Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:12]2[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1.O>O1CCCC1.C(OCC)C>[CH3:1][C:2]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[C:12]2[C:13]3[C:8]([CH:9]=[CH:10][CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]1=[O:14]
Reactant: CC1C(=O)c2cccc3cccc1c23
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC1(Cc2cccc(C#N)c2)C(=O)c2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-methyl-1-acenaphthenone (1.00 g, 0.005 mole) in tetrahydrofuran (20.0 ml) was added dropwise to a solution of sodium hydride (0.580 g, 0.024 mole, 50% oil dispersion) in tetrahydrofuran (35.0 ml) at 0°. The reaction mixture was stirred for 2 hours at room temperature. At 0°, α-Bromo-m-tolunitrile (1.37 g, 0.007 mole) in tetrahydrofuran (10.0 ml) was added dropwise. The mixture was stirred for 24 hours at room temperature, poured into water, and isolated by extraction with diethyl ether. The material was chromatographed on silica with ethylacetate/hexane providing the title compound as an oil (1.55 g, 95%).
Reaction SMILES: [OH:1][C:2](/[C:5](=[CH:8]/[I:9])/[CH2:6][OH:7])([CH3:4])[CH3:3].C(Cl)Cl.CO>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:1][C:2](/[C:5](=[CH:8]/[I:9])/[CH:6]=[O:7])([CH3:4])[CH3:3]
Reactant: CC(C)(O)/C(=C/I)CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)/C(C=O)=C/I
Yield: 95 %

Procedure:
To a solution of E-2-(1-hydroxy-1-methylethyl)-3-iodoprop-2-en-1-ol (III) (5.7 mmol, 1.4 g) in dry methylene chloride (25 ml), manganese dioxide (10 eq., 57 mmol, 5 g) is added in portions, at room temperature (rt), under an inert atmosphere. The progress of the reaction is monitored by analytical chromatography on a silica gel plate (eluent CH2Cl2/MeOH 97/3). After the disappearance of the starting material, the mixture is filtered on Celite®. The filtrate, evaporated under reduced pressure, gives Z-2-(1-hydroxy-1-methylethyl)-3-iodopropenal (IV) (1.3 g, 94%) in the form of a slightly yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(O)C>[CH2:17]([NH:20][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:18][CH3:19]
Reactant: CCOC(=O)c1cc2ccccc2nc1Cl
Reactant: CCCN
Solvent: CCO
Product: CCCNc1nc2ccccc2cc1C(=O)OCC
Yield: 81.3 %

Procedure:
An solution of ethyl 2-chloroquinoline-3-carboxylate (1.1 g) [(K. Shimizu et al., J. Pharm. Soc. Jpn., 87, 672(1967)] and propylamine (1.8 g) in ethanol (20 ml) was heated at 95° C. for 8 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, to which was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, then the solvent was distilled off. The residue was purified by column chromatography on silica gel to afford the title compound as a yellow oil (0.98 g, 80%).
Reaction SMILES: CS[C:3](=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])[CH:4]([CH3:6])[CH3:5].[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([C:21]([NH:23][NH2:24])=O)=[CH:17][CH:16]=1>CN(C)C=O>[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]([C:21]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:3]([CH:4]([CH3:6])[CH3:5])=[N:24][N:23]=2)=[CH:17][CH:16]=1
Reactant: NNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CSC(=Nc1ccccc1F)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Temperature: 120 °C
Reaction time: 59 h
Yield: 67.6 %

