Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][C:6]([OH:8])=[O:7])#[N:4].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O.Cl>>[C:3]([C:5](=[CH:13][C:12]1[CH:15]=[CH:16][C:17]([OH:18])=[C:10]([OH:9])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: N#CCC(=O)O
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2N aqueous sodium hydroxide solution (175 ml, 350 mmol) heated at 60° C. were added cyanoacetic acid (7.2 g, 86.7 mmol) and 3, 4-dihydroxybenzaldehyde (12.0 g, 86.9 mmol), and the resulting mixture was stirred for 30 minutes. The reaction mixture was allowed to cool at room temperature and gradually mixed with dilute hydrochloric acid until the reaction mixture became acidic. The product was filtered and dried to give α-cyano-3, 4-dihydroxycinnamic acid (hereinafter referred to as "Compound A" (10.0 g, 56% in yield).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4](O)[CH:3]=1.O=P(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl:17][C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=1
Reactant: Cc1ccc(C)c2c(C)cc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c2c(C)cc(Cl)nc12
Yield: 85 %

Procedure:
A solution of 4,5,8-trimethylquinolin-2-ol (2.40 g, 12.8 mmol) and 1.4 mL (1.2 eq) of POCl3 in toluene was reacted as outlined in Scheme 1 above to yield the desired title compound (2.2 g, 85%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.68 (s, 3 H) 2.82 (s, 3 H) 2.85 (s, 3 H) 7.12 (s, 1 H) 7.18 (d, J=7.33 Hz, 1 H) 7.39 (d, 1 H).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH:9]=[O:10].[NH4+].[Cl-]>C1COCC1>[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9](=[O:10])[CH:1]([CH3:3])[CH3:2]
Reactant: O=Cc1c(F)cccc1Br
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(=O)c1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (18 mL of 2 M in Et2O, 35 mmol) is added to a solution of 2-bromo-6-fluoro-benzaldehyde (6.0 g, 30 mmol) in THF (40 mL) at −78° C. and the mixture is stirred for 1 hour at 0° C. The mixture is poured into saturated NH4Cl and extracted with EtOAc. The resulting crude alcohol is oxidized directly by Swern oxidation to yield 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one. 1H NMR (CDCl3) 7.38 (d, 1H), 7.22 (m, 1H), 7.03 (t, 1H), 3.10 (m, 1H), 1.11 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.N1C=CC=CC=1.[CH2:32]([O:34]CC)C>>[CH:32]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1])=[O:34]
Reactant: CCOCC
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Solvent: c1ccncc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCOC=O)c(Cl)cc2F)c1=O

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)pyrimidinedione with pyridine in diethyl ether there is obtained 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenoxy}-ethyl formate, 1H-NMR (CDCl3, 400 MHz): 8.11 ppm (t,1H), 7.33 ppm (d,1H), 6.82 ppm (d,1H), 6.35 ppm (s,1H), 4.54 ppm (m,2H), 4.22 ppm (t,2H), 3.56 ppm (d,3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]#[N:13])=[CH:4][N:3]=1.[N:14]1([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.CCOCC>CC(O)CC>[N:14]1([CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:2]3[N:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[C:5]([C:12]#[N:13])=[CH:4][N:3]=3)=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1ccc(S(=O)(=O)NCCN2CCCCC2)cc1
Reactant: CC(C)Oc1nc(Cl)ncc1C#N
Agent: Cl
Solvent: CCOCC
Solvent: CCC(C)O
Product: CC(C)Oc1nc(Nc2ccc(S(=O)(=O)NCCN3CCCCC3)cc2)ncc1C#N
Temperature: 70 °C
Reaction time: 18 h
Yield: 2.6 %

