Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([OH:29])=[O:28]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=4)[C:27]([OH:29])=[O:28])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(C(=O)O)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-carboxyphenyl boronic acid were reacted to give 144. MS: (ESI+) 490.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[N:25]1([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C@H:11]2[CH2:15][N:14]([C:34]([C:31]3([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:32][CH2:33]3)=[O:35])[C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Cl)c3)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Cl)c3)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 39 %

Procedure:
The reaction of (2S,4R)-4-(3-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7F with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-4-(3-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a white solid (39%). MS ISP (m/e): 505.2/507.3 (100/34) [(M+H)]+.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13].N1C=CC=CC=1.O>C(Cl)Cl>[Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)Cl
Reactant: Nc1cccc(F)c1Br
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cccc(F)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH2Cl2 (50 mL) was added butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) at 0° C. The mixture was stirred at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with CH2Cl2 (50 mL×3). The organic layers were dried anhydrous over Na2SO4 and evaporated under vacuum to give N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 73%), which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:31]C(=O)C)=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:31])=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc([N+](=O)[O-])c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccc([N+](=O)[O-])c3)c2)=C(C)C1=O
Yield: 93.7 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3-nitroaniline (0.070 g, 0.142 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.060 g, 0.133 mmol, 94%).
Reaction SMILES: [OH:1][CH:2]([CH2:17][N:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:19][CH:20]([OH:35])[CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:48]([CH:50]1[O:52][CH2:51]1)[Cl:49]>C1(C)C(C)=CC=CC=1>[OH:35][CH:20]([CH2:19][N:18]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:17][CH:2]([OH:1])[CH2:3][N:4]([CH2:51][CH:50]([OH:52])[CH2:48][Cl:49])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:21][N:22]([CH2:51][CH:50]([OH:52])[CH2:48][Cl:49])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: ClCC1CO1
Reactant: CCCCCCCCCCCCNCC(O)CN(CCCCCCCCCCCC)CC(O)CNCCCCCCCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCN(CC(O)CCl)CC(O)CN(CCCCCCCCCCCC)CC(O)CN(CCCCCCCCCCCC)CC(O)CCl
Yield: 99.4 %

Procedure:
A reactor was charged with 16.6 g (0.025 mole) of 15,19-dihydroxy-17-dodecyl-13,17,21-triazatritriacontane obtained in Example 1 and 200 g of xylene, and the contents were kept at 50° C. To the contents, 6.9 g (0.075 mole) of epichlorohydrin was added dropwise over one hour and ten minutes, and the resultant mixture was aged for 36 hours. Thereafter, the solvent and unreacted epichlorohydrin were distilled off under reduced pressure at room temperature, thereby obtaining 21.2 g of 15,19-dihydroxy-13,21-bis(3-chloro-2-hydroxypropyl)-17-dodecyl-13,17,21-triazatritriacontane represented by the following formula. ##STR14##
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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[O:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](O)=[O:34]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (24.3 mg, 69.4%), MS (ISP) m/z=430 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and tetrahydrofuran-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:8].NC1C=C(C=CC=1N)C(N)=O.[Cl:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1.C1(C2(C3C=CC(C=O)=CC=3)OCCO2)C=CC=CC=1.N>CO>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([C:31]2[CH:38]=[CH:37][C:34]([C:35]3[NH:8][C:7]4[CH:6]=[CH:5][C:4]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:3][C:2]=4[N:1]=3)=[CH:33][CH:32]=2)=[O:30])=[CH:39][CH:40]=1
Reactant: O=Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Agent: N
Agent: NC(=O)c1ccc(N)c(N)c1
Agent: O=Cc1ccc(C2(c3ccccc3)OCCO2)cc1
Solvent: CO
Product: NS(=O)(=O)c1ccc2[nH]c(-c3ccc(C(=O)c4ccc(Cl)cc4)cc3)nc2c1

