Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:15])/[C:5](=[N:13]/[CH3:14])/[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:10][C:8]([C:7]1[S:6]/[C:5](=[N:13]\[CH3:14])/[N:4]([CH3:15])[C:3]=1[CH2:2][NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:21][CH2:22]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1s/c(=N\C)n(C)c1CBr
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1s/c(=N\C)n(C)c1CNC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 67.8 %

Procedure:
Ethyl (2Z)-4-bromomethyl-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazole-5-carboxylate (3.0 g) obtained in Example 13) as a synthetic intermediate and benzyl 4-aminopiperidine-1-carboxylate (3.3 g) were dissolved in DMF (50 mL). Potassium carbonate (3.8 g) was added thereto, and the mixture was mixed at 70° C. for 4 hours. The solvent was distilled off, and the residue was poured into water. The mixture was then extracted with a mixed solution of chloroform-methanol, and the extract was dried over anhydrous magnesium sulfate. The solvent-was distilled off, and the residue was purified with a silica gel column to give the title compound (3.1 g) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Br[CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:28]=1.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[O:21][CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:28]=3)[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: COc1ccc(O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1csc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1csc(COc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1

Procedure:
210 mg (7 mmol) of sodium hydride (80% in oil) and 10 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 1.8 g (7 mmol) of 3-(1-adamantyl)-4-methoxyphenol in 20 ml of DMF was added dropwise and the mixture was stirred until the evolution of gas had ceased. A solution of 1.7 g (7.2 mmol) of methyl 2-bromomethyl-4-thiophenecarboxylate in 15 ml of DMF was then added and the mixture was stirred at room temperature for two hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The solid obtained was triturated from hexane, filtered off and dried. 2.6 g (90%) of the expected methyl ester, having a melting point of 97°-8° C., were recovered.
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18]#[N:19])[CH2:16][CH2:15][C@H:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[C:18]([CH:17]1[NH:8][C@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:15][CH2:16]1)#[N:19]
Reactant: CCOC(=O)[C@@H]1CCC(C#N)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CCC(C#N)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained from Step C (2.20 g) in CH2Cl2 (10 mL) was added trifluoroacetic acid (11.0 mL). The mixture was stirred at rt for 1.0 h before the solvent was removed under reduced pressure. The residue was further chased with toluene to remove residual trifluoroacetic acid. The TFA salt obtained was used in the next Step without further purification.
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[C:12]1[N:13]=[C:14]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:15]2[S:20][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][N:25](S(C)(=O)=O)[CH2:24][CH2:23]3)=[CH:18][C:16]=2[N:17]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:4]1[N:5]([C:12]2[N:13]=[C:14]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:15]3[S:20][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][C:16]=3[N:17]=2)[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncc[nH]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nccn1-c1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 2-isopropylimidazole (28 mg) in dry N,N-dimethylformamide (1 ml) was added sodium hydride (10 mg, 60% dispersion in mineral oil). After 30 minutes, 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was added and the reaction mixture was heated in the microwave for 45 minutes at 120° C. The reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo and the residue purified using flash chromatography to yield 176. NMR (400 MHz CDCl3): 1.19 (1H, s, CH), 1.30 (6H, d (J=6.84), 2.61-2.63 (4H, m, CH2), 2.74 (3H, s, CH3), 3.23-3.25 (4H, m, CH2), 3.79-3.82 (6H, m, CH2), 3.92-3.94 (4H, m, CH2), 6.92 (1H, s, ar), 7.18 (1H, s, ar), 7.66 (1H, d (J=1.49), ar). MH+506.30
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[C:50]([O:54][C:55](=[O:58])[CH2:56][Zn+])([CH3:53])([CH3:52])[CH3:51].C(OCC)C>CCOC(C)=O>[C:9]([NH:8][C:5]1[N:6]=[N:7][C:2]([CH2:56][C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:58])=[CH:3][CH:4]=1)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)nn1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(NC(=O)C(C)(C)C)nn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of N-(6-bromopyridazin-3-yl)pivalamide (2.00 g, 7.75 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.222 g, 0.465 mmol), and tris-dipalladium(dibenzylideneacetone) (0.213 g, 0.232 mmol) was flushed with nitrogen for 30 min. THF (20 mL) was added, followed by a 1.0 M solution of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in diethyl ether (38.7 mL, 19.4 mmol) and the reaction was sealed and stirred for 2 h at 50° C. An additional amount of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (15.5 ml, 7.75 mmol) was added and the mixture stirred for 2 h at 50 C. The resulting mixture was diluted with EtOAc and filtered, then washed with water and brine. The organic layer was dried (sodium sulfate), filtered and concentrated. MPLC (3−>30% EtOAc:Hex) provided title compound. LC-MS (IE, m/z): 294 [M+1]+.
Reaction SMILES: [O:1]=[P:2]([Cl:5])(Cl)[Cl:3].[Cl:6][C:7]([Cl:11])([Cl:10])[CH2:8][OH:9].Cl>>[P:2]([Cl:5])([Cl:3])(=[O:1])[O:9][CH2:8][C:7]([Cl:11])([Cl:10])[Cl:6]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: O=P(Cl)(Cl)OCC(Cl)(Cl)Cl
Yield: 56.3 %