Procedure:
N-(2-Fluorophenyl)-2-methylthiopropionimidate methyl ester (7.84 g) prepared in the Reference Example 1 and biphenyl-4-carboxylic acid hydrazide (5.25 g) were dissolved in N,N-dimethylformamide (50 ml), followed by addition of p-toluenesulfonic acid·monohydrate (941 mg), and stirred at 120° C. for 59 hours. After the reaction solution was cooled to ambient temperature, the resulting solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform-chloroform/methanol=100/1 to 50/1 to 20/1), to afford 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole as pale yellow solid (5.98g, 68%). A part of the product was recrystallized from ethyl acetate, to afford the entitled compound as pale yellow crystal. The physico-chemical values are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([I:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH2:10]([O:9][C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cc(Br)cc(I)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Brc1cc(I)cc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-5-iodophenol (1.40 g, 4.68 mmol), benzyl bromide (0.89 g, 5.20 mmol) and anhydrous K2CO3 (1.44 g, 10.4 mmol) in anhydrous NMP (8 mL) was stirred under argon at +70° C. for 1 hour. The reaction mixture was partitioned between aqueous NH4Cl and hexanes. Aqueous layer was additionally extracted with hexanes and combined organic layers were washed with 1N NaOH, brine, dried over anhydrous MgSO4 and concentrated under reduced pressure to give 1-(benzyloxy)-3-bromo-5-iodobenzene as a colorless oil. Yield (2.14 g, 99%); 1H NMR (400 MHz, CDCl3) δ 7.45 (t, J=1.4 Hz, 1H), 7.32-7.40 (m, 5H), 7.26 (dd, J=1.4, 2.2 Hz, 1H), 7.09 (t, J=2.0 Hz, 1H), 5.00 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@H:15]3[CH2:17][C@@H:16]3[C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[CH:26]=3)[CH:9]=2)[N:3]=1.[I:27]I>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[I:27])[CH:9]=2)[N:3]=1
Reactant: Cc1nc([C@H]2C[C@@H]2c2cn3ccccc3n2)cc(-n2nc(C)nc2C)n1
Reactant: II
Solvent: ClCCl
Product: Cc1nc([C@@H]2C[C@H]2c2nc3ccccn3c2I)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To Example 1 (142 mg, 0.41 mmol) in DCM (4 mL) was added iodine (2.1 g, 8.2 mmol) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with aqueous saturated sodium thiosulfate (2 mL) and methanol (2 mL) and continued to stir at room temperature for 1 h. The reaction mixture was diluted with DCM (15 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate (2×10 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (25-70% EtOAc/hexanes) to give Example 8 as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=6.8 Hz, 1H), 7.60 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.22 (app t, J=7.7 Hz, 1H), 6.89 (app t, J=6.7 Hz, 1H), 2.90 (s, 3H), 2.80-2.71 (m, 2H), 2.69 (s, 3H), 2.39 (s, 3H), 2.00-1.96 (m, 1H), 1.92-1.88 (m, 1H); MS: m/z=472.2 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])(=[O:18])=[O:17])[CH:12]=[N:13][CH:14]=2)O1.Cl[C:29]1[CH:30]=[CH:31][C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:37]=2[N:38]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:43]1[CH2:42][CH2:41][CH:40]([O:39][C:36]2[C:37]3[N:38]=[C:29]([C:9]4[CH:10]=[C:11]([NH:15][S:16]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])(=[O:17])=[O:18])[CH:12]=[N:13][CH:14]=4)[CH:30]=[CH:31][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:45][CH2:44]1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 108 %