Procedure:
The title compound was prepared as described in Example 1 substituting 3,4-diamino-benzenesulfonamide for 3,4-diamino-benzamide and 4-(4-chloro-benzoyl)-benzaldehyde for 4-(2-phenyl-[1,3]dioxolan-2-yl)-benzaldehyde in Step C (reaction mixture was heated to 60° C.). TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH2Cl2): Rf=0.32. HPLC (Method A): Rt=8.03. MS (ESI+): mass calculated for C20H14ClN3O3S, 411.0; m/z found, 412.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 13.48 (br s, 1H), 8.31 (d, J=8.3 Hz, 2H), 8.16 (br s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.76 (br s, 1H), 7.74 (d, J=8.5 Hz, 2H), 7.73 (br s, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.25 (br s, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].[Cl:36]C(OCC)=O>>[CH3:30][N:31]([CH3:35])[C:32]([N:25]1[CH2:24][CH2:23][CH:22]([NH:21][S:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:36])=[CH:11][CH:12]=2)(=[O:29])=[O:28])[CH2:27][CH2:26]1)=[O:33]
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)Cl
Product: CN(C)C(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)Nc3ccccc3Cl)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid (2-chloro-phenyl)-amide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and dimethylcarbamyl chloride for ethyl chloroformate. Wt.: 28 mg (36%). 1H NMR (300 MHz, CDCl3) δ 8.69 (d, 1H), 8.60 (d, 1H), 8.47 (d, 1H), 8.35 (d, 1H), 8.20 (s, 1H), 7.82 (d, 1H), 7.72 (m, 2H), 7.43 (m, 2H), 7.17 (m, 1H), 4.83 (d, 1H), 3.46 (m, 2H), 3.31 (m, 1H), 2.71 (s, 6H), 2.70 (m, 2H), 1.67 (m, 2H), 1.35 (m, 2H); LC/MS m/z 516 (M+H)+.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=O)=[CH2:2].O=[C:7]([CH:9]=[C:10]([CH3:12])[CH3:11])[CH3:8].[OH-:13].[K+]>O1CCCC1>[CH3:5][C:3]1[CH2:8][CH2:7][C:9](=[C:10]([CH3:12])[CH3:11])[C:2](=[O:13])[CH:1]=1
Reactant: CC(=O)C=C(C)C
Reactant: C=CC(C)=O
Reactant: [OH-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1=CC(=O)C(=C(C)C)CC1

Procedure:
A similar process is described by S. Ohshiro et al (Yakugaku Zasshi, 88, 417 (1968)). Here again the reaction of methyl vinyl ketone with excess mesityl oxide takes place in the presence of potassium hydroxide powder but without addition of tetrahydrofuran as the solvent. The piperitenone obtained is converted into a mixture of menthone and isomenthone by catalytic hydrogenation. However, in this process of yields of piperitenone are again only about 53%; furthermore, using this process the menthone/isomenthone mixture is obtained in only 64.6% yield and in a purity of only 89.8%. For this reason, the further reaction to give pure methol has to be carried out in an involved manner via menthone-oxime (Jap. Pat. No. 7,009,375) and menthylamine, which makes it doubtful whether the process is suitable for commercial operation.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:16]=[CH:17][C:18]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[C:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:16]=[CH:17][C:18]=2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CCl)cc1
Reaction time: 1 h

Procedure:
4-(chloromethyl)benzoyl chloride (12 g, 63.5 mmol) was dissolved in THF (120 mL) and a solution of 1,1-dimethylethyl (3-aminobiphenyl-4-yl)carbamate (19.86 g, 69.8 mmol) and DIPEA (12.2 mL, 69.8 mmol) in THF (300 mL) was added dropwise at room temperature. After stirring for 1 hour, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was triturated in Et2O to give 1,1-dimethylethyl [3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 9.92 (s, 1H), 8.75 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.83 (s, 1H), 7.63 (m, 3H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (dd, J=8.4 and 1.8 Hz, 1H), 7.44 (t, J=7.2 Hz, 2H), 7.33 (t, J=7.2 Hz, 1H), 4.84 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH2:18])[CH2:4][CH2:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[F:1][CH2:2][CH:3]([NH:18][C:26](=[O:28])[CH3:27])[CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: NC(CF)CCCN1C(=O)c2ccccc2C1=O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NC(CF)CCCN