Procedure:
To 90 g (0.59 mol) of POCl3 at 25° C. was slowly added 72 g (0.48 mol) of 2,2,2-trichloroethanol over a two hour period. The mixture was heated and maintained at 100°-125° C. for 14 hours during which time 22 g (0.60 mol) of HCl was recovered in the water scrubber. The mixture was distilled to give 72 g (0.27 mol) of 2,2,2-trichloroethyl phosphorodichloridate, bp 84° C. at 3 mm (57% yield).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1)([O-:4])=[O:3].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)Cl>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH:12]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccccc1C1=CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2ccccc2[N+](=O)[O-])CC1
Reaction time: 0.5 h

Procedure:
4-(2-Nitro-phenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride (0.44 g, 1.8 mmol) was dissolved in a solution of pyridine (0.4 mL) and DCM (20 mL). Acetyl chloride (0.142 mL) was added and the mixture was stirred for 0.5 hours. The mixture was diluted with DCM (20 mL) and the organic solution washed with water then 1 N hydrochloric acid. The solution was dried with magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as an orange oil (0.4 g). LCMS m/z 247.4 [M+H]+. R.T.=3.70 min (Analytical Method 4).
Reaction SMILES: C1(C)C=CC=C(C(O)=O)C=1.S(=O)(=O)(O)O.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)=[O:19].[Br:27]N1C(=O)CCC1=O>CO>[CH3:16][O:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][Br:27])[CH:21]=1
Reactant: COC(=O)c1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc(CBr)c1

Procedure:
This is prepared as follows: 3-Toluic acid is converted with methanol in the presence of sulfuric acid into 3-toluic acid methyl ester, which reacts with N-bromosuccinimide to give 3-bromomethyl-benzoic acid methyl ester. Reaction of bromomethyl-benzoic acid methyl ester with triphenylphosphane finally leads to 3-(benzoic acid methyl ester)-methyltriphenylphosphonium bromide.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]#[N:9].C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1>C(OCC)(=O)C.C1CCCCC1>[C:8]([C:2]1([CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2)#[N:9]
Reactant: BrCC1OCCO1
Reactant: N#CC1CC2CCC1C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: N#CC1(CC2OCCO2)CC2CCC1C2
Yield: 92.1 %

Procedure:
7.2 g of norbornane-2-carbonitrile are reacted with 60 mmoles of lithium diisopropylamide (prepared from 8.2 ml of diisopropylamine and 40 ml of n-butyllithium) and with 7 g of 2-bromomethyl-1,3-dioxolane in analogy to Example 1a. After chromatography on silica gel with ethyl acetate/cyclohexane (1:6) as the mobile phase, 8.0 g of the title compound are obtained as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]=[C:9]1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:21]>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:21])=[O:14])[N:10]=[C:9]1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c(CO)n1
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cn(Cc2ccccc2)c(CO)n1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 1-benzyl-2-hydroxymethylimidazole-4-carboxylate (described immediately above, 1 g), an aqueous ammonium hydroxide solution (specific gravity 0.88 g/ml, 60 ml) and ethanol (25 ml) was stirred at laboratory temperature for 48 hours and then heated to 50° C. for 4 hours. The mixture was evaporated to give 1-benzyl-2-hydroxymethylimidazole-4-carboxamide, m.p. 204°-207° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13](=O)[CH:14]([CH3:16])[CH3:15].C(=O)C>>[CH2:13]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C=O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: CC=O
Product: CC(C)CN[C@H](Cc1ccccc1)C(=O)O