Procedure:
A mixture of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluoro benzenesulfonamide (0.110 g, 0.278 mmol) (Intermediate 4), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.081 g, 0.305 mmol), 1 N aq. sodium bicarbonate (0.555 ml, 0.555 mmol) and PdCl2(dppf)-CH2Cl2Adduct (23.0 mg, 2.80 μmol) in dioxane (2.78 ml) was subjected to microwave irradiation for 1 hour at 110° C. The reaction mixture was cooled to room temperature, filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=2:1) to give N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.15 g, 18%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.78-1.98 (2H, m), 2.12-2.26 (2H, m), 3.55-3.72 (2H, m), 3.90-4.05 (2H, m), 5.58-5.72 (1H, m), 7.20-7.42 (1H, m), 7.48-7.62 (2H, m), 7.90-8.05 (1H, m), 8.36-8.52 (2H, m), 8.58 (1H, d, J=8.2 Hz), 8.86 (1H, s), 9.13 (1H, s), 11.29 (1H, br s). m/z=500.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21]([NH2:25])=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(N)=O)n(C)n1
Yield: 20 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using ammonia instead of 2-hydroxy-2-methylpropylamine, to the title compound (12 mg, 20%) which was obtained as an off white solid. MS: m/e=330.4 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([OH:24])[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.C[O:26][C:27](=[O:50])[C@H:28]([C@@H:47]([CH3:49])O)[NH:29]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([O:24][C@H:47]([CH3:49])[C@@H:28]([C:27]([OH:50])=[O:26])[NH2:29])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: OC1(c2ccc3ccccc3c2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: C[C@@H](OC1(c2ccc3ccccc3c2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-(2-naphthyl)-9H-fluoren-9-ol (Example 3p) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of 2,5-dibromo-3-nitropyridine (0.533 g, 1.89 mmol), 2-methoxyphenylboronic acid (0.29 g, 1.91 mmol), trans-dichlorobis(triphenylphosphine)-palladium (II) (68.9 mg, 0.098 mmol), and 2.0M sodium carbonate (2.9 mL, 5.8 mmol) in 1,4-dioxane (6 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 7 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on silica gel (0-15% EtOAc in hexanes) to afford a yellow solid as 5-bromo-2-(2-methoxyphenyl)-3-nitropyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.93 (1H, d, J=2.2 Hz), 8.37 (1H, d, J=2.0 Hz), 7.66 (1H, dd, J=7.6, 1.8 Hz), 7.51 (1H, m), 7.16 (1H, td, J=7.5, 1.0 Hz), 6.92 (1H, dd, J=8.3, 0.9 Hz), 3.72 (3H, s).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][CH:8]([C:10]1[CH:18]=[C:14]([C:15]([NH2:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)[OH:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(CC)=O>[CH2:26]([O:19][C:13]1[CH:12]=[CH:11][C:10]([CH:8]([OH:9])[CH2:7][NH:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:18][C:14]=1[C:15]([NH2:17])=[O:16])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(C(N)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)NCC(O)c1ccc(OCc2ccccc2)c(C(N)=O)c1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
5-(2-tert.butylamino-1-hydroxyethyl)-salicylamide hydrochloride (2.0g) in ethyl methyl ketone (50 ml) and anhydrous potassium carbonate (1.5 g) were refluxed together with stirring for 1/2 hour. Benzyl chloride (1.75 g) in ethyl methyl ketone (5 ml) was added dropwise with stirring and the mixture was refluxed for 17 hours. The potassium salts were filtered off and the filtrate was evaporated to dryness in vacuo leaving a cream solid which was crystallised from ethyl acetate to afford 2-(benzyloxy)-5-(2-tert. butylamino-1-hydroxyethyl)-benzamide as colourless needles (1.4g) m.p. 120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:4]1[C:3]([O:2][CH3:1])=[N:7][N:6]([CH3:8])[C:5]1=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nn(C)c(=O)n1-c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1nn(C)c(=O)n1-c1ccccc1CBr
Yield: 34.2 %

Procedure:
To a solution/suspension of 6.7 g 2,4-dihydro-5-methoxy-2-methyl-4-(2-methylphenyl)-3H-1,2,4-triazol-3-one dissolved in 95 mL carbon tetrachloride under N2 was added N-bromosuccinimide (6.53 g) followed by a catalytic amount of benzoyl peroxide. The solution was heated at reflux for 2 h. Another 1.63 g N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added and the solution was heated at reflux for an hour. After cooling, methylene chloride was added and the organic layer was washed successively with water, then 0.1 N sodium thiosulfate solution, then saturated aqueous NaCl. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (3 -10% diethylether/methylene chloride as eluent) to afford 3.12 g of the title compound of Step D. 1H NMR (CDCl3) δ7.5 (m,1H), 7.44 (m,2H), 7.22 (m,1H), 4.60 (d,1H), 4.36 (d,1H), 3.96 (s,3H), 3.47 (s,3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[CH3:13][C:14](N(C)C)=[O:15].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:14](=[O:15])[CH3:13]
Reactant: Cc1ccccn1
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(=O)Cc1ccccn1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
2-Picoline (2 g) was dissolved in tetrahydrofuran (30 ml) and the solution was cooled to −75° C. Butyl lithium (14.73 ml. of a 1.6M-solution in hexane) was added dropwise and the mixture stirred for 2 h. Dimethylacetamide (1.87 ml) was then added dropwise and the reaction was allowed to warm up to room temperature and stirring was continued for a further 2 h. Water (8.6 ml) and 36% hydrochloric acid (1.3 ml) were added and after stirring for another 30 minutes, ethyl acetate was added. The separated solvent phase was washed with brine and then dried (MgSO4). On evaporation an oil was obtained and used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:23][C:24](=[O:50])[CH:25]([N:29]([C:31](=[O:49])[CH:32]([NH:41]C(OCCCC)=O)[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:14](=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:23][C:24](=[O:50])[CH:25]([N:29]([C:31](=[O:49])[CH:32]([NH2:41])[CH2:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH3:30])[CH:26]([CH3:28])[CH3:27])[C:14](=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)N(C)C(=O)C(N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
To a solution of 2-((2-butoxycarbonylamino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(2-pyridylcarbamoyl)ethylamide (1.67 g, 2.41 mmol) in methylene chloride (30 ml), TFA (5 ml) was added and stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure; the thus obtained residue was mixed with chloroform, washed with a saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: methanol:aqueous ammonia:methylene chloride=3:0.1:100), giving the titled compound (370 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[OH:21])[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[C:38](O)=[O:39])[CH:31]=[CH:30]1>>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[C:38]([N:17]2[CH2:18][CH:19]([CH:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[OH:21])[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:39])[CH:31]=[CH:30]1
Reactant: Cn1ccc2cccc(C(=O)O)c21
Reactant: OC(c1ccccc1)C1CNCC1CN1CCC(c2ccc(F)cc2)CC1
Product: Cn1ccc2cccc(C(=O)N3CC(CN4CCC(c5ccc(F)cc5)CC4)C(C(O)c4ccccc4)C3)c21