Procedure:
A solution of 1 mmole of N-(4-fluoromethyl-4-aminobutyl)phthalimide in 10 ml of chloroform is treated with 1 ml of triethylamine followed by 78 mg (1 mM) of acetyl chloride in 5 ml of chloroform. After 1 hour at 25° C the solution is washed with water, dried and concentrated. The resulting residue is dissolved in 10 ml of ethanol and treated with 60 mg (1.1 mM) of hydrazine hydrate at reflux for 2 hours after which the solvent is evaporated. The residue is treated with 1 N sodium hydroxide solution until the solid dissolves then is extracted with dichloromethane. The organic phase is dried and concentrated to give N-(1-fluoromethyl-4-aminobutyl)-acetamide.
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:28](Cl)(=[O:33])[CH2:29][C:30](Cl)=[O:31]>C1COCC1>[O:31]=[C:30]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:28](=[O:33])[CH2:29]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 35.9 %

Procedure:
To 20 mL of THF at 0° C. is added dropwise over 10 min simultaneously a solution of 1.97 g (5.48 mmol) of N-isopropyl-N-phenyl-2-(2-phenylamino-phenylamino) acetamide in 20 mL of THF and 0.53 mL (5.48 mmol) of malonyl dichloride in 20 mL of THF. The resulting red-brown solution is stirred at RT for 5.5 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash chromatography (50 to 75% ethyl acetate/petroleum ether) followed by recrystallization from ethyl acetate/petroleum ether gave 0.84 g of the title compound as a white powder: mp. 199°-200° C.; 1H NMR (CDCl3, 300 MHz) δ7.6-7.2 (m, 12H), 7.09 (t, 1H, J=8), 6.90 (d, 1H, J=8), 5.05 (m, 1H), 4.38 (d, 1H, J=17), 4.04 (d, 1H, J=17), 3.54 (dd, 2H, J=5, 22), 1.10 (d, 6H, J=7); low resolution MS (FAB) m/e 428 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][C:12]#[CH:13])[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[C:15]([OH:20])(=[O:19])[CH2:16][C:17]#[CH:18]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[C:1]([O:5][C:6]([N:7]1[CH2:8][C:9]2[C:12](=[CH:13][CH:18]=[C:17]([CH2:16][C:15]([OH:20])=[O:19])[CH:10]=2)[CH2:11]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN(CC#C)C(=O)OC(C)(C)C
Reactant: C#CCC(=O)O
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2ccc(CC(=O)O)cc2C1
Temperature: 0 °C

Procedure:
A mixture of di-prop-2-ynyl-carbamic acid tert-butyl ester (4.78 g, 24.7 mmol) and ethanol (120 mL) was prepared under argon and cooled to 0° C. for 15 min. 3-Butynoic acid (3.64 g, 43.3 mmol) and tris(triphenylphosphine)rhodium (I) chloride (1.14 g, 1.23 mmol) were added and reaction was gradually warmed to room temperature over 1.3 hr. The reaction was then heated to 45° C. for 17 hr. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with IN NaOH and extracted with diethyl ether (3×). The aqueous layer was acidified to pH˜1 with IN HCl and extracted with EtOAc (3×). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc:Hexane, 5-100%). ESI-MS m/z 278 (MH)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[N+:19]([O-])=O)=[N:6][CH:7]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1.O.[Fe]>[NH2:19][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Nc2cnc(Br)cn2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Nc2cnc(Br)cn2)c(N)c1
Temperature: 65 °C
Yield: 74.1 %

