Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[O:17]1CCCC1>O.CCOCC.[B-](F)(F)(F)F.[Ag+]>[OH:17][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: C1CCOC1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1 h

Procedure:
To a stirred solution of 56.0 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 400 ml. of tetrahydrofuran and 133 ml. of water at 3° C. is added 44.1 g. (0.226 moles) of silver fluoborate during 25 minutes. The mixture is stirred at 0°-5° C. for 60 minutes, diluted with water and ether, and filtered. The aqueous portion of the filtrate is saturated with solid sodium chloride and extracted with additional ether. The combined organic phases and washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue gives the subject compound as a mixture with 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one. NMR (CDCl3) 3.60 (multiplet, O-methylene hydrogens) and 4.60 f (multiplet, O-methine hydrogen).
Reaction SMILES: [C:1]1([C:7]2N[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(N[C@H:23]([C:25](OC1C=C(C2C=CC(Cl)=CC=2)NC=1)=[O:26])C)(C1C=CC(C)=CC=1)(=O)=O>CC(C)=O>[CH2:25]([OH:26])[CH2:23][CH2:9][CH2:10][CH2:11][CH2:7][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: c1ccc(-c2ccc[nH]2)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Oc2c[nH]c(-c3ccc(Cl)cc3)c2)cc1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCO

Procedure:
Test devices were prepared as in Experiment 7.3.3 except that the acetone solution contained, in place of the phenylpyrrole, 1.3 mM 3-(N-tosyl-L-alaninyloxy)-5-(p-chlorophenyl)pyrrole.
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.[CH3:17][O:18][CH2:19][CH2:20][N:21]([CH2:23]C1C=C(C=CC=1)C#N)[CH3:22]>>[OH:16][NH:15][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][CH:6]=[C:11]([CH2:22][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH3:23])[CH:12]=1
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Reactant: COCCN(C)Cc1cccc(C#N)c1
Product: COCCN(C)Cc1cccc(C(=N)NO)c1
Yield: 93 %

Procedure:
The title compound was obtained following procedure and work up described for Intermediate 47 step 2 but starting from 3-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-benzonitrile obtained in step 1 (6.4 g, 31.3 mmol) to give the title compound as yellow viscous liquid (6.9 g, 93%). 1H NMR (DMSO-d6, 400 MHz) δ 9.57 (s, 1H), 7.59 (s, 1H), 7.50-7.53 (m, 1H), 7.28-7.29 (m, 2H), 5.75 (s, 2H), 3.48 (s, 2H), 3.41-3.44 (m, 2H), 3.21 (s, 3H), 2.48-2.52 (m, 2H), 2.13 (s, 3H). LC/MS (Method A): 238.1 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>O1CCCC1>[O:3]1[CH2:4][CH2:5][N:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=3[N+:27]([O-:29])=[O:28])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of trans-4-morpholinocyclohexanamine dihydrochloride (5 g, 19.44 mmol), 4-fluoro-3-nitrobenzenesulfonamide (4.32 g, 19.63 mmol) and triethylamine (20 ml, 143 mmol) in tetrahydrofuran (60 ml) was stirred for 16 hours at room temperature. The solid product was filtered off, washed with tetrahydrofuran, ether, dichloromethane (3×) and dried under vacuum.
Reaction SMILES: IC1C=CC2C(CCN)=COC=2C=1.[I:14][C:15]1[CH:28]=[CH:27][C:18]2[C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:20][O:21][C:17]=2[CH:16]=1>>[I:14][C:15]1[CH:28]=[CH:27][C:18]2[C:19]([C:22]([CH3:26])([CH3:25])[CH2:23][NH2:24])=[CH:20][O:21][C:17]=2[CH:16]=1
Reactant: CC(C)(C#N)c1coc2cc(I)ccc12
Agent: NCCc1coc2cc(I)ccc12
Product: CC(C)(CN)c1coc2cc(I)ccc12

Procedure:
Synthesized as described for 2-(6-iodo-1-benzofuran-3-yl)ethanamine using 2-(6-iodo-benzofuran-3-yl)-2-methyl-propionitrile as the starting material.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[OH:1][CH:2]([CH2:20][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)c1cc2c(OCC3CO3)cc(C)cc2[nH]1
Reactant: CC(C)(C)N
Product: CCOC(=O)c1cc2c(OCC(O)CNC(C)(C)C)cc(C)cc2[nH]1
Reaction time: 72 h
Yield: 71 %

