 (d, J=4.4 Hz, 1H), 4.37 (t, J=6.4 Hz, 2H), 3.40 (s, 3H), 3.34 (t, J=6.4 Hz, 2H), 3.02 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 645.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:6]=2[CH:7]=1.[CH:15]1[C:27]2[N:26]([C:28]3[CH:29]=[CH:30][C:31]4[NH:32][C:33]5[C:38]([C:39]=4[CH:40]=3)=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[K]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C(C)=CC=CC=1>[CH:30]1[C:31]2[N:32]([C:2]3[CH:3]=[CH:4][C:5]4[O:14][C:13]5[C:8](=[N:9][CH:10]=[CH:11][CH:12]=5)[C:6]=4[CH:7]=3)[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[CH:40]=[C:28]([N:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:27]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:29]=1
Reactant: Clc1ccc2oc3cccnc3c2c1
Reactant: c1ccc2c(c1)[nH]c1ccc(-n3c4ccccc4c4ccccc43)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: c1cnc2c(c1)oc1ccc(-n3c4ccccc4c4cc(-n5c6ccccc6c6ccccc65)ccc43)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
The 100 mL round bottom flask, equipped with magnetic stirrer and refluxed condenser, was charged with 8-chlorobenzofuro[3,2-b]pyridine (2.04 g, 10 mmol), 3-(9-carbazolyl)carbazole (3.32 g, 10 mmol), Pd(OAc)2 (450 mg, 20 mol %), P(t-Bu)3 (10 mL of 1M solution in toluene, 10 mmol), potassium tert-buthoxide (1.92 g, 1.5 eq) and 150 ml of xylene. The flask was filled with nitrogen, and the reaction mixture was heated to reflux and stirred under nitrogen atmosphere for 24 hours. Then reaction was cooled down to room temperature, filtered through silica plug and evaporated. The residue was subjected to column chromatography on silica gel, eluent hexane/ethyl acetate mixture 9:1, providing 2.5 g of 8-(9H-3,9′-bicarbazol-9-yl)benzofuro[3,2-b]pyridine as white solid. The structure was confirmed by NMR and MS spectroscopy.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-:9]>>[C:1]([NH2:2])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: [OH-]
Product: NC(=O)c1cccnc1

Procedure:
As to preparative methods for these compounds, cyanopyridines have frequently been hydrolyzed in batch and continuous processes with catalytic to stoichiometric excesses of a base. A majority of the methods reported have been batch processes. For example, 4-cyanopyridine in the presence of sodium hydroxide at a molar ratio of 1:(0.03-0.075) and at 120°-170° C. is reported to give isonicotinamide. See U.S.S.R. SU 1,553,531 (1990); CA:113:78174f (1990). Similarly, 2-cyanopyridine is reported to react with sodium hydroxide at a molar ratio of 1:(0.03-0.20) and at temperatures ranging from 100°-130° C. to give 2-picolinamide. See U.S.S.R. SU 1,553,530 (1990); CA:113:78173e (1990). With a molar ratio of 4-cyanopyridine:sodium hydroxide of 1:(1.5-1.75) and a hydrolysis temperature of 50°-80° C., the reported hydrolysis product was isonicotinic acid. See U.S.S.R. SU 1,288,183; CA:106:176187n (1987). The hydrolysis of 3-cyanopyridine with excess ammonia at 107°-109° C. for 12 hours was reported to give mixtures of nicotinamide and niacin. See J. Am Chem. Soc. 65, at pages 2256-7 (1943). In still another variation, the hydrolysis of 3-cyanopyridine has been reported with a polymeric base, Dowex 1X4 (in the hydroxide form), to yield nicotinamide. See Dutch Patent Application No. 7706612-A; CA:90:186814e. U.S. Pat. No. 4,314,064 describes the continuous hydrolysis of 3-cyanopyridine with 0.3 to 3.0 moles of an alkali metal hydroxide for each 100 moles of cyanopyridine at pressures of between 3 to 20 bars and with heating or cooling to maintain the prescribed reaction temperature. Similarly, 3-cyanopyridine is reported to react in a continuous process with aqueous ammonia at a molar ratio of 1:0.5 and a contact time of 40-50 minutes at 200°-260° C. to give nicotinamide. See Journal of Applied Chemistry of the USSR (English Translation: 45:2716-2718 (1972).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH:5]([C:10]2[N:11]([CH3:29])[C:12](=[O:28])[C:13]([OH:27])=[C:14]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:17])[N:15]=2)[CH2:4]1)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][NH:18][C:16]([C:14]2[N:15]=[C:10]([CH:5]3[CH2:4][NH:3][CH2:8][CH2:7][N:6]3[CH3:9])[N:11]([CH3:29])[C:12](=[O:28])[C:13]=2[OH:27])=[O:17])=[CH:21][CH:22]=1
Reactant: CCN1CCN(C)C(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCNCC1c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C

Procedure:
The crude product from Step 3 was stirred in CH2Cl2/TFA (1:1) for 2 hours to remove the Boc protective group from the piperazinyl nitrogen.