Procedure:
Starting from 8.25 g (0.05 mole) of D-phenylalanine, and using the procedure described in Example 3, Step A, except that 9.1 ml (0.1 mole) of isobutyraldehyde are used instead of acetaldehyde, 8.7 g (70%) of the product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[Cl:35])=[N:26][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[S:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[Cl:35])=[N:26][N:27]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1cccc(-c2nnc(CBr)s2)c1Cl
Product: O=c1n(Cc2nnc(-c3cccc(Cl)c3Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of Example 18, 36 mg (0.12 mmol) of the compound from Example 5A were reacted with 38 mg (0.12 mmol) of the compound from Example 87A. This gave 33 mg (48% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH3:10])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH3:10])[C:5]([CH2:8][O:9][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[N:6][CH:7]=1
Reactant: COc1c(Br)cnc(CO)c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cnc(CO[Si](C)(C)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
The above (5-bromo-4-methoxy-3-methylpyridin-2-yl)methanol (500 mg) was dissolved in dichloromethane (10 ml), and t-butyldimethylsilyl chloride (487 mg), triethylamine (0.48 ml), and dimethylaminopyridine (30 mg) were then added to the solution under cooling in an ice bath. The resulting mixture was stirred at room temperature overnight. Thereafter, the reaction solution was diluted with dichloromethane, and was then washed with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain the title compound (743 mg) as an oily substance.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH:9]2[O:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH2:5][CH2:4][NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH:9]2[O:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH2:5][CH2:4][N:3]1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C1NCCC1CCC1COCCO1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(CCC2COCCO2)C1=O
Reaction time: 0.33 h

Procedure:
To a rapidly stirred solution of 2-3 (0.86 g, 4.3 mmol) and THF (25 mL) at -78° C. was added NaN(TMS)2 (5.2 mL, 5.2 mmol, 1.0 M in THF). After 20 min, ethyl bromoacetate (0.58 mL, 5.2 mmol) was added followed by removal of the cooling bath. After 1 h, the reaction mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 2-4 as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:23]=[CH:22][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22]2[CH:23]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccccc1Oc1ccc(I)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A 1000 mL 3-necked round-bottomed flask fitted with a Dean-Stark trap, condenser, stir-bar and nitrogen gas adaptor was charged with 4-iodophenol (19.0 g, 0.086 mol), 4-fluorobenzophenone (15.72 g, 0.079 mol), potassium carbonate (7.16 g, 0.0518 mol), DMF (157 mL) and toluene (16 mL). The resulting mixture was stirred and refluxed for 2 hours (solution temperature ˜160° C.) under nitrogen atmosphere. Water was collected at the trap during this period of time. After 2 hours, the reaction was cooled to room temperature, and water (400 mL) was added to the reaction mixture and the desired product precipitated out of solution as a cream white solid. The product was further purified by re-crystallization isopropanol (400 mL) to give the desired product as a white crystalline solid (25 g, 87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[F:11][C:12]([F:18])([F:17])[C:13](OC)=[O:14].Cl>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13](=[O:14])[C:12]([F:18])([F:17])[F:11])=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COC(=O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
At −60° C., a solution of 10.5 g of 4-methoxyphenylmagnesium bromide in 50 ml of THF was added dropwise over a period of 1 hour to a solution of 7.2 g of methyl trifluoroacetate in 50 ml of ether. Stirring was then continued at −20° C. for 2 hours and at 0° C. for a further hour. The reaction solution was mixed with 25 ml of 2N hydrochloric acid and extracted with ethyl acetate. The extract was dried and concentrated. The residue was distilled under reduced pressure (b.p. 41° C., 4.5×10−1 torr), to give the title product as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]=NC2C=CC=CC=2)=[C:6]([CH3:16])[N:5]=[C:4]([NH2:17])[CH:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:16])[N:5]=[C:4]([NH2:17])[CH:3]=1
Reactant: Cc1cc(N)nc(C)c1N=Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)nc(C)c1N
Yield: 72.8 %

