Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5C5C=CC=CC=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C1([CH:47]2CC[CH2:49][NH:48]2)C=CC=CC=1>>[CH3:47][N:48]([CH3:49])[C@H:29]1[CH2:30][CH2:31][N:27]([CH2:26][C:24]2[S:23][CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:38]([NH2:40])=[O:39])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH:25]=2)[CH2:28]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5ccccc5)c4)cc23)CC1
Reactant: c1ccc(C2CCCN2)cc1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CC[C@H](N(C)C)C5)c4)cc23)CC1
Yield: 18 %

Procedure:
The title compound was prepared according to the general procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl}1H-indole-7-carboxamide, substituting (2R)—N,N-dimethyl-2-pyrrolidinamine (114 mg, 1.0 mmol) for 2-phenylpyrrolidine to afford 11 mg of the title compound (18%).
Reaction SMILES: [N:1]1[N:9]2[C:4]([O:5][CH2:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[C:10]([O-])=[O:11].[BH4-].[Li+].CO>C1COCC1>[NH:1]1[N:9]2[CH:4]([O:5][CH2:6][CH:7]=[CH:8]2)[CH2:3][CH:2]1[CH2:10][OH:11]
Reactant: O=C([O-])c1cc2n(n1)CCCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC1CC2OCC=CN2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To the stirred solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate: (4.0 g, 20 mmol) of in 100 ml of THF was added 0.71 g of lithium borohydride and 1.03 g of methanol. The solution was heated at 40 C for 2.5 hour. The reaction was quenched by 1N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated to an oil and column chromatographed to give 2.08 g of the desired product (67%); (M+H) 155.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)#[N:29]>>[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:35])=[CH:32][CH:31]=1)#[N:29]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, off-white solid (110 mg, 96%), MS (ISP) m/z=460.5 [(M+H)+], mp 243.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-cyano-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[C:18]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:21]([O:20][C:18](=[O:19])[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:14]2[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:13]=2)[CH:27]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-(N-Boc-amino)phenylboronic acid gives “A82”; method 1: HPLC/MS: 1.56 min, [M+H]=406.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[C:22]3[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(Br)cc2C(F)(F)F)c1

Procedure:
[4-Bromo-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde was prepared from 4-bromo-2-(trifluoromethyl)benzyl bromide and 1H-indazol-5-carbaldehyde following General Procedure A.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:41](=[O:63])[C:42]([C:45]([N:47]3[CH2:52][CH2:51][N:50]([C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[O:54])[CH2:49][CH2:48]3)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:64])=[C:28]([CH:65]([CH3:67])[CH3:66])[NH:27][N:26]=1)(=O)C.C[O-].[Na+]>CO>[CH2:56]([O:55][C:53]([N:50]1[CH2:51][CH2:52][N:47]([C:45]([C:42]([CH3:44])([CH3:43])[C:41]([NH:40][CH2:39][CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:30][C:29]3[C:25]([O:24][C@@H:6]4[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]4[OH:4])=[N:26][NH:27][C:28]=3[CH:65]([CH3:67])[CH3:66])=[C:32]([CH3:64])[CH:33]=2)=[O:63])=[O:46])[CH2:48][CH2:49]1)=[O:54])[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCNC(=O)C(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.14 g) in methanol (3 mL) was added sodium methoxide (28% methanol solution, 0.015 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1) to give 4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)-methyl]-3-(β-D-galactopyranosyloxy)-5-isopropyl-1H-pyrazole (70 mg). This material was dissolved in methanol (4 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (54 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH3:70])[CH:65]1[CH2:69][CH2:68][NH:67][CH2:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH:65]([N:64]([CH3:70])[CH3:63])[CH2:66]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(C)C1CCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(N(C)C)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-dimethylamino-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][CH:16]([CH2:19][N:25]4[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]4)[CH2:17][CH2:18]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: OC1CCNCC1
Product: OC1CCN(CC2CCN(c3ccc(CN4CCCC4)cc3)CC2)CC1

Procedure:
Prepared from the product of Example 16 and 4-hydroxypiperidine.
Reaction SMILES: N.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2.[Na].[Cl-].[NH4+]>C(O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)C1CCc2cc(O)ccc2C1
Reaction time: 0.33 h
Yield: 73 %

