Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:6]1=[O:20].C[N:23]([CH3:26])C=O.[C:27](Cl)(=[O:31])[C:28](Cl)=O>ClC(Cl)C>[NH2:5][C:6]1[CH:7]=[CH:8][CH:28]=[C:27]([OH:31])[C:26]=1[NH:23][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([C:7]2[C:6](=[O:20])[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH:10]=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCn1cccc(-c2ccc(C(=O)O)cc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: CN(C)CCn1cccc(-c2ccc(C(=O)Nc3c(N)cccc3O)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{1-[2-(Dimethylamino)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzoic acid (1.46 g) was suspended in dichloroethane (15 ml), dimethylformamide (125 μL) was added, and oxalyl chloride (367 μL) was dropwise added dropwisely at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was evaporated under reduced pressure. A dichloromethane (10 ml)-pyridine (10 ml) solution of 2-amino-3-nitrophenol (499 mg) was added to the resulting residue, followed by stirring overnight at room temperature. The reaction suspension was filtered, and the filtrate was evaporated under reduced pressure. The substance collected by filtration and the filtration residue were dissolved in a mixed solvent of ethanol (14.6 mL)-water (14.6 mL), and an aqueous 1 M hydrochloric acid solution (3.24 mL) and iron (904 mg) were added, followed by heating under reflux for 3 hours. An aqueous saturated sodium hydrogencarbonate solution and chloroform were added to the reaction suspension, followed by vigorous stirring and filtration through Celite. The filtrate was extracted with chloroform, the organic layer was evaporated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain N-(2-amino-6-hydroxyphenyl)-4-{1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridin-3-yl}benzamide (600 mg) as a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O-].[Na+].CI.O>CO>[C:1]([C:5]1[CH:10]=[C:9]([N:11]([CH3:27])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CI
Product: Cc1ccc(S(=O)(=O)N(C)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 5.1 %

Procedure:
To a solution of 3.75 grams (0.01 mole) of the product of Example 1, 2,6-di-tert-butyl-4(p-toluenesulfonamido)phenol, and 0.54 grams (0.01 mole) of sodium methylate in 50 ml of methanol was added 1.42 grams (0.01 mole) of methyl iodide. The reaction mixture was heated with stirring for 72 hours in a pressure tube at 100° C. The reaction mixture was then cooled, poured into 150 ml of water and extracted with heptane. The heptane layer was separated and allowed to stand after cooling. Crystals formed which were isolated by filtration, washed and dried to weigh 0.5 gram and melted at 123°-142° C. Recrystallization from heptane gave 0.2 gram of crystals melting at 130°-142° C. Proton NMR spectra confirmed the expected, desired structure. (Compound 6)
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.Cl.[CH3:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[NH2:20].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH3:16][O:17][C:18](=[O:23])[C:19]([NH:20][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])=[O:14])([CH3:22])[CH3:21]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccccc2c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
1.0 g 1-Bromo-naphthalene-2-carboxylic acid and 0.61 g 2,2-dimethylglycine methyl ester hydrochloride were suspended in 30 ml of dichloromethane and 10 ml of DMF. 1.31 ml N-methylmorpholine, 0.70 g 1-hydroxybenzotriazole and, finally, 0.99 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added and the reaction stirred at room temperature for 14 h. The reaction mixture was chromatographed on silica gel without aqueous work-up to give 1.3 g 2-[(1-bromo-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester (93%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:12][C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:14].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:12]/[C:13]([C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)=[O:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.3 %