Procedure:
The title compound was prepared from 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(phenylhydroxymethyl)pyrrolidine and 1-methyl-7-indolecarboxylic acid according to procedures described in Example 39. The crude product was purified by chromatography (silica, acetone:hexane=1:2) to give the separate diastereomers of the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17]CC)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][N:30]1[Si](C)(C)CC[Si]1(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN1C(=O)CCC1>[O:17]=[C:15]1[NH:30][CH2:29][CH2:28][CH2:27][N:1]2[C:5]3[N:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=3[CH:3]=[C:2]12
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Reactant: C[Si]1(C)CC[Si](C)(C)N1CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc2cc3n(c2n1)CCCNC3=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
To a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 2.00 g, 7.23 mmol) in NMP (20 mL) is added potassium carbonate (3.16 g, 22.9 mmol) and 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (2.28 mL, 9.15 mmol). The mixture is stirred at room temperature for 16 h. 1M TBAF in THF (9.15 mL, 9.15 mmol) is added and the mixture is stirred at room temperature for 3 h. The reaction is poured over ice and the resulting solid is collected by filtration. The crude material is purified via trituration with CH2Cl2/diethyl ether to afford the title compound as a yellow solid (1.84 g, 88%). LCMS: 274.70 (M+H+).
Reaction SMILES: [NH2-:1].[Na+].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[C:23]([NH2:31])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[NH2:1][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH2:31])=[O:30])=[CH:25][N:26]=1
Reactant: [NH2-]
Reactant: NC(=O)c1cccnc1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: NC(=O)c1ccc(N)nc1
Temperature: 25 °C
Yield: 17.4 %

Procedure:
A mixture of 50.7 g (1.3 moles) of sodamide preformed in situ as in Example 1, 400 cc of xylene containing 0.1 cc of oleic acid and 73.3 g (0.6 mole) of nicotinamide was placed in an autoclave such as the one described in Example 2. The autoclave was closed and purged of air with ammonia. It was pressurized to 60 psig with ammonia and 200 psig with nitrogen. The pressure relief valve was set at 360 psiq. The autoclave was heated to 122°-145° C. and maintained within this temperature range for 3 hours during which time hydrogen was evolved. The reaction mixture was cooled to room temperature and carefully hydrolyzed with 150 cc of water. Maximum temperature during hydrolysis was 18° C. The hydrolyzed mixture was filtered. The filter cake was washed with water and dried to give 14.3 g of 6-aminonicotinamide, m. p. 240°-247° C. The aqueous phase of the filtrate was separated and adjusted to pH 6.0 with concentrated hydrochloric acid. A precipitate formed which was filtered, washed with water and dried to give 5.4 g of 6-aminonicotinic acid, m.p. 314° C. with decomposition. The yield of 6-aminonicotinamide was 17.4% and the yield of 6-aminonicotinic acid was 6.5%. Both structures were confirmed by IR and NMR spectra. This result significantly differed from prior art references which report the classic Chichibabin amination product of nicotinamide to be exclusively 2-aminonicotinamide. Caldwell, Tyson and Lauer, J. Am. Chem. Soc., 66, 1479 (1944). Uses for the 6-aminonicotinic acid product of applicants' reaction were the same as stated in Example 4, whereas the recovered 6-aminonicotinamide was found effective as a rodenticide as reported in Johnson, Can. Patent 1,089,763, and for its inhibitory effect against Lactobacillus arabinosus as reported in Kitamura, et al., Yakuqaku Zasshi, 95, 547 (1975).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][NH2:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:13][N:14]1[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:10][N:11]=[C:15]1[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: NNC(=O)Cc1ccccc1
Reactant: C=CCCCC(=NC)NC
Agent: Cl
Product: C=CCCCc1nnc(Cc2ccccc2)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.18 g yield starting from phenylacetic hydrazide (0.5 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.62 g). MS (m/z): 242 [MH]+.