Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(C1C=CC2C(=CC=C(OC3C=CC(OC4C=CC=CC=4)=CC=3)C=2)C=1)(CO)CO.[CH2:31]([O:38][C:39]1[CH:64]=[CH:63][C:42]([O:43][C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[CH:50]=[C:49]([C:54]2([NH2:62])[CH2:59][O:58]C(C)(C)[O:56][CH2:55]2)[CH:48]=[CH:47]3)=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[NH2:62][C:54]([C:49]1[CH:48]=[CH:47][C:46]2[C:51](=[CH:52][CH:53]=[C:44]([O:43][C:42]3[CH:63]=[CH:64][C:39]([O:38][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:40][CH:41]=3)[CH:45]=2)[CH:50]=1)([CH2:55][OH:56])[CH2:59][OH:58]
Reactant: CC1(C)OCC(N)(c2ccc3cc(Oc4ccc(OCc5ccccc5)cc4)ccc3c2)CO1
Agent: NC(CO)(CO)c1ccc2cc(Oc3ccc(Oc4ccccc4)cc3)ccc2c1
Product: NC(CO)(CO)c1ccc2cc(Oc3ccc(OCc4ccccc4)cc3)ccc2c1
Yield: 81 %

Procedure:
2-amino-2-(6-(4-(benzyloxy)phenoxy)naphthalen-2-yl)propane-1,3-diol was synthesized as per 2-amino-2-(6-(4-phenoxyphenoxy)naphthalen-2-yl)propane-1,3-diol (Example 245) in 81% yield using 5-(6-(4-(benzyloxy)phenoxy)naphthalen-2-yl)-2,2-dimethyl-1,3-dioxan-5-amine as starting material. MS: m/z=438.24 [M+Na+]. 1H NMR (MeOD) δ: 7.95 (s, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.66-7.70 (m, 1H), 7.59-7.63 (m, 1H), 7.47 (d, J=7.5 Hz, 2H), 7.37-7.43 (m, 2H), 7.34 (d, J=7.0 Hz, 1H), 7.22 (dd, J=8.8, 2.5 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 7.00-7.08 (m, 4H), 5.11 (s, 2H), 3.87-3.93 (m, 2H), 3.80-3.86 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:34]=O)=C(C(OCC)=O)[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:9].Cl.[NH2:37]O.C([O-])(=O)C.[Na+].[C:44]([O:47][C:48](=O)[CH3:49])(=[O:46])[CH3:45]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([C:34]#[N:37])=[C:45]([C:44]([O:47][CH2:48][CH3:49])=[O:46])[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Reactant: NO
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C#N)NC(C)=C(C(=O)OCCOc2ccccc2)C1c1ccccc1[N+](=O)[O-]

Procedure:
Starting from a mixture of 2-phenoxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.03 g), hydroxylamine hydrochloride (178.6 mg) and sodium acetate (352 mg) in acetic acid (8 ml) and acetic anhydride (1 ml), there was obtained in a similar manner to that of Example (4-2) an oil (420 mg) of 2-phenoxyethyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][C@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[C@H:84]([CH3:88])[CH2:83]1)=[O:81])[CH3:78]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCN[C@H](C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)[C@H](C)C1
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 28 μl DIPEA, 64 mg HATU and 28 mg (R)-3-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 360 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:39])=[C:11]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:33]=[CH:34][C:35]=3[N+:36]([O-])=O)[O:19][CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1>[Pd].C(O)C>[NH2:36][C:35]1[CH:34]=[CH:33][C:18]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]2)=[CH:17][C:16]=1[C:14]([NH:13][C:11]1[CH:12]=[C:7]([C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])[CH:8]=[CH:9][C:10]=1[CH3:39])=[O:15]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Yield: 92 %