Procedure:
To a stirred solution of 4-ethoxybenzaldehyde (1.32 ml, 9.5 mmol) and 3,4,5-trimethoxyacetophenone (2.0 g, 9.5 mmol) in methanol (30 ml) was added 50% w/v of aqueous sodium hydroxide (7.6 ml, 0.095 mol). The reaction was stirred for 24 h at room temperature. A precipitate was isolated by filtration, washed with pet:ether and subsequently recrystallised from ethanol. 1.8 g (55%) of a pale yellow powder was isolated. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.3 (d, 1H), 6.9 (d, 2H), 4.1 (q, 2H), 3.9 (s×2, 9H), 1.4 (t, 3H). 13C-NMR (CDCl3) δ 189.2, 161.1, 153.1, 142.3, 133.8, 127.4, 63.4. Mass Spectrum m/e (M+1) 343.
Reaction SMILES: C1COCC1.[OH:6][C@@H:7]1[C@@:14]([CH3:29])([CH2:15][CH2:16][CH2:17][C:18]([CH3:28])([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:19])[C@@H:13]2[C@:30]([OH:33])(OC)[C@@:9]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])([C:10]([O:35][CH3:36])=[CH:11][C:12]2=[O:34])[CH2:8]1.C([Li])CCC.[CH:47]1[CH:52]=[CH:51][C:50]([O:53][C:54](Cl)=[S:55])=[CH:49][CH:48]=1>CCOC(C)=O.CCCCCC>[C:54](=[S:55])([O:53][C:50]1[CH:51]=[CH:52][CH:47]=[CH:48][CH:49]=1)[O:6][C@H:7]1[CH2:8][C@@:9]2([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:30](=[O:33])[C@H:13]([C:12](=[O:34])[CH:11]=[C:10]2[O:35][CH3:36])[C@:14]1([CH3:29])[CH2:15][CH2:16][CH2:17][C:18]([CH3:19])([O:20][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:26][CH3:27])[CH3:28]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1O)[C@@]2(O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@@]1(C)[C@H]2C(=O)C=C(OC)[C@@](CC=C(C)C)(C[C@@H]1OC(=S)Oc1ccccc1)C2=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 57.9 %

Procedure:
A THF (2 mL) solution of 39 (71 mg, 0.14 mmol, 1 equiv.) was cooled to −78° C. in a 10-mL recovery flask, and a hexane solution of n-butyllithium (2.02 M, 141 μL, 0.28 mmol, 2.1 equiv.) was added dropwise over 5 min. After stirring the solution at −78° C. for 20 min, O-phenyl chlorothionoformate (39 μL, 0.28 mmol, 2.1 equiv.) was added in one portion. The resulting yellow solution was allowed to slowly warm to room temperature over 90 min and was subsequently quenched at room temperature with saturated aqueous NaHCO3. The mixture was extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to an orange oil. Flash column chromatography (50 mL SiO2, 95:5 hexane:EtOAc) afforded 51 mg (81 μmol, 60% yield) of 40 as a colorless oil. TLC Rf 0.58 (7:3 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 7.41 (dd, J=8.4, 7.6 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 7.08-7.06 (m, 2H), 5.74 (s, 1H), 5.53 (dd, J=11.5, 5.4 Hz, 1H), 4.99 (t, J=7.0 Hz, 1H), 3.80 (s, 3H), 3.25 (s, 1H), 2.56-2.53 (m, 2H), 2.44 (dd, J=14.6, 7.4 Hz, 1H), 1.86 (dd, J=12.9, 11.7 Hz, 1H), 1.69-1.65 (m, 7H), 1.58-1.56 (m, 1H), 1.47-1.41 (m, 2H), 1.37 (m, 2H), 1.23 (s, 3H), 1.23 (s, 3H), 1.03 (s, 3H), 0.95 (t, J=7.9 Hz, 9H), 0.58 (q, J=7.8 Hz, 6H). 13C NMR (126 MHz; CDCl3): δ 204.2, 194.6, 192.2, 177.0, 153.4, 134.9, 129.8, 126.9, 122.0, 118.6, 106.3, 84.6, 73.5, 69.8, 57.3, 55.7, 45.65, 45.58, 38.1, 34.3, 30.5, 29.7, 29.3, 26.1, 18.2, 17.8, 17.5, 7.4, 7.0. HRMS-ESI (m/z): [M+Na]+ calculated for C35H52O6SSi, 651.3152. found, 651.3130.
Reaction SMILES: [N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=O)=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([N:26]=C=NC2CCCCC2)CCCCC1.C(Cl)(Cl)Cl.C(O)(=O)C>C(OCC)(=O)C>[N:1]1[C:11]2[S:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([NH2:26])=[O:19])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1S2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)Cc1ccc2c(c1)CCc1cccnc1S2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.1 %