Procedure:
1.7 g 4-(2,3-epoxypropoxy)-2-ethoxycarbonyl-6-methyl-indole are dissolved in 25 ml tert.-butylamine. The solution is stored at room temperature for three days and then evaporated in vacuum. The residue is triturated with ether and aspirated. The crude product is dissolved in hot acetic ester and the solution is mixed with 0.3 ml glacial acetic acid. The precipitate resulting after cooling of the solution is aspirated and dried. There is obtained 1.8 g (~71% of theory) of 4-(2-hydroxy-3-tert.-butylamino-propoxy)-2-ethoxycarbonyl-6-methylindole as acetate; m.p. 181°-183° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH:18](Br)[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH:21]([Br:24])[CH2:22]Br)=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:19]2[C:20]([CH3:26])([CH3:25])[CH:21]([Br:24])[CH2:22][O:27]2)=[CH:15][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C(=O)C(Br)Oc1ccc(Cl)cc1)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C(=C(Oc2ccc(Cl)cc2)n2ccnc2)OCC1Br
Temperature: 90 °C
Reaction time: 10 h
Yield: 10.3 %

Procedure:
35 g (0.5 mole) of imidazole and 103.5 g (0.75 mole) of potassium carbonate are dissolved in 700 ml of toluene at 60° C. 132 g (0.269 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-1,4,5-tribromo-2-pentanone in 100 ml of toluene are added dropwise to this solution in the course of 20 minutes. The reaction mixture is subsequently stirred at 90° C. for 10 hours and cooled and water is added. The organic phase is separated off, washed with water dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; ethyl acetate/cyclohexane=3:1). 10.6 g (10% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-(4-bromo-3,3-dimethyltetrahydrofuran-2-ylidene)-methane of refractive index nD20 1.5837 are obtained.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(Cl)(Cl)Cl.CO>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH:3]2[O:17][C:6]3=[C:7]4[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]3[CH2:4]2)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]4)[CH2:28][CH2:27]1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: COc1ccccc1N1CCNCC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(CC2Cc3cc(C)c4[nH]c(=O)ccc4c3O2)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.824 g) and 1-(2-methoxyphenyl)piperazine (5.000 g) was stirred in a hot bath at 150° C. in the stream of argon gas for 1 hour. The reaction product was dissolved in a solvent mixture of chloroform and methanol (5:1), and washed with sodium bicarbonate water, and water in this order. After dried and condensed, n-hexane was added to the residue, and the mixture was allowed to stand. As a result, 4.349 g of a free base of the title compound was obtained as pale yellow flakes (mp.: 245°-247° C. (dec.)).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc([N+](=O)[O-])nn1C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (8.8 g, 40 mmol), sodium methoxide (4.3 g, 80 mmol), and methanol (50 mL). The reaction mixture was heated at reflux for 2 h. After this time the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (60 mL) and water (60 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to afford 336a as a yellow oil (6.1 g, 90%). MS-ESI: [M+H]+ 172.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CC(N(C)C)=O>CO>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:25][CH:24]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CO
Product: O=S(=O)(Nc1nc2ccccc2nc1Nc1ccc(F)cc1)c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
A CEM microwave reaction vessel was charged with N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (52 mg, 0.16 mmol), prepared using procedures similar to those described in the above step, 4-fluoroaniline (36 mg, 0.32 mmol), and 0.8 mL of dimethylacetamide. The vessel was sealed and the reaction mixture was heated under microwave radiation for 25 m at 120° C. in a CEM Discover microwave instrument. Methanol (1 mL) was added to the reaction mixture and after 20 minutes the product precipitated out of the solution. Filtration yielded N-(3-(4-fluorophenylamino)quinoxalin-2-yl)benzenesulfonamide (39 mg, 62%). 1H-NMR (400 MHz, d6-DMSO): δ 12.30 (s, 1H), 9.11 (s, 1H), 8.16-8.10 (d, 2H), 8.02-7.90 (m, 3H), 7.68-7.58 (m, 3H), 7.55-7.51 (m, 1H), 7.41-7.32 (m, 2H), 7.25-7.16 (m, 2H); MS (EI) m/z C20H15FN4O2S: 395.0 (MH+).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:48])[C@@H:24]([NH:25][C:26](=[O:47])[C:27]([C:30]4[N:31]=[C:32]([NH:36][C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[S:33][C:34]=4[F:35])=[N:28][OH:29])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:51])=[N-]>ClCCl.CCOCC>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:48])[C@@H:24]([NH:25][C:26](=[O:47])[C:27]([C:30]4[N:31]=[C:32]([NH:36][C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])[S:33][C:34]=4[F:35])=[N:28][O:29][CH3:51])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1nc(C(=NO)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=CCS[C@H]23)c(F)s1)OCc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(NC(=O)OCc2ccccc2)sc1F
Reaction time: 0.5 h

