Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[N:15]1([CH2:3][C:4]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1c[nH]cn1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(Cn2ccnc2)c2cccnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.6 %

Procedure:
A mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (3.45 g; 15 mmol), imidazole (1.02 g; 15 mmol) and diisopropylethylamine (5.25 ml; 30 mmol) in CHCl3 (60 ml) was stirred for 24 h at room temperature and then for 3 h at 60° C. After cooling, the mixture was evaporated, washed with ethyl acetate (50 ml) and then hexane (50 ml). The residue was crystallized from a mixture of toluene and ethanol (abs.) to give 0.83 g (29%) of title product. M.p. 182° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:17]1[CH:16]=[C:15]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[N:25][CH:26]=3)[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COCCOCOc1ccc(-c2cccc(F)c2)cc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COCCOCOc1ccc(-c2cccc(F)c2)cc1-c1ccc(C(F)(F)F)nc1
Temperature: 80 °C
Yield: 87.6 %

Procedure:
A mixture of 3-bromo-3′-fluoro-4-((2-methoxyethoxy)methoxy)-1,1′-biphenyl (1.56 g, 4.39 mmol), 2-(trifluoromethyl)pyridine-5-boronic acid [purchased from Frontier Scientific] (1.09 g, 5.709 mmol) and potassium carbonate (0.91 g, 6.59 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (253.8 mg, 0.22 mmol) was added and the reaction mixture heated at 80° C. in a sealed vial for 2 days. The cooled reaction mixture was partitioned between ethyl acetate (80 mL) and 1.0 M aqueous sodium hydroxide solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 20% ethyl acetate (containing 2% methanol) in hexanes to give 5-(3′-fluoro-4-((2-methoxyethoxy)methoxy)-[1,1′-biphenyl]-3-yl)-2-(trifluoromethyl)pyridine (1.62 g, 88% yield) as a yellow syrup.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[SH:11])[C:6]#[N:7])#[N:2].[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@@H:17]1Br)(=[O:14])[CH3:13]>[O-2].[Zn+2]>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@H:17]1[S:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:1]#[N:2])(=[O:14])[CH3:13]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1ccc(S)c(C#N)c1
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C#N)cc2C#N)SC[C@H]1OC(C)=O
Yield: 47.9 %

Procedure:
If the procedure described in Preparation IV is followed starting from 1.6 g (9.73.10-3 mol) of 3-cyano-4-mercaptobenzonitrile, 4.07 g (11.45.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 0.84 g (10.10-3 mol) of zinc oxide (ZnO), 2.08 g (yield: 47%) of the expected product are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:33][C:32]([F:35])([F:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccccc1I
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-carboxybenzeneboronic acid (1.218 g, 7.340 mmol) and Na2CO3 (2.40 g, 22.6 mmol) in water (75 mL) was added p-dioxane (75 mL). This mixture was treated sequentially with 2-iodobenzotrifluoride (1.05 mL, 7.48 mmol) and palladium (II) acetate (151 mg, 0.673 mmol) and allowed to stir at ambient temperature for 16 hours. The solvent was evaporated in vacuo. To the residue was added EtOAc (400 mL) and water (300 mL). The aqueous layer was acidified to pH 1 with 1.0 N aq. HCl and the layers separated. The aqueous layer was extracted with EtOAc (2×200 mL). The organic extracts were combined, washed with brine (200 mL), 5% aq. Na2S2O3 (200 mL), saturated NaCl (200 mL), dried (Na2SO4), and the solvent evaporated in vacuo to afford the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz) d 8.14(2H, d, J=8.1 Hz), ), 7.77(1H, d, J=7.9 Hz), 7.60(1H, t, J=7.5 Hz), 7.52(1H, t, J=7.3 Hz), 7.44(2H, d, J=8.1 Hz) and 7.33(1H, d, J=7.5 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2OC(=O)[S:11][N:10]=2)=[CH:5][CH:4]=1.[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:16]>CCCCCCCCCCCC>[CH2:20]([O:19][C:17]([C:15]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:16]=1)=[O:18])[CH3:21]
Reactant: COc1ccc(-c2nsc(=O)o2)cc1
Reactant: CCOC(=O)C#N
Solvent: CCCCCCCCCCCC
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)ns1
Temperature: 150 °C
Yield: 40.5 %