Procedure:
tert-Butyl 4-{3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-4-nitrophenoxy}piperidine-1-carboxylate (4.03 g) and 10% Palladium on carbon (0.4 g) were stirred in ethanol (90 ml) under an atmosphere of hydrogen gas. After cessation of hydrogen uptake, the catalyst was removed by filtration through diatomaceous earth (Celite®). The filtrate was concentrated under reduced pressure to provide the crude tert-butyl 4-{4-amino-3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}piperidine-1-carboxylate (3.50 g) which was used without further purification; NMR Spectrum: (DMSOd6) 0.59 (m, 2H), 0.70 (m, 2H), 1.40 (s, 9H), 1.52 (m, 2H), 1.38 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 3.18 (m, 2H), 3.64 (m, 2H), 4.36 (m, 1H), 6.03 (s, 21, 6.71 (d, 1H), 6.96 (d, 1H), 7.31 (d, 1H), 7.34 (s, 1H), 7.62 (d, 1H), 7.79 (s, 1H), 8.37 (d, 1H), 9.72 (s, 1H); Mass Spectrum: M+Na+ 531. C) Triethyl orthoformate (1.0 ml) was added to a stirred mixture of tert-butyl 4-{4-amino-3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}piperidine-1-carboxylate (1.02 g) and glacial acetic acid (0.057 ml) in ethanol (15 ml). The mixture was heated to 80° C. and stirred for 2 hours and then concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution, brine, dried (magnesium sulfate) and concentrated to provide tert-butyl 4-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]piperidine-1-carboxylate (0.994 g) as a light brown solid; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.70 (m, 2H), 1.42 (s, 9H), 1.58 (m, 2H), 1.94 (m, 2H), 2.13 (s, 3H), 2.85 (m, 1H), 3.23 (m, 2H), 3.65 (m, 2H), 4.77 (m, 1H), 7.52 (d, 1H), 7.55 (d, 1H), 7.63 (s, 1H), 7.72 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.18 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 519.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc([N+](=O)[O-])cc1C(=O)Cl
Yield: 100 %

Procedure:
2-Methoxy-5-nitro benzoic acid (500 mg, 2.5 mmol) was heated to reflux with thionyl chloride (5 ml) for 4 hr. The excess thionyl chloride was evaporated under reduced pressure to yield 2-methoxy-5-nitro-benzoyl chloride (0.55 g, 100%), which was used as such for the next step.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:42]4[CH2:43][CH2:44][CH:39]([CH2:38][NH2:37])[CH2:40][CH2:41]4)=[CH:20][CH:19]=2)=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: NCc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(OC(=O)c3c4ccccc4nc4ccccc34)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCC1CCN(CCc2ccc(OC(=O)c3c4ccccc4nc4ccccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.1 %

Procedure:
In 30 ml of DMF, 2.9 g of the compound (3) obtained in Example 3 were dissolved, followed by the addition of 0.59 g of 4-aminomethylpyridine. The resultant mixture was stirred at room temperature, to which 0.60 g of t-BuOK was added under ice cooling. The thus-obtained mixture was stirred at room temperature for 5 hours. The DMF was distilled off under reduced pressure, and the residue was dissolved in CHCl3. The solution so obtained was washed with water and then dried over anhydrous magnesium sulfate (MgSO4). The solvent was distilled off under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (eluent: CHCl3/MeOH=7/3), whereby 0.41 g of the compound (4) was obtained (yield: 18%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:26](OC1C=CC=CC=1)=[O:27].Cl.Cl.[N:37]1([CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:26]([N:46]3[CH2:47][CH2:48][CH:43]([CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:44][CH2:45]3)=[O:27])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Nitrophenoxy)pyridin-2-ylamine (160 mg) was dissolved in tetrahydrofuran (7 ml) under a nitrogen atmosphere, and then triethylamine (0.289 ml) and phenyl chloroformate (0.260 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, and N,N-dimethylformamide (8 ml) was added thereto. And then 4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (668 mg) and triethylamine (0.772 ml) were added thereto, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing a target compound were concentrated to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (295 mg) as pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:12])[O:8][CH2:9][CH2:10]Cl)([C:4]#[CH:5])[CH3:3].[H-].[Na+].Cl>C1COCC1>[CH3:1][C:2]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:12])([C:4]#[CH:5])[CH3:3]
Reactant: C#CC(C)(C)NC(=O)OCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(C)(C)N1CCOC1=O
Reaction time: 24 h
Yield: 67.3 %