Procedure:
To a solution of 7β-[2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (180 mg) in dichloromethane (3 ml) is added a solution of diazomethane in ether until yellow color of the solution does no more fade out. After 30 minutes, the reaction mixture is concentrated to give 7β-[2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (153 mg). Similarly prepared are compounds of Table 1.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]=[CH:6][S:5][CH:4]1[C:8]#[N:9].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]#[N:9]
Reactant: COC1C=CSC1C#N
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccsc1C#N
Yield: 91 %

Procedure:
14.1 parts of 3-methoxy-2-cyanodihydrothiophene in 80 parts by volume of chloroform are reacted with 6.75 parts of sulfuryl chloride in 20 parts by volume of chloroform for 0.5 hour at 0° C. The end product is isolated from the reaction mixture by the method described in Example 14(c). 12.6 parts (91% of theory) of 3-methoxy-2-cyanothiophene of boiling point 73° C./0.16 mbar are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)Nc3nc4ccc(F)cc4nc3OC)CC2)cc1
Yield: 84 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 84%). 1H NMR (200 MHz, CDCl3): δ 3.15-3.18 (m, 4H), 3.78 (s, 4H), 4.15 (s, 3H), 6.85-6.96 (m, 4H), 7.22-7.42 (m, 3H), 7.81 (dd, J=9.0 and 6.0 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 76.2 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example S-2, 0.18 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.15 g of the title compound as a solid, mp 183-185° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C.O>C1COCC1>[CH3:20][O:19][N:18]([CH3:17])[C:11]([CH:8]1[CH2:7][CH2:6][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:10][CH2:9]1)=[O:13]
Reactant: CNOC
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1CCC2(CC1)OCCO2
Yield: 98.4 %

Procedure:
Ethyl 1,4-dioxaspiro[4,5]decane-8′-carboxylate (6.28 g, 29.3 mmol) obtained in Step 1 was dissolved in THF, and N,O-dimethylhydroxylamine hydrochloride (4.30 g, 44.1 mmol) was added thereto, followed by stirring. In an atmosphere of argon at −30° C., a 2.0 mol/L solution of isopropylmagnesium chloride in THF (44.1 mL, 88.2 mmol) was added dropwise to the reaction mixture, followed by stirring at −5° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate) to afford N-methoxy-N-methyl-1,4-dioxaspiro[4,5]decane-8-carboxamide (6.61 g, 99%).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:15](=[O:30])[NH:14]2)=O)=CC=1)([O-])=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35][NH2:36]>CCO>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:35][NH:36][C:11]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15](=[O:30])[NH:14]1)=[O:10]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C1NN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(c2ccccc2)C1c1ccccc1
Solvent: CCO
Product: O=C1NN(C(=O)NCc2ccc(Cl)c(Cl)c2)C(c2ccccc2)C1c1ccccc1
Yield: 23 %

Procedure:
A solution of 1-[(4-nitrophenyl)oxycarbonyl]4,5-diphenyl-3-pyrazolidinone (1.00 g, 2.48 mmol) and 3,4-dichlorobenzylamine (5 mL) in 50 mL abs. EtOH was heated to reflux for 8 hours. Solvent was removed in vacuo, the residue taken up in CH2Cl2, washed twice with 1N HCl and once with pH 7 buffer, and dried over Na2SO4. After removal of solvent in vacuo, the product was purified by chromatography (0-35% EtOAc:hexane gradient) to give 250 mg (23%) solid:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C(O[Na])(C)(C)C>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].C1(C)C=CC=CC=1>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: Brc1cncnc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncnc2)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A mixture of 5-bromopyrimidine (325 mg, 2.04 mmol), 4-amino-1-Boc-piperidine (425 mg, 2.12 mmol), Pd2(dba)3 (41 mg, 0.045 mmol), (±)-BINAP (78 mg, 0.13 mmol) and t-BuONa (210 mg, 2.19 mmol) in freshly degassed toluene (7.0 mL) was stirred at 85° C. under argon for 2 hours. Basic work-up and purification gave 4-(pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale brown solid (415 mg, 73%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[F:14][C:15]1([F:20])[CH2:18][CH:17]([NH2:19])[CH2:16]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([NH:19][CH:17]2[CH2:18][C:15]([F:20])([F:14])[CH2:16]2)[N:3]=[C:4]([S:12][CH3:13])[N:5]=1
Reactant: CSc1nc(Cl)c(CCO)c(Cl)n1
Reactant: NC1CC(F)(F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1nc(Cl)c(CCO)c(NC2CC(F)(F)C2)n1
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 92.9 %