Procedure:
To a solution of 5-(4-methoxyphenyl)-[1,3,4]oxathiazol-2-one (0.47 g, 2.24 mmol) in n-dodecane (0.70 ml) was added ethyl cyanoformate (0.90 ml, 8.10 mmol). The resulting reaction mixture was refluxed for 20 h at 150° C. After the completion of the reaction (TLC monitoring), added ice-cold water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue washed with ether to get the desired product (0.24 g, 40%). MS ES+ (265.08).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:18]([CH3:19])[CH2:17][O:16][CH2:15][C:14]1=[O:20])[C:5]([O:7]CC)=[O:6].[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:18]([CH3:19])[CH2:17][O:16][CH2:15][C:14]1=[O:20])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(N2C(=O)COCC2C)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1COCC(=O)N1c1ccc(C(=O)O)cc1Cl

Procedure:
Prepared analogously to Example 31b from ethyl 3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoate with lithium hydroxide in THF and water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[C:27]([CH3:37])=[N:28][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[C:27]([CH3:37])=[N:28][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:30]=1)[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1cn(-c2ccccn2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2cn(-c3ccccn3)nc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 67.5 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.28 g), tetraethyl methylenediphosphonate (0.18 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.030 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.24 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (5:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15].C(N(CC)CC)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CC(c2ccc(Br)c(F)c2)=NO1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
[3-(4-Bromo-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl]methanol (7.518 g, 27.4 mmol) was dissolved in a mixture of triethylamine (4.59 ml, 33.0 mmol) and dichloromethane (100 ml). The resulting solution was cooled to 0° C., then a 1M solution of tert-butyldimethylsilylchloride (30.2 ml) in dichloromethane was added dropwise over 30 minutes. 4-Dimethylamino pyridine (0.67 g, 5.48 mmol) was added and the reaction mixture left to stir overnight at room temperature. The reaction mixture was washed with water (200 ml). The dichloromethane layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 9.263 g (87%) of the desired compound as a colourless oil.
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[C:12]([C:13]#[N:14])=[C:11](I)[C:10]([O:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C1COCC1.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]1[C:12]([C:13]#[N:14])=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:10]([O:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1
Reactant: Brc1ccccn1
Reactant: COc1cc(F)c(C#N)c(I)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COc1cc(F)c(C#N)c(-c2ccccn2)c1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
Under nitrogen, to a vigorously stirred suspension of zinc dust (25.5 g, 391 mmol) in anhydrous THF (700 ml) was added chlorotrimethylsilane (10.7 ml, 85 mmol) and the suspension heated to 60° C. After 1 hour at 60° C. the reaction was allowed to cool to 40° C. and a solution of 6-fluoro-2-iodo-3,4-dimethoxybenzonitrile (as prepared in Example 1(a), 100 g, 330 mmol) was added slowly over a period of 20 minutes, keeping the temperature in the range 40° C. to 50° C. The resulting suspension was heated to 60° C. for 1 hour then allowed to cool to room temperature. 2-Bromopyridine (61.8 g, 391 mmol), palladium acetate (0.73 g, 3.3 mmol) and triphenylphosphine (1.71 g, 6.5 mmol) were added and the suspension heated to 60° C. for 1 hour then allowed to cool to room temperature. The reaction was quenched with a 5% aqueous solution of the dipotassium salt of ethylenediaminetetraacetic acid (1 liter), followed by DCM (2 liters) and the resulting mixture stirred for 15 minutes. After this time the mixture was filtered through Arbocel™ filter aid and the pad washed with DCM (100 ml). The phases were separated and the organic phase washed with water (1 liter). The organic phase was distilled and replaced with acetonitrile to give a final volume of 1 liter and the resulting solution left to cool to room temperature overnight. The resulting suspension was filtered and the solid dried in vacuo overnight at 45° C. to give 54.0 g of the title product (67%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=O)[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6][C@@H:5]1[OH:28])[CH3:2].Cl.[NH2:30][OH:31].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=[N:30][OH:31])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6][C@@H:5]1[OH:28])[CH3:2]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@@]2(C)[C@H]3CCC23OCCO3)C[C@@H]1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=NO)C[C@@]2(C)[C@H]3CCC23OCCO3)C[C@@H]1O