Procedure:
A mixture of 7.5 parts of 4,6-dimethyl-5-(phenylazo)-2-pyridinamine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.3 parts (72.8%) of 4,6-dimethyl-2,5-pyridinediamine as a residue (int. 96).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[CH:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH2:27]([NH2:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl.C(N(CC)CC)C>[CH2:27]([NH:37][C:9](=[O:11])[CH:8]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCN
Reactant: O=C(O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 8.0 g. of 3-phenyl-3-(3-nitrophenyl)propenoic acid in 260 ml. of methylene chloride was added 3.3 g. of triethylamine. The mixture was stirred for 20 minutes and then it was cooled in an ice-bath. To the cooled solution was added, dropwise, during 15 minutes, a solution of 3.6 g. of ethyl chloroformate in 30 ml. of methylene chloride. Stirring was continued for 20 minutes, and then a solution of 5.2 g. of decylamine in 30 ml. of methylene chloride was added, dropwise, during 10 minutes. The reaction mixture was allowed to warm to room temperature, and then it was washed successively with 1 N potassium hydroxide, 1 N hydrochloric acid, water, and saturated sodium chloride solution. The resulting solution was dried (Na2SO4) and evaporated in vacuo to give the 10.7 g. of the title compound as a oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CN(C=O)C.S(Cl)([Cl:22])=O>ClC1C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([Cl:22])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2ccccc2cc1O
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: O=C(Cl)c1cc2ccccc2cc1O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 723 %

Procedure:
99.0 g (0.52 mol) of 3-hydroxy-2-naphthoic acid and 1 ml of N,N'-dimethylformamide are initially introduced into 600 ml of chlorobenzene and 68.5 g=42 ml (0.58 mol) of thionyl chloride are added at 40° C. The mixture is subsequently stirred at 40° C. for 1.5 h and excess thionyl chloride is then distilled off in vacuo. 776.8 g of 3-hydroxy-2-naphthoyl chloride are obtained as a clear solution in chlorobenzene.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25])[C:15]=3[OH:27])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:35]=[C:34]([Br:36])[CH:33]=[C:32]([Br:37])[C:31]=1[OH:38].C(N(CC)CC)C>C1COCC1>[CH:1]1[C:13]2[N:12]([C:14]3[C:15]([OH:27])=[C:16]([CH:17]=[CH:18][CH:19]=3)[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[C:32]([Br:37])[C:31]=3[OH:38])[CH3:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1c(Br)cc(Br)cc1CBr
Reactant: CNCCN(C)Cc1cccc(-n2c3ccccc3c3ccccc32)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCN(C)Cc1cccc(-n2c3ccccc3c3ccccc32)c1O)Cc1cc(Br)cc(Br)c1O
Reaction time: 8 h
Yield: 56.9 %

Procedure:
2 (0.218 g, 0.606 mmol) and 2-bromomethyl-4,6-dibromophenol (0.209 g, 0.606 mmol) were dissolved in 20 mL of THF. Triethylamine (1.2 mL, 8.61 mmol) was added to the slightly pink solution. A white precipitate formed immediately. The reaction was allowed to stir overnight after which time the volatiles were removed and methanol added to make a slurry. The solids were filtered and dried under vacuum resulting in a white solid (0.215 g, 57% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([OH:23])=O)[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[NH:27][CH:24]2[CH2:26][CH2:25]2)[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Reactant: NC1CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)NC2CC2)ccc1Cl)C1CC1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a sol. of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-acetic acid (4.30 g, 12.6 mmol) in CH2Cl2 (130 mL) was added 1-chloro-N,N-2-trimethylpropenyl amine (1.87 mL, 15.2 mmol), and the mixture was stirred for 60 min. A sol. of cyclopropylamine (3.62 mL, 50.6 mmol) in CH2Cl2 (50 mL) was added, and the mixture was stirred for 60 min. More CH2Cl2 was added, and the mixture was washed with water and brine, was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 7:3) yielded the title compound (3.14 g, 65%). LC-MS: tR=0.97 min; ES+: 323.29.