Procedure:
Into a 250 mL 3-necked roundbottom flask, was placed a solution of methyl 4-(5-bromopyrazin-2-ylamino)-3-nitrobenzoate (x) (5.0 g, 14.2 mmol) in THF (75 mL). This was followed by the addition of a solution of NH4Cl (3.8 g, 71 mmol) in H2O (25 mL). To the above was added Fe (4.0 g, 71 mmol) in several batches, while warming to a temperature of 65° C. The resulting solution was allowed to react for 3 hours at 65° C. The reaction progress was monitored by TLC (EtOAc/PE=1:2). Undissolved material was removed by filtration. The filtrate was extracted three times with 200 mL of EtOAc and the organic layers were combined and dried (Na2SO4). After removal of the solvent, the residue was separated by silica gel chromatography eluting with a mixture of PE/EtOAc (starting at 10:1 and proceeding through 5:1, 3:1, and 2:1, v/v) to afford the product methyl 3-amino-4-(5-bromopyrazin-2-ylamino)benzoate (xi) (3.4 g, yield 74%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:9]2[CH:14]=[C:13]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[OH:25])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[Cl-:28].Cl[C:30]1[CH:35]=[CH:34][C:33]([N+:36]#[N:37])=[C:32]([N+:38]([O-:40])=[O:39])[CH:31]=1>>[Cl:28][C:35]1[CH:30]=[CH:31][C:32]([N+:38]([O-:40])=[O:39])=[C:33]([N:36]=[N:37][C:11]2[CH:12]=[C:13]([C:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:16])[CH3:17])[CH:14]=[C:9]([C:6]([C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:8])[CH3:7])[C:10]=2[OH:25])[CH:34]=1
Reactant: [Cl-]
Reactant: CC(C)(c1ccc(Cl)cc1)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1
Reactant: N#[N+]c1ccc(Cl)cc1[N+](=O)[O-]
Product: CC(C)(c1ccc(Cl)cc1)c1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccc(Cl)cc2)c1

Procedure:
The title compound is prepared according to the procedure of Example 23 using 45 g of 2,4-di-(4-chloro-α-cumyl)phenol prepared in Example 6 and 138 g of the diazonium salt solution prepared in Example 11 in a yield of 66.3 g. The desired product is a crimson red solid containing some residual salt and melts at 163-165° C. The structure is confirmed by 1Hnmr and mass spectroscopy analyses.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Li+].CC([N-]C(C)C)C.[CH3:27][O:28][C:29]([C@@H:31]1[C@@H:35]([OH:36])[CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30].IC>C1COCC1>[CH3:27][O:28][C:29]([C@@:31]1([CH3:1])[C@@H:35]([OH:36])[CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: COC(=O)[C@@]1(C)[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 20.4 %

Procedure:
To diisopropylamine (4.88 mL, 34.8 mmol) in THF (33 mL) at −78° C. was added a 1.37 M solution of n-butyllithium in hexane (24.6 mL, 33.7 mmol). After stirring at the same temperature for 40 min, the LDA solution was transferred via cannula over 30 min to a solution of compound 1B (2.75 g, 11.2 mmol) in THF (112 mL) at −78° C. The reaction was stirred for 1.5 h when iodomethane (10.5 mL, 168 mmol) was added and the reaction was stirred at −78° C. for 2 h then was stored at −40° C. overnight. After warming to rt and stirring overnight, the reaction was quenched with saturated aqueous ammonium chloride. Ethyl acetate was added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was back-extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified using preparative HPLC (Luna C-18, 30×250 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O- 90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide compound 3A as a yellow oil (591 mg).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.O>CN(C)C=O.C(Cl)(Cl)Cl>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: BrCC1OCCO1
Reactant: O=c1ccc2cnccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1ccc2cnccc2n1CC1OCCO1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g of 1,6-naphthyridin-2(1H)-one in 10 mL of N,N-dimethylformamide, 0.30 g of 60% sodium hydride was added, and the mixture was stirred at 50 to 60° C. for 1 hour. Thereto was added 0.78 mL of 2-bromomethyl-1,3-dioxolan, and the reaction mixture was stirred at 90 to 100° C. for 30 minutes. Thereto were further added 0.30 g of 60% sodium hydride and 0.78 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 90 to 108° C. for 5 hours 30 minutes. The reaction mixture was cooled to room temperature, water and chloroform were then added thereto, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.60 g of 1-(1,3-dioxolan-2-ylmethyl)-1,6-naphthyridin-2(1H)-one as a yellow solid.