Procedure:
2β-Ethoxy-17,17-ethylenedioxy-3α-hydroxy-5α-androstan-11-one (8.2 g) was added to hydroxylamine hydrochloride (15 g) in ethanol (500 ml) containing 44% sodium hydroxide solution (90 ml). After refluxing for 24 hours about half the solvent was evaporated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The washed and dried (Na2SO4) organic solution was evaporated in vacuo to afford a froth which on crystallization from ethyl acetate-petroleum ether afforded the title compound m.p. 136°-140°, [α]D +41.1°.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N:23]=[C:24]=[O:25]>C(Cl)Cl>[C:11]([C:3]1[NH:4][C:5]([C:7]([CH3:10])([CH3:8])[CH3:9])=[CH:6][C:2]=1[NH:1][C:24]([NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[Cl:15])=[O:25])([O:13][CH3:14])=[O:12]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Solvent: ClCCl
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1NC(=O)Nc1cccc(Cl)c1Cl
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of methyl 3-amino-5-tert-butylpyrrole-2-carboxylate (0.99 g, 5.00 mmol) in anh. CH2Cl2 (50 ml) at room temp. was added a solution of 2,3-dichlorophenyl isocyanate (0.948 g, 5.00 mmol) in CH2Cl2 (10 mL) and the resulting mixture was allowed to stir overnight. The resulting white precipitate formed overnight was separated and washed with CH2Cl2 to give the desired urea (1.39 g, 67%) as a white powder: mp 200-201° C.; 1H-NMR (DMSO-d6) δ1.23 (s, 9H), 3.78 (s, 3H), 6.50 (d, J=2.95 Hz, 1H), 7.26-7.30 (m, 2H), 7.88-7.91 (m, 1H), 9.12 (s, 1H), 9.40 (s, 1H), 10.91 (br s, 1H); FAB-LRMS m/z 384 (M+H). Anal. Calcd for C17H19N3O3Cl2: C, 53.14; H, 4.98; N, 10.94. Found: C, 53.03; H, 4.79; N, 10.86.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)SC)#[N:2].[NH2:17][CH2:18][CH2:19]SCC1C=CSN=1.C(N)C>>[C:1]([NH:3][C:4]([NH:17][CH2:18][CH3:19])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1)#[N:2]
Reactant: NCCSCc1ccsn1
Reactant: CSC(=NCCSCc1ccsn1)NC#N
Agent: CCN
Product: CCNC(=NCCSCc1ccsn1)NC#N

Procedure:
Reacting N-cyano-N'-[2-(3-isothiazolylmethylthio)ethyl]-S-methylisothiourea, prepared from 3-[(2-aminoethyl)thiomethyl]isothiazole by the procedure of Example 3(c) (i), with ethylamine by the procedure of Example 4 gives N-cyano-N'-ethyl-N"-[2-(3-isothiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].[OH-].[Na+]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)=[O:20]
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccccc1Cl)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCN(C(=O)c1ccccc1Cl)c1cccc(Cl)c1