Procedure:
Crude 2-chloroethyl 2-methylbut-3-yn-2-ylcarbamate (1.05 g, 5.5 mmol) was dissolved in dry THF (20 mL) and 60% NaH in oil (665 mg, 16.6 mmol) was added. The mixture was stirred under N2 for 1 day and 5% aq HCl (25 mL) was added. The mixture was extracted with EtOAc (175 mL). The organic layer was washed with brine (25 mL) and dried over Na2SO4. Removal of the solvent left an oil (1.03 g) which was purified by chromatography on a 12-g cartridge eluted with a 0-80% EtOAc in hexanes gradient to afford 3-(2-methylbut-3-yn-2-yl)oxazolidin-2-one (567 mg, 67%) as a white solid. 1H NMR (CDCl3) 1.72 (s, 6H), 2.43 (s, 1H), 3.74 (dd, 2H), 4.18 (dd, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]=[O:26])=[CH:19][CH:18]=1)=[O:16].[C-:27]#[N:28].[Na+].[C:30]([O:33]C(=O)C)(=O)[CH3:31].ClCCl>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.O>[C:30]([O:26][CH:25]([CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:15](=[O:16])[CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:22][CH:21]=1)[C:27]#[N:28])(=[O:33])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CCC=O)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(C#N)CCc1ccc(C(=O)CCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
A mixture of 3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]phenyl]propionaldehyde (1.47 g), sodium cyanide (0.25 g), acetic anhydride (0.52 g), benzyltributylammonium chloride [(C4H9)3 (C6H5CH2)N+Cl- ](0.66 g) and dichloromethane (30 ml)- water (10 ml) was stirred at room temperature for 18 hours. The organic layer was separated, washed with water, dried (MgSO4) and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:2), 2-acetoxy-4-[4-[3-(5-methyl- 2-phenyl-4-oxazolyl)propionyl]phenyl]butyronitrile (1.75 g, quantitative) was obtained as an oily substance. NMR (δ ppm in CDCl3): 2.13 (3H, s), 2.15-2.3 (2H, m), 2.38 (3H, s), 2.8-3.0 (4H, m), 3.39 (2H, t, J=7 Hz), 5.29 (1H, t, J=6.5 Hz), 7.28 (2H, d, J=8 Hz), 7.35-7.5 (3H, m), 7.9-8.05 (4H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([C:14]#[N:15])[CH2:7]C2C=CC=CC=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:26][N:27]=[C:28]=[S:29]>O1CCCC1>[CH3:26][NH:27][C:28](=[S:29])[C:6]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=1)([C:14]#[N:15])[CH3:7]
Reactant: CN=C=S
Reactant: N#CC(Cc1ccccc1)c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(=S)C(C)(C#N)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
To a 10 ml tetrahydrofuran solution containing 1.00 g (6 mmole) of 4-chlorophenylmethylbenzylcyanide was added a 3.2 ml tetrahydrofuran solution containing 2 M of lithium diisopropylamide at -60° C. After stirring for 30 minutes under the same conditions, a 5 ml tetrahydrofuran solution containing 0.44 g (6 mmol) of methyl isothiocyanate was added to the mixture and the mixture was allowed to stand at room temperature overnight. The solvent was removed from the reaction mixture under reduced pressure and water was added to the residue. The mixture was extracted with 50 ml of ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography and recrystallized from hexane to obtain 0.45 g (yield: 31.4 %) of N-methyl-2-(4-chlorophenyl)-2-cyano-thiopropionamide.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[SH:13].[CH3:14]Br>>[NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:10])([CH3:12])[CH3:11])=[N:5][N:4]=[C:3]1[S:13][CH3:14]
Reactant: CC(C)(C)c1nnc(S)n(N)c1=O
Reactant: CBr
Product: CSc1nnc(C(C)(C)C)c(=O)n1N