Procedure:
Liquid ammonia (7 equi.) is condensed into a solution of 6-hydroxy-naphthalene-2-carboxylic acid (15) (1 equi) in ethanol (1.2 mL/mmole) at −78 C. Sodium (4.3 equi.) was added in 4 portions to the reaction mixture. Each portion gave blue color, but it disappeared quickly. The reaction mixture was stirred for 20 min, ammonium chloride (4.3 equi.) was added, it was stirred for another 1 h and anmmonia was distilled off by warming reaction pot to room temperature. The reaction mixture was quenched with water and 10% hydrochloric acid, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by recrystallization from acetonitrile gave 6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (29) as a white solid (73%).
Reaction SMILES: Cl(O)(=O)(=O)=[O:2].[CH3:6][O:7][N:8]=[C:9]([C:26](=NNC(OCC)=O)[CH3:27])[C:10]([NH:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[CH:17]([OH:20])[CH2:18][S:19][C@H:14]12)=[O:11]>CC(C)=O>[CH3:6][O:7][N:8]=[C:9]([C:26](=[O:2])[CH3:27])[C:10]([NH:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[CH:17]([OH:20])[CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CCOC(=O)NN=C(C)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Solvent: CC(C)=O
Product: CON=C(C(C)=O)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
70% Aqueous perchloric acid (0.05 ml.) was added to a solution of 7-(2-methoxyimino-3-ethoxycarbonylhydrazonobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 40 mg.) in acetone (5 ml.), and stirred at room temperature for 30 minutes. The reaction mixture was treated in a similar manner to that of Example 10-(4) to give 7-(2-methoxyimino-3-oxobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 26 mg.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1F.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[C:43]([O:45][CH2:46][CH3:47])=[O:44].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[CH2:46]([O:45][C:43]([C@@H:35]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:44])[CH3:47]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (5.26 g, 20.9 mmol, Eq: 2) and pyridine (2.8 mL, 34.5 mmol, Eq: 3.3) in DCM (60 mL), cyanuric fluoride (4.66 g, 2.99 mL, 34.5 mmol, Eq: 3.3) was added. The reaction mixture was stirred at 23° C. for 2 h. The resulting precipitate was filtered off and the mother liquor was concentrated in vacuo. The residue was taken up in EtOAc, and washed with saturated aqueous NaHCO3, 0.5 M aqueous citric acid and brine, and concentrated in vacuo. The light brown oil was taken up in DCM (20 mL) and cooled in an ice bath. To this acid fluoride solution was added a solution of (S)-ethyl indoline-2-carboxylate (2 g, 10.5 mmol, Eq: 1) and 2,6-di-tert-butylpyridine (4.00 g, 4.62 mL, 20.9 mmol, Eq: 2) in DCM (20 mL). The resulting mixture was stirred at rt overnight. The reaction was concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 5% to 20% EtOAc in hexanes) to give (S)-1-((S)-2-tert-butoxycarbonylamino-2-phenyl-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.78 g) as a light yellow foam, m/z=425 (M+H).
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:16])[CH3:13].CN(CCN(C)C)C.[Mg+2].[Br-].[Br-].CCOCC.C(OO[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])(=O)C1C=CC=CC=1>C1COCC1>[CH3:55][C:54]([CH3:57])([O:53][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[C:15]([NH:14][CH2:12][CH3:13])=[O:16])[CH3:56]
Reactant: CC(C)(C)OOOC(=O)c1ccccc1
Reactant: CCNC(=O)c1cccc2ccccc12
Agent: CN(C)CCN(C)C
Agent: [Br-]
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1c(OC(C)(C)C)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (34 mL, 44 mmol) was added dropwise to a -78° C. cooled solution of N-ethyl-1-naphthalenecarboxamide (20 mmol) and TMEDA (6.0 mL, 40 mmol) in THF (100 mL). After 30 min, MgBr2.Et2O (15.5 g, 60 mmol) was added portion wise, and the reaction was briefly warmed to ambient temperature then was recooled to -78° C. After 1 h at -78° C., t-butylperoxy benzoate (4.3 g, 22 mmol) was added. The resulting reaction was warmed to -30° C. and worked up in the usual manner, then was purified by chromatography with 3:7 ethyl acetate/hexanes to afford 1.7 g of desired compound as a white solid, a 33% yield. m.p. 126-127° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29][NH2:30]>>[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[CH3:34])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([O:23][CH3:24])=[CH:17][CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2c(OC)cccc2OC)n(C)c(=O)c1O
Reactant: Cc1ccc(CN)cc1C
Product: COc1cccc(OC)c1-c1nc(C(=O)NCc2ccc(C)c(C)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-dimethoxy-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (50 mg, 0.15 mmol) and 3,4-dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a brown solid (52 mg, 82% yield). 1HNMR (500 MHz, CDCl3) δ: 12.28 (1H, s), 7.88 (1H, t, J=5.50 Hz), 7.38 (1H, t, J=8.24 Hz), 7.10–7.03 (3H, m), 6.61 (2H, d, J=8.54 Hz), 4.48 (2H, d, J=6.11 Hz), 3.75 (6H, s), 3.28 (3H, s), 2.23 (3H, s), 2.22 (3H, s). HRMS (ESI) calcd for C23H26N3O5 (M+H): 424.1873; found: 424.1863.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3](=[O:32])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[C:6]1=[O:31].[OH-].[Na+:35]>CCO>[CH3:33][N:2]([CH3:1])[C:3](=[O:32])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([O-:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25])[C:6]1=[O:31].[Na+:35]
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCNC(=O)c1c([O-])c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15.5 g, 33.96 mmol) and EtOH (600 mL) was treated with 1N NaOH (39 mL, 39 mmol) and stirred 2 h at rt. The reaction mixture was partially concentrated at reduced pressure; the solid material was filtered, washed with EtOH and dried under high vacuum to afford the product as an off-white solid: 1H NMR (d6-DMSO) δ 10.60 (1H, br), 8.14 (1H, s), 7.26 (3H, m), 7.10 (2H, t, J=8.8 Hz), 4.92 (2H, s), 3.99 (2H, s), 3.36 (4H, m), 3.24 (3H, s), 3.08 (3H, s); ES− MS: 455 (M−, 100).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31](O)=[O:32])[CH:20]=[C:19]1[CH:34]([CH3:36])[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:41]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:21]([C:31](=[O:32])[NH2:41])[CH:20]=[C:19]1[CH:34]([CH3:36])[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 39, 0.65 g, 1.24 mmol) following the procedure described for Intermediate 20. The desired product was obtained as an off-white solid (0.322 g, 51%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(C1C=CC(NC(=O)NCCC(OCC)=O)=CC=1)CCCCCCC>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)CCNC(=O)N1CCc2c(-c3noc(-c4ccc(OCC)c(OCC)c4)n3)cccc21
Agent: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4C(=O)NCCC(=O)O)no2)cc1OCC
Yield: 61 %