Procedure:
To a stirred suspension of 2-chloro-4-isopropoxy-5-cyanopyrimidine (Method 26; 505 mg, 2.56 mmol) and 4-[N-(2-piperidinoethyl)sulphamoyl]aniline (Method 43; 362 mg, 1.28 mmol) in 2-butanol (10 ml) was added 1M HCl in ether (3.6 ml, 3.6 mmol). The reaction was warmed to 70° C. and stirred for 18 hours. The reaction was filtered and the solvent removed under reduced pressure to yield a yellow solid. This solid was partitioned between DCM (40 ml) and 2M sodium hydroxide (40 ml). The phases were separated and the aqueous layer was extracted with DCM (30 ml). The organic phases were combined and washed with water (30 ml) and brine (30 ml). Solvent was removed under reduced pressure and the resulting solid was recrystallized from methanol to give the title compound (15 mg). NMR: 1.35 (m, 2H), 1.45 (m, 10H), 2.25 (m, 6H), 2.85 (m, 2H), 5.45 (m, 1H), 7.30 (br s, 1H), 7.80 (d, 2H), 7.90 (d, 2H),8.75 (s, 1H), 10.60 (br s, 1H); m/z 444.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=4)[N:28]=[C:27]([C:41]4[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=4)[N:26]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.Br[C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>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.O1CCCC1>[C:47]([C:44]1[CH:45]=[CH:46][C:41]([C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[N:30]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:16]4[CH:17]=[CH:18][C:13]([C:52]5[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=5)=[CH:14][CH:15]=4)=[CH:20][CH:21]=3)[N:26]=2)=[CH:42][CH:43]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(Br)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5cccnc5)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
Under a stream of argon, 1.4 ml of a hexane solution containing 2.2 mmol of butyl lithium was slowly added to 50 ml of tetrahydrofuran cooled to −78° C. in which 1.15 g of 2-(4′-bromobiphenyl-4-yl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine obtained in Reference Example 5 had been dissolved. After stirring at −78° C. for 15 minutes, 0.61 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 10 ml portion of tetrahydrofuran prepared by dissolving 0.38 g of 3-bromopyridine and 0.09 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 4 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was purified by a silica gel column chromatography (eluting solution hexane:chloroform=2:1 to chloroform) and an alumina gel column chromatography (eluting solution hexane:chloroform=2:1 to 3:2) and then recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4′-(3-pyridyl)biphenyl-4-yl]-1,3,5-triazine (0.71 g, yield 62%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.Cl[Si](C)(C)C.C(N(CC)CC)C.Cl[C:26]([O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1(OC)[O:35]C)=[O:27]>ClCCl>[C:30]1(=[O:35])[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: COC1(OC)CCCCC1OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CC1(CNC(=O)OC2CCCCC2=O)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred solution of gabapentin (2.56 g, 15 mmol) and chlorotrimethylsilane (3.7 mL, 30 mmol) in dichloromethane (25 mL) at 0° C. under nitrogen atmosphere was added triethylamine in portions. After having stirred for 15 min at 0° C. the chloroformate (45) was added dropwise into the reaction mixture. The mixture was stirred at 0° C. for 2 h and then at room temperature for 2 h (monitored by TLC). The reaction mixture was concentrated in vacuo and the residue was poured into cold water (50 mL) and then acidified to about pH 5.0 using 0.1 N HCl. The crude product was then extracted using ethyl acetate (2×50 mL). The combined extracts were washed with brine (40 mL), dried over MgSO4 and the solvent removed in vacuo. The crude product was dissolved in acetone (25 mL) and treated using Amberlyst-15 (1.0 g) for 1.5 h (monitored by LC/MS). The reaction mixture was filtered and the filtercake was washed with acetone (2×15 mL). The combined extracts were evaporated under reduced pressure and the residue was purified using prep-HPLC/MS method to provide 1.71 g (55% yield) of compound 46 as a white solid. 1H NMR (CDCl3, 400 MHz): 5.42 (1H, t), 5.12 (1H, m), 3.35-3.16 (2H, m), 2.39 (4H, m), 1.80-1.40 (16H, m). MS (ESI): m/z=310.27 (M−H−), and 312.28 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([Cl:15])=[O:6]
Reactant: Cc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Reaction time: 2 h
Yield: 110.3 %

Procedure:
A mixture of 3,5-dichloro-4-methylbenzoic acid (230 g, 1.12 moles), thionyl chloride (204 g, 1.71 moles), and dimethylformamide (30 milliliters(ml), in toluene (1 liter) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 276 g of 3,5-dichloro-4-methylbenzoyl chloride, used in the next step as such.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[C:19]([NH:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCOC(=O)c1ccc(N)s1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)OCC)s1
Reaction time: 20 h