Procedure:
This invention relates to improvements in the process of methylation of 4-amino-6-t-butyl-3-mercapto-1,2,4-triazin-5-one, hereinafter referred to as butylthion, using methyl bromide to produce 4-amino-6-t-butyl-3-methylmercapto-1,2,4-triazin-5-one, hereinafter referred to as metribuzin.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:6][C:5]=1[F:21])=[N+:2]=[N-:3].[BH4-].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1.C[OH:30]>>[F:21][C:5]1[CH:6]=[C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:26]=[C:25]([CH:24]([OH:30])[CH3:28])[N:3]=[N:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N=[N+]=[N-])c(F)c2)C(=O)O1
Reactant: CO
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cc(C(C)O)nn3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A solution of 150 mg (0.40 mmol) of the compound of Example 17 in 10 mL 1:1 THF-methanol was treated with 15 mg (0.4 mmol) of sodium borohydride followed by stirring at ambient temperature for 18 h. The mixture was concentrated in vacuo, dissolved in 1:1 methanol-dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue was subjected to radial chromatography on a 2 mm chromatotron plate. These procedures afforded 120 mg (80%) of the title compound as a white solid. Mass Spectrum (EI): m/z 363, 291, 276, 232, 217, 207, 191, 179, 163, 148, 135, 123, 85, 56.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.C([N:23](CC)[CH:24]([CH3:26])[CH3:25])(C)C.CN(C(ON1N=N[C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:23][C:24]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][N:43]=2)[CH2:26][CH2:25]1)=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)NC2(c3ccccn3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
To a 2 dram vial was added 5-bromo-2,4-dimethoxybenzoic acid (1.044 g, 4 mmol), DMF (48.2 mL), N,N-Diisopropylethylamine (2.79 mL, 16.00 mmol), 1-(pyridin-2-yl)cyclopropanamine, 2 HCl (0.911 g, 4.40 mmol), and finally HATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyl isouronium hexafluorophosphate(V), 6.08 g, 16.00 mmol). The vial was capped and shaken for 16 hours at room temperature. The crude reaction mixture was diluted with 10 mL of DCM, washed with 5 mL of 1M HCl, extracted, washed with 20 mL of brine, and dried over magnesium sulfate. The solution was pushed through a plug of silica gel and evaporated to dryness. Trituration with 20 mL of diethyl ether gave 1.6 grams of 5-bromo-2,4-dimethoxy-N-(1-(pyridin-2-yl)cyclopropyl)benzamide as a tan solid (76% yield). 1H NMR (400 MHz, THF-d8) δ ppm 1.22-1.32 (m, 2H), 1.59-1.67 (m, 2H), 3.94 (s, 3H), 4.02 (s, 3H), 6.72 (s, 1H), 7.09 (m, 1H), 7.47 (d, J=8.03 Hz, 1H), 7.62 (td, J=7.72, 1.88 Hz, 1H), 8.20 (s, 1H), 8.39-8.52 (m, 2H). LCMS Rt=2.162 min., m/z 379.2 (M+2H), 96% purity.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([CH3:37])([CH3:36])[C:30]#[C:31][CH:32]=[CH:33][CH2:34]O>ClCCl>[Br:1][CH2:34][CH:33]=[CH:32][C:31]#[C:30][Si:29]([CH3:37])([CH3:36])[CH3:28]
Reactant: C[Si](C)(C)C#CC=CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)C#CC=CCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
N-Bromosuccinimide (85.3 g, 0.48 mol) was added in portions to a nearly homogeneous solution of triphenylphosphine (128.2 g, 0.49 mol) and 5-trimethylsilylpent-2-en-4-yn-1-ol (72.5 g, 0.47 mol) in dichloromethane (600 mL) under nitrogen and cooled in a dry ice/2-propanol bath to an initial temperature of below −20° C. The internal temperature of the reaction mixture was maintained at −10° C. to 0° C. throughout the addition by adjusting the rate of addition. The bath was allowed to warm to ambient temperature. After 2 hours, the reaction was complete. The reaction mixture was concentrated under vacuum to a thick paste and the residue was triturated with hexane (250 mL). The suspension was filtered and the solids and silica gel were rinsed with hexane (10×150 mL). The filtrate was concentrated under vacuum (30° C./60 mtorr) to obtain 44 g (89% yield) of 1-bromo-5-trimethylsilylpent-2-en-4-yne, a compound of formula (P), as a pale yellow oil:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[CH3:25][O:26][C:27]([NH:29][C@@H:30]([CH:34]([CH3:36])[CH3:35])[C:31](O)=[O:32])=[O:28]>>[CH3:25][O:26][C:27](=[O:28])[NH:29][C@@H:30]([CH:34]([CH3:35])[CH3:36])[C:31]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1)=[O:32]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: COC(=O)N[C@H](C(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12)C(C)C

Procedure:
The product of Example 42 and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid were treated using a method similar to that described in Example 56 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.59-11.62 (bs, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.32 (dd, J=7.5, 1.7 Hz, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.88-7.99 (m, 2H), 7.37-7.45 (m, 4H), 7.09-7.13 (m, 1H), 4.52-4.67 (m, 2H), 3.78-3.86 (m, 1H), 3.67 (s, 2H), 3.51 (s, 3H), 1.85-1.96 (m, 1H), 0.71-0.83 (d, 6H); MS (ESI+) M/Z 500 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](S(C1C=CC(C)=CC=1)(=O)=O)[C:10]1[C:9]([C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])([O:26][Si](C)(C)C)[CH2:8][CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9]([C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])([OH:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4cc(Cl)c(Cl)cc42)CCCC3(O[Si](C)(C)C)C(F)(F)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)C(F)(F)F)CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
To 6,7-Dichloro-1-(perfluoroethyl)-9-tosyl-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.25 g, 0.47 mmol) in THF (5 mL) was added 6N KOH (6 mL). The reaction mixture was stirred at room temperature for 10 min. and then refluxed for 36 h, diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography [EtOAc-hexane (3:22) as eluant] to give the title compound as a white solid (0.06 g, 34%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.21 (bs, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 2.82-2.80 (m, 1H), 2.68-2.62 (m, 1H), 2.45 (s, 1H), 2.28-2.23 (m, 1H), 2.18-2.15 (m, 1H), 2.12-2.06 (m 1H), 2.03-2.0 (m, 1H).