Procedure:
When the product of Step A was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B the identical process afforded the title compound in 61% yield. 1H-NMR (CDCl3) 8.03 (d, 1H, J=9 Hz); 7.72 (dd, 1H, J=1.9, 8.4 Hz): 7.59-7.56 (m, 2H); 7.27 (t, 1H, J=7.9 Hz); 7.16 (d, 1H, J=8.6 Hz); 6.76 (t, 1H, J=5.3 Hz); 4.04-4.16 (m, 4H); 3.92 (t, 2H, J=8.6 Hz); 3.43 (tr, 2H, J=8.4 Hz); 3.36-3.28 (m, 2H+H2O); 2.48-2.42 (m, 2H); 1.37-1.32 (m, 6H).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.C(O)(C(F)(F)F)=O>C(O)C>[N:1]1([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCCCCC1
Agent: NN
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: NCCCN1CCCCCC1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-(azepan-1-yl)propyl)isoindoline-1,3-dione (3.5 g) in Ethanol (20 mL) was added hydrazine (0.58 mL). The reaction mixture was reflux for 13 h and then cooled down to room temperature. TFA (2.0 mL) was added, the resulted white solid was filtered and the solvent was evaporated to give 3-(azepan-1-yl)propan-1-amine, used without further purification.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C(CBr)OCc1ccccc1
Product: CCCCN(CC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide ( ) and benzyl bromoacetate according to the procedure of Intermediate 2 as a gum; 1H NMR (CDCl3) δ 0.85 (t, J=7.23 Hz, 3H), 1.19-1.32 (m, 2H), 1.43-1.53 (m, 2H), 2.56 (t, J=6.12 Hz, 4H), 3.19 (t, J=7.47 Hz, 2H), 3.72 (t, J=6.06 Hz, 4H), 4.09 (s, 2H), 5.10 (s, 2H), 6.84-6.89 (m, 2H), 7.29-7.40 (m, 5H), 7.69-7.74 (m, 2H); MS (ES) m/z 45.94 (MH+); HRMS for C25H30N2O6S: 459.1945 (MH+).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([CH2:27][C:28](O)=S)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([CH2:27][C:28]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)=[N:12][N:13]=2)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(S(=O)(=O)CC(O)=S)cc1OC
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: COc1ccc(S(=O)(=O)Cc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3,4-dimethoxyphenylsulfonylthioacetic acid (261 mg; 1 mmol) as described in method 2 but purified by flash chromatography on silica using a CHCl3/MeOH gradient; yield: 0.022 g (5.5%); MS m/z: 401.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.75 (s, 3H); 3.82 (s, 3H); 5.29 (s, 2H); 7.15 (d, 1H3J=8.7 Hz); 7.328-7.333 (m, 1H); 7.38 (dd, 1H, 4J=2.1 Hz, 3J=8.7 Hz); 7.68-7.72 (m, 1H); 7.78-7.82 (m, 1H); 8.01 (br s, 1H); 8.38 (s, 1H); 12.80 (br s, 1H); HPLC (METHOD [A]): rt 10.19 min (90.6%)
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11](O)=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27].C(Cl)(=O)C([Cl:31])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]([Cl:31])=[O:12])[C:5]2[CH:24]=[CH:25][NH:26][C:4]=2[C:3]1=[O:27]
Reactant: Cn1cc(-c2cc(C(=O)O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(-c2cc(C(=O)Cl)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of Example 10 (0.24 g, 0.67 mmol) in dichloromethane (10 mL) was treated with oxalyl chloride (0.17 g, 1.33 mmol) and dimethylformamide (5 mg, 10 mol %). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford the title compound (0.25 g, quantitative).