Procedure:
A mixture of 100 mg of (5,6-dihydro benzo[b]pyrido[3,2-f]-thiepin-8-yl)-acetic acid, 100 mg of dicyclohexylcarbodiimide and 20 ml of chloroform was stirred under a nitrogen atmosphere at 0° C. for 20 minutes. To the resulting mixture was slowly added 1 ml of chloroform containing excess ammonia. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 1 hour. To this was added 500 g of ice water, and the mixture was acidified with acetic acid and extracted with 50 ml of chloroform. The extract was washed with water, a 5% sodium hydrogen carbonate solution and then with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, to which was added ethyl acetate, and the mixture was filtrated to remove any unsoluble substance. Thereafter, the solvent was removed by distillation to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/ethanol (100/1) to obtain a solid. This was recrystallized from benzene/n-hexane to give 24 mg (yield: 24%) of (5,6-dihydro benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetamide as a colorless powder having a melting point of 165°-166° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH:38]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium chloride in 200 ml of t-butyl methyl ether was treated within 10 minutes with 9.7 g of potassium t-butylate while gassing with argon at -10° C. and the mixture was stirred for a further 1 hour. The mixture was then treated dropwise within 15 minutes at -10° C. with a solution of 12.0 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 90 ml of t-butyl methyl ether and the resulting mixture was stirred for a further 1 hour at 0° C. The reaction mixture was subsequently poured into 150 ml of water and extracted three times with 150 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The resulting, viscous oil was dissolved in 20 ml of ethyl acetate and the clear solution was diluted with 300 ml of petroleum ether and left to stand for 10 minutes at -20° C. The precipitated triphenylphosphine oxide was subsequently filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the residue (16.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 10.1 g (74%) of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile as colourless crystals; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.32.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C(N([CH2:14][CH3:15])CC)C.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>O1CCCC1>[C:20]1([O:19][C:17](=[O:18])[N:1]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[C:17]([O:19][C:15]2[CH:14]=[CH:22][CH:21]=[CH:20][CH:25]=2)=[O:18])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Cl)ccn1
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.2 %

Procedure:
2-Amino-4-chloropyridine (5.00 g, 38.9 mmol, WO 02/32872) was dissolved in tetrahydrofuran (200 ml); and triethylamine (17.9 ml, 128 mmol) was added thereto. While stirring with a waterbath, phenyl chloroformate (14.6 ml, 117 mmol) was added thereto dropwise; the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between water and ethyl acetate; the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was filtered by silica gel; the crystals obtained after the concentration were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (3.77 g, 10.2 mmol, 26.3%) as pale yellow crystals. The mother liquor was concentrated under reduced pressure, which was then treated by the similar methods to yield the title compound (3.98 g, 10.5 mmol, 27.1%) as pale yellow crystals (secondary crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12.[H-].[Na+].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])[C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: Cc1cc2c(Cl)ccnc2[nH]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(Cl)ccnc2n1[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine (0.85 g) in N,N-dimethylformamide (8.5 ml) was added 60% oil-suspended NaH (245 mg) under nitrogen atmosphere while being cooled in an ice water bath. The reaction solution was stirred at ambient temperature for 1 hour and cooled again in the ice water bath. To the reaction solution was added triisopropylsilyl chloride (1.3 ml) slowly dropwise for 10 or more minutes. The reaction solution was stirred for 3 hours at ambient temperature and diluted with ethyl acetate (30 ml). The solution was washed with saturated aqueous sodium hydrogencarbonate (30 ml) and brine (20 ml). The solution was dehydrated with anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane) to obtain 4-chloro-2-methyl-1-(triisopropylsilyl)-pyrrolo[2,3-b]pyridine (1.45 g) as a colorless transparent liquid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=1)SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:4]
Reactant: CCOc1cccnc1CSCCN=C(NC#N)SC
Reactant: CN
Solvent: CCO
Product: CCOc1cccnc1CSCCN=C(NC)NC#N
Reaction time: 8 h

Procedure:
Methylamine in ethanol (33%, 10 cc) was added to a stirred suspension of N-cyano-N'-[2-((3-ethoxy-2-pyridyl)-methylthio)ethyl]-S-methylisothiourea (1.0 g) in ethanol (5 cc) and the mixture was left to stand overnight. Nitrogen was bubbled through the solution for one hour and the solution was concentrated and crystals which deposited were filtered off and recrystallised from ethanol/ether to give the title product (0.7 g) m.p. 126.5°-127.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17])([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17])([O-:12])=[O:11]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 91.1 %

Procedure:
Using m-anisidine (2.03 g, 16.5 mmol) and 3-nitrobenzoic acid (2.51 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 3.72 g (91.3%) of the title compound in the form of colorless powder.
Reaction SMILES: C1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][N:15]1[C:19]([OH:20])=[C:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:17]([CH3:31])=[N:16]1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>CCOCC>[CH3:14][N:15]1[C:19]([O:20][C:34](=[O:35])[CH2:33][Cl:32])=[C:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:17]([CH3:31])=[N:16]1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CCOCC
Product: Cc1nn(C)c(OC(=O)CCl)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 82 %