Procedure:
To a vial containing 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]ethanol (600 mg, 2.51 mmol) and 3,3-difluorocyclobutylamine (540 mg, 3.76 mmol) in acetonitrile (12.5 mL) was added DIPEA (2.21 mL, 12.5 mmol) at room temperature, and the mixture was stirred at 100° C. in an oil bath for 6.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified via silica gel chromatography using a gradient of EtOAc/heptane (20-40%) to afford the title compound (722.5 mg, 93%) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J=5.5 Hz, 1 H), 4.82 (br s, 1 H), 4.38-4.26 (m, 1 H), 3.56-3.47 (m, 2 H), 3.03-2.87 (m, 2 H), 2.83-2.65 (m, 4 H), 2.42 (s, 3 H). m/z (APCI+) for C11H14ClF2N3OS 310.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 105 °C
Reaction time: 0.67 h
Yield: 97.7 %

Procedure:
28.7 g of ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.088 mol), 160 ml of acetic acid, and a mixture of 100 ml of water and 18 ml of concentrated sulfuric acid were stirred at 100-110° C. for 40 minutes. The reacting mixture was cooled and filtered. The precipitate was recrystallized from chloroform-ethanol to give 25.6 g 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Sparcarboxylic acid, 0.086 mol), mp. 293-295C., in 98.0% yield.
Reaction SMILES: Br[CH:2]1[C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.Cl.[NH:13]1[CH:17]=[C:16]([CH2:18][C:19]([NH2:21])=[S:20])[N:15]=[CH:14]1>>[NH:13]1[CH:17]=[C:16]([CH2:18][C:19]2[S:20][C:2]3[O:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[C:10]=3[N:21]=2)[N:15]=[CH:14]1
Reactant: NC(=S)Cc1c[nH]cn1
Reactant: O=C1c2ccccc2OC1Br
Agent: Cl
Product: c1ccc2c(c1)oc1sc(Cc3c[nH]cn3)nc12

Procedure:
Starting compounds: 2-bromo-3-coumaranone, 4-imidazolyl thioacetamide hydrochloride
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:17]=[C:16]([O:18][CH3:19])[C:12]([C:13]([O-])=[O:14])=[C:11]([CH:20]=[CH2:21])[N:10]=1.[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([CH3:32])=[C:29]([CH:31]=1)[NH2:30])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:17]=[C:16]([O:18][CH3:19])[C:12]2[C:13](=[O:14])[N:30]([C:29]3[CH:31]=[C:25]([CH:22]([CH3:23])[CH3:24])[CH:26]=[CH:27][C:28]=3[CH3:32])[CH2:21][CH2:20][C:11]=2[N:10]=1
Reactant: Cc1ccc(C(C)C)cc1N
Reactant: C=Cc1nc(-c2c(C)cccc2C)cc(OC)c1C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(-c2c(C)cccc2C)nc2c1C(=O)N(c1cc(C(C)C)ccc1C)CC2
Reaction time: 12 h

Procedure:
A solution of 6-(2,6-dimethylphenyl)-4-methoxy-2-vinylnicotinate (1.77 g, 5.95 mmol) and 5-isopropyl-2-methylaniline (4.44 g, 29.8 mmol) in toluene (26.5 mL) and acetic acid (13.2 mL) was heated to 110° C. and stirred at that temperature. After 12 h, the reaction mixture was removed from the heat and concentrated on the rotovap to remove the bulk of the solvent. The residue was partitioned between EtOAc and aqueous 1 N sodium hydroxide solution with added brine. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (0-15% EtOAc/DCM) to provide 2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one. The product contained some 5-isopropyl-2-methylaniline and was used in the next step without further purification. MS (ESI+) m/z 415.2 (M+H)+.