Procedure:
To a solution of 8.6 g. of ethyl 5-amino-2-thiophenecarboxylate and 25 ml. of triethylamine in 100 ml. of methylene chloride is added dropwise 16.5 g. of palmitoyl chloride. The reaction mixture is stirred for 20 hours. Evaporation affords an oil. A methylene chloride solution of the oil is filtered and the filtrate passed through Magnesol. Removal of the solvent by evaporation yields a solid which is recrystallized from hexane. A second recrystallization from carbon tetrachloride affords the product.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([CH3:33])[CH:9]=1)=[O:6])C.[OH-].[Na+]>CCO>[F:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]([OH:34])=[O:3])=[CH:9][C:10]=2[CH3:33])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NC(=O)C(=O)O)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 1 h

Procedure:
A solution of the title E compound, N-{4-[3-(4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid ethyl ester (773 mg, 1.58 mmol) in 15 mL of EtOH is treated with aqueous 1N sodium hydroxide (NaOH; 4.75 mL, 4.75 mmol) at RT. After 1 h, the reaction is quenched with aqueous 1N HCl (5.5 mL) and the product is taken up in EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated. The product is triturated with Et2O and dried in vacuo to afford N-{4-[3-(4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid: NMR (DMSO-d6) 2.06 (s, 6H), 6.88 (d, 1H, J=9), 7.03 (dd, 1H, J=9,3), 7.13 (d, 1H, J=3), 7.43 (app t, 2H, J=9), 7.61 (s, 2H), 7.94 (dd, 2H, J=9,5), 10.5 (s, 1H), 10.69 (s, 1H); IR (KBr) 1240, 1481, 1685, 1764; ESI-MS 458 [M−1]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N:8]#[C:9][NH2:10].[ClH:11]>>[ClH:11].[ClH:11].[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:9]([NH2:10])=[NH:8])[CH:3]=1
Reactant: N#CN
Reactant: Nc1cccnc1
Agent: Cl
Product: N=C(N)Nc1cccnc1

Procedure:
3-Aminopyridine (38.96 g, 413.96 mmol) and cyanamide (21.40 g, 509.2 mmol) in 12N hydrochloric acid (271 mL) were stirred at 140-150° C. for 4 hours. Concentration under reduced pressure provided a heavy syrup which was purified by recrystalization from 1:1 isopropanol:diethyl ether (500 mL) to provide 60.2 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.5 g, 1.32 mmol) in 30 mL of dimethylformamide was treated with excess ethyl bromoacetate (0.7 mL, 6.60 mmol). After heating at 70° C. for 1 h, triethylamine (0.9 ml, 6.6 mmol) was added dropwise; the reaction mixture was then heated at 70° C. for an additional 30 min, after which it was partitioned between saturated sodium bicarbonate and dichloromethane. The organic extract was concentrated in vacuo, and the residue was applied to a 10 g SCX column which was washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo to afford an orange oil, which was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol, then 9:3 dichloromethane-methanol provided 0.31 g (51%) of the title compound as a yellow solid.
Reaction SMILES: [IH:1].[C:2](=[NH:7])(SC)[NH:3][NH2:4].[NH2:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1>C(O)C>[IH:1].[NH2:4][NH:3][C:2]([NH:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1)=[NH:7]
Reactant: NCc1cnccn1
Reactant: CSC(=N)NN
Agent: I
Solvent: CCO
Product: N=C(NN)NCc1cnccn1

Procedure:
A solution of 3.66 g. of methyl thiocarbazimidate hydriodide and 3.42 g. of (aminomethyl)pyrazine [A. Hirschberg and P. Mattner, J. Med. Chem., 11, 911 (1961)] in 50 ml. of absolute ethanol is heated at reflux for 20 hours and then concentrated to dryness under reduced pressure to give the desired product as an orange solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): • 7.59 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.36 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.14-7.11 (m, 3H), 7.08-7.04 (m, 2H), 6.91 (t, 1H, J=7.43 Hz), 6.82-6.77 (m, 3H), 4.15 (t, 2H, J=6.65 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.19 (d, 1H, J=14.08 Hz), 2.94 (t, 2H, J=6.65 Hz), 2.33 (s, 3H), 2.17 (s, 3H, 1.48 (s, 3H). MS [ES+] m/z exact mass calcd for C27H28NO5S 478.1688, found 478.1676.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[N+:16]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[CH:13][C:12]=1[OH:15])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O