Procedure:
In a mixture of 10 ml. of benzene and 0.2 ml. of triethylamine is dissolved 0.285 g. of 1,3-dimethyl-4-(2.4-dichlorobenzoyl)-5-hydroxypyrazole and then a solution of 0.18 g. of chloroacetylchloride in 5 ml. of benzene is added dropwise under ice-cooling and stirring. After completion of the dropwise addition, the resulting mixture is stirred at room temperature for 2 hours. After completion of the reaction, ether is added to the reaction mixture and the mixture is then washed successively with 3 portions of 50 ml. of water and dried over anhydrous sodium sulfate. Then, the solvent is distilled off from the mixture and the resulting residue is recrystallized from n-hexane to give 0.297 g. of the desired product as white crystals melting at 120°-122° C. Yield 82.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][Si:7]([CH2:10]Cl)([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][Si:7]([CH2:10][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)([CH3:9])[CH3:8])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: C[Si](C)(CCl)Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(Cc1ccc(Cl)cc1)CN1CCOCC1
Product: Cl

Procedure:
A solution containing 11.15 g of (4-chlorobenzyl)chloromethyl-dimethylsilane and 10.9 g of morpholine in 40 ml of toluene is refluxed for 9 hours, then cooled down and washed 5 times with a total of 250 ml of water. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated to solvent-free. The pale yellow oily residue is dissolved in 40 ml of acetone and acidified to pH 4.5 by adding ethereal hydrogen chloride solution. The named product is obtained as a crystalline precipitate in a yield of 12.1 g (76%), m.p.: 208°-210° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:18]([C:24]([CH3:26])=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:24]([CH3:26])[N:16]=2)[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncc(Br)cc1OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(Br)cn12

Procedure:
Under argon, 200 g (0.72 mol) of 3-(benzyloxy)-5-bromopyridine-2-amine, 590 g (3.58 mol) of ethyl 2-chloroacetoacetate and 436 g of 3 Å molecular sieve were suspended in 6 l of ethanol and stirred at reflux for 72 h. The reaction mixture was filtered off through silica gel and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 9:1, then 6:4) and the product fractions were concentrated. This gave 221 g (79% of theory) of the target compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].Cl.N1C=CC=CC=1>N1C=CC=CC=1>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:5][NH:4][C:3]([NH:2][CH3:1])=[S:6])=[O:11]
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=S)NNC(=O)c1ccccc1F

Procedure:
To a stirred room temperature solution of 4-methylthiosemicarbazide (10.5 g, 1.00×10-1 mole) and pyridine (250 ml), 2-fluorobenzoyl chloride (11.9 ml, 1.00×10-1 mole) was added dropwise. After stirring overnight at room temperature the excess pyridine was evaporated at reduced pressure first on a rotary evaporator and then at high vacuum. This afforded a mixture of the desired product and pyridine hydrochloride which is used without further purification in the subsequent cyclization step.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=4)[N:9]=3)[N:7]=2)[CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)n3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)c1

Procedure:
The title compound was prepared from 2-(6-bromo-pyridin-2-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.100) (0.600 g, 1.34 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.448 g, 1.74 mmol) according to the general procedure VI. Obtained as a light yellow foam (0.318 g, 41%). MS (ISP) 581.6 [(M+H)+]; mp 75° C.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C@H:16]1[C@@H:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:18][N:17]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:6])=[O:5])([CH3:3])[CH3:2]>[Pd].CO.C1COCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[C:8]([C@H:16]2[C@@H:20]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:18][N:17]2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH:9]=1
Reactant: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
To 10% palladium on carbon (1.3 g) was added 50F (5.7 g) in methanol (150 mL) and THF (50 mL) under a stream of nitrogen. The vessel was flushed and degassed with nitrogen gas (3×) and a balloon containing hydrogen gas was introduced. The reaction was stirred at rt for 4.0 h. The catalyst was filtered through Celite® and washed with methanol several times. The filtrate and the combined washings were evaporated and dried to give 5.5 g of 50G. 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 1.10 (d, J=6.60 Hz, 3H) 1.21-1.30 (m, 12H) 2.01-2.13 (m, 2H) 3.20 (s, 3H) 3.29-3.40 (m, 1H) 3.44-3.53 (m, 1H) 3.65 (ddd, J=10.17, 7.97, 5.50 Hz, 1H) 3.70-3.78 (m, 1H) 5.64 (d, J=8.25 Hz, 1H) 6.46-6.55 (m, 2H) 7.41 (d, J=7.70 Hz, 1H).