Procedure:
As described in example 1(b), the reaction is carried out with 3.8 g (9 mmol) of 8-[2-chloro-N-(3-chlorophenyl)-benzamido]-caprylic acid methyl ester, 0.48 g (12 mmol) of sodium hydroxide and 50 cc. of methanol. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24]([O:26]CC)=O)=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].C1COCC1.[NH4+:41].[OH-]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:30])[CH3:31])[C:21]([C:24]([NH2:41])=[O:26])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1c(C(N)=O)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
To a vial containing Ethyl 5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate (59 mg, 0.1 mmol) was added THF (0.6 mL) and NH4OH (0.2 mL). The solution was stirred at room temperature for 16 h. EtOAc (30 mL) was added. The organic phase washed with water (2×10 mL) and dried over Na2SO4. The volatiles were removed in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (4.0 mg, 8% yield). HPLC retention time=2.76 minutes. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.0, 1H), 8.16 (d, J=2.0, 1H), 8.05 (d, J=2.4, 1H), 7.85 (dd, J=2.4, 8.4, 1H), 7.53 (d, J=8.4, 1H), 5.75 (sept, J=6.8, 1H), 1.52 (d, J=6.8, 6H). MS (ES) [M+H]+ expected 523.0, found 522.9.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:4]=1.Cl.[CH3:20]O>>[ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:20])=[O:11])=[C:5]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:4]=1
Reactant: CO
Reactant: Nc1ccc(CC(=O)O)c(OCC(F)(F)F)c1
Agent: Cl
Product: COC(=O)Cc1ccc(N)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Into a stirred solution of 4-amino-2-(2,2,2-trifluoroethoxy)phenylacetic acid hydrochloride (0.95 g, 3.5 mmol) from Step 6 above in MeOH (25 mL) at 0° C. was bubbled HCl gas for 10 min. The resulting solution was warmed to ambient temperature and stirred for 14 h. The solvent was removed under reduced pressure to give methyl 4-amino-2-(2,2,2-trifluoroethoxy)phenylacetate hydrochloride as a solid (HPLC retention time=5.6 min (method A)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:23])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: Cc1ccc[n+]([O-])c1-c1ccc(F)cc1
Temperature: 50 °C
Yield: 85 %

Procedure:
A solution of 2-(4-fluorophenyl)-3-methylpyridine (26.8 g, 0.143 mol) and m-chloroperbenzoic acid (purity 69%, 39 g, 0.157 mol) in tetrahydrofuran (100 mL) was stirred with heating at 50° C. for 5 hr. The solvent was evaporated under reduced pressure, and the obtained residue was purified 3 times by silica gel column chromatography (NH silica gel, ethyl acetate) to give a white solid. The obtained solid was washed with ethyl acetate to give the title compound (24.7 g, 85%) as a white solid.
Reaction SMILES: [CH:1]1([N:5]2[C:10]3[N:11]=[C:12](S(C)=O)[N:13]=[C:14]([CH3:15])[C:9]=3[CH:8]=[C:7]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6]2=[O:27])[CH2:4][CH2:3][CH2:2]1.[N:28]1C2NC(=O)C=CC=2C=N[CH:29]=1>>[CH:1]1([N:5]2[C:10]3[N:11]=[C:12]([NH:28][CH3:29])[N:13]=[C:14]([CH3:15])[C:9]=3[CH:8]=[C:7]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6]2=[O:27])[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc3c(C)nc(S(C)=O)nc3n(C3CCC3)c2=O)cn1
Reactant: O=c1ccc2cncnc2[nH]1
Product: CNc1nc(C)c2cc(-c3ccc(OC)nc3)c(=O)n(C3CCC3)c2n1
Yield: 35 %

Procedure:
Following the procedure described in Example 22, using 8-cyclobutyl-6-(6-methoxypyridin-3-yl)-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one in place of 6-(6-methoxypyridin-3-yl)-4-methyl-2-ethylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one, the title compound was obtained in 35% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:12]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Fluorobenzenesulfonylchloride (25 g) were dissolved in dichloromethane (250 ml) and treated at 0° C. with an aqueous solution of ammonia (25%, 50 ml). The mixture was stirred for 2 hours with cooling and overnight at room temperature. The reaction mixture was acidified and the organic solvent evaporated. The residue was extracted with ethyl acetate to yield 20 g 4-fluorobenzenesulfonamide, which were dissolved in water (300 ml), treated with 1-benzyl-piperazine (102 g) and refluxed for 24 hours. The reaction mixture was filtered to yield 26 g of the title compound. (mass spec APCI [M+H]=332)
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]2[CH:14]=[N:15][C:16](Cl)=[N:17][C:6]1=2)[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(O)C>Cl.O>[CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)O)cc3OC)nc21
Yield: 70.1 %

Procedure:
A mixture of 0.08 g (0.0003 mole) of 9-butyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-44), 0.060 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.084 g of 4-(9-butyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-44a) as an off-white solid.