Procedure:
4-Phenylmethoxy-phenol in acetic acid is nitrated by contact with a slight molar excess of nitric acid at room temperature, giving 2-nitro-4-phenylmethoxy-phenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:18])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[OH:48][C:49]1([C@@H:53]2[CH2:58][CH2:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:52][NH:51][CH2:50]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([N:51]1[CH2:52][C:49]([C@@H:53]2[CH2:58][CH2:57][CH2:56][CH2:55][N:54]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])([OH:48])[CH2:50]1)=[O:18]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Reaction time: 0.17 h
Yield: 105 %

Procedure:
3-[(2-Fluoro-4-iodophenyl)amino]pyridine-4-carboxylic acid (200 mg, 0.559 mmol), prepared using procedures similar to those described in WO 2006/045514, was suspended in DMF (7 mL) and 1-hydroxybenzotriazole (151 mg, 1.12 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (214 mg, 1.12 mmol) were added. The mixture was stirred at ambient for 10 minutes and then triethylamine (0.078 mL, 0.559 mmol) was added. After a further 20 minutes, 1,1-dimethylethyl (2S)-2-(3-hydroxyazetidin-3-yl)piperidine-1-carboxylate (143 mg, 0.559 mmol), prepared using similar procedures to those described in Example 22(a) and 22(b), and triethylamine (0.16 mL, 1.15 mmol) were added and the mixture was stirred for 15 hours. The mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic portion was washed with 5% lithium chloride and twice with saturated sodium bicarbonate, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 60-80% ethyl acetate in hexanes) to give 1,1-dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (368 mg, 0.587 mmol, 74% yield): 1H NMR (400 MHz, CDCl3): 8.73 (br m, 1H), 8.62 (br s, 1H), 8.14 (d, 1H), 7.47 (dd, 1H), 7.43-7.39 (m, 1H), 7.20-7.12 (m, 2H), 4.38-4.21 (m, 2H), 4.16-4.01 (m, 2H), 4.01-3.88 (m, 1H), 3.44-3.30 (m, 1H), 2.98-2.83 (m, 1H), 2.00-1.88 (m, 1H), 1.71-1.50 (m, 6H), 1.44 (s, 9H); MS (EI) for C25H30FIN4O4: 597 (MH+).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH2:25]([CH:27]([CH2:30][CH3:31])[CH:28]=O)[CH3:26]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:28][CH:27]([CH2:30][CH3:31])[CH2:25][CH3:26])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CCC(C=O)CC
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CCC(C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21)CC
Temperature: 25 °C
Yield: 68.3 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 2-ethylbutanal (0.5 g, 5.2 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.082 g, 68%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[C:10]([OH:13])(=[S:12])[CH3:11]>>[C:10]([S:12][CH:4]([CH3:5])[CH:2]([CH3:3])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:11]
Reactant: C/C=C(\C)C(=O)OCC
Reactant: CC(O)=S
Product: CCOC(=O)C(C)C(C)SC(C)=O

Procedure:
A mixture of 3.20 g (0.025 mol) of ethyl tiglate and 4.76 g (0.0625 mol) of thioacetic acid was prepared and allowed to react under nitrogen atmosphere at 85° C. for 24 hours. The results showed that the conversion rate of ethyl tiglate was 35.3%, and that the selectivity for the objective compound was 91.6%.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[S:21](=[O:35])(=[O:34])[NH:22][CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[CH:27]2)[C:14]([O:16][CH3:17])=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[S:21](=[O:34])(=[O:35])[N:22]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[CH:27]2)[C:14]([O:16][CH3:17])=[O:15]
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C)c2)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C)c2)c2ncc(Cl)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 3-chloro-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 24).