Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:25]([OH:34])=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30]>>[CH3:23][C:24]1[C:25]([OH:34])=[C:26]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[OH:22])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: Cc1ccc(B(O)O)c(O)c1C
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4ccc(C)c(C)c4O)n3)n2)c1
Yield: 50 %

Procedure:
6-(3,4-Dimethyl-2-hydroxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 3,4-dimethyl-2-hydroxyphenylboronic acid in 50% yield using method F; δH [2H6]-DMSO 12.40,(1H, b), 8.38,(1H, d), 8.31,(1H, d), 8.28-8.20,(2H, m), 8.14,(1H, d), 8.09,(1H, d), 7.86,(1H, d), 7.66,(1H, s), 7.00,(1H, d), 6.94,(1H, d), 6.81,(1H, d), 3.82,(3H, s), 2.30,(3H, s), 2.19,(3H, s).
Reaction SMILES: [F:1][C:2]([C:9]1[CH:13]=[C:12]([Si](C)(C)C)[S:11][C:10]=1[S:18]([NH2:21])(=[O:20])=[O:19])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)S(O)(=O)=O>O>[F:1][C:2]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[S:18]([NH2:21])(=[O:20])=[O:19])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: C[Si](C)(C)c1cc(C(F)=C(F)C(F)(F)F)c(S(N)(=O)=O)s1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)c1sccc1C(F)=C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
One gram of the 3-(1,2,3,3,3-pentafluoropropen-1-yl)-5-trimethylsilyl-2-thiophenesulfonamide prepared in (3) was treated with 4 ml of trifluoromethanesulfonic acid under stirring at room temperature for 2 hours. After completion of the reaction, the resulting product was poured into water and extracted with methylene chloride. The extracted layer was washed with water and dried. After distilling off methylene chloride, the residue was purified by column chromatography on silica gel (eluent: methylene chloride) to provide 0.67 g of 3-(1,2,3,3,3-pentafluoropropen-1-yl)-2-thiophenesulfonamide having a melting point of 108° to 111° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:18][CH2:19]O>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: O=C(O)Cc1ccc(O)c(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C

Procedure:
(3-Bromo-4-hydroxy-phenyl)-acetic acid (5.6 mmol) in EtOH (20 mL) was treated with sulfuric acid (1 mL) and stirred at room temperature over the weekend. The mixture was concentrated to give the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:9][C:8]=1[N+:25]([O-])=O)(=[O:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:9][C:8]=1[NH2:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])cc(NC(=O)OC(C)(C)C)c2ccccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)OCCc1c(N)cc(NC(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[4-(N-t-butoxycarbonylamino)-2-nitronaphthalen-1-yl]ethyl acetate (1.0 g, 2.67 mmol) in THF (40 mL) was added to a suspension of 10% Pd—C (0.1 g) in chilled THF (10 mL) and the suspension was hydrogenated (with shaking) at 55 psi at room temperature for 1 h. The suspension was filtered over Celite and the filtrate was concentrated under reduced pressure to afford 2-[2-amino-4-(N-t-butoxycarbonylamino)naphthalen-1-yl]ethyl acetate as an orange foam. The compound was washed with diisopropyl ether to afford as a pale yellow solid (0.48 g, 52%).: mp 138-140° C.; 1H NMR (CDCl3, 500 MHz) δ 7.86 (d, 9.0, 1H), 7.72 (d, 8.5, 1H), 7.56 (brs, 1H), 7.46 (t, 7.0, 1H), 7.27 (m, 1H), 6.85 (brs, 1H), 4.26 (t, 8.0, 2H), 4.22 (brs, 2H), 3.24 (t, 7.5, 2H), 2.10 (s, 3H), 1.56 (s, 9H); FABMS (NBA) m/z 344 (M+), IR (neat) νmax 3379, 2977, 1727, 1626, 1534, 1504, 1456, 1391, 1367, 1238, 1158, 1043, 894, 758, 730 cm−1.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7]([C:20]#[N:21])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.C(OB(OC(C)C)OC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.I[C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.Cl[Pd]Cl.CN(C=O)C>[NH2:48][C:47]1[CH:49]=[CH:50][C:44]([C:6]2[N:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[C:13]3[C:8]([C:7]=2[C:20]#[N:21])=[CH:9][CH:10]=[C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:12]=3)=[CH:45][CH:46]=1
Reactant: Nc1ccc(I)cc1
Reactant: N#Cc1cn(C2CCC2)c2cc(N3CCOCC3)ccc12
Agent: Cl[Pd]Cl
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(N3CCOCC3)ccc12
Temperature: -78 °C
Yield: 93.7 %

Procedure:
To a solution of 1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (1.20 g, 4.27 mmol), triisopropylborate (1.28 mL, 5.55 mmol) in THF (15 mL) at −78° C. was added LDA (1.5M mono THF in cyclohexane, 3.27 mL, 4.91 mmol) with stirring. The mixture was stirred at −78° C. for 10 minutes and at room temperature for 30 min followed by the addition of 4-iodoaniline (1.03 g, 4.70 mmol) and PdCl2 (dppf) (0.16 g, 0.2 mmol). The reaction system was cooled to −78° C., flushed with nitrogen followed by the addition of DMF (30 mL) and aq. K2CO3 (2.0M, 6.4 mL, 12.8 mmol). The cooling bath was removed and the mixture was stirred overnight and poured into ice water (500 mL). The precipitate was filtered, washed with water, dried in air and purified on silica gel (CH2Cl2/EtOAc, 9:1) to give 2-(4-amino-phenyl)-1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (1.49 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]2
Reactant: Cc1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CC(c1ccccc1)N2
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a stirred solution of 5-methyl-2-phenyl-1H-indole (0.96 g, 0.00463 mol) in acetic acid (28.8 mL) was added sodium cyanoborohydride (0.873 g, 0.0139 mol) at RT and the resulting reaction mixture was stirred for 4 h. After completion of reaction (monitored by TLC), the reaction mixture was basified with sodium hydroxide solution and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx 0.5 inch) to provide the desired compound as a brown colored oil (0.7 g, 72% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH:15]([CH3:20])[C:16](OC)=[O:17])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH2:25]([NH2:28])[CH:26]=[CH2:27]>>[CH2:25]([NH:28][C:16](=[O:17])[CH:15]([O:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:8][N:7]=2)=[CH:22][CH:21]=1)[CH3:20])[CH:26]=[CH2:27]
Reactant: C=CCN
Reactant: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: C=CCNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 60 °C

Procedure:
A mixture containing 11.85 g (0.035 mol) of methyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-propionate and 11.5 g (0.2 mol) of allylamine is boiled under reflux (about 60° C.) for 10 hours. (The reaction is followed by gas chromatography.) Thereafter, the excess of allylamine is distilled off and the residue is dissolved in benzene. After washing the solution cooled down with 5% aqueous hydrochloric acid and then with saturated sodium chloride solution, the organic phase is dried over anhydrous magnesium sulfate and evaporated. The crude product is recrystallized from petroleum ether (b.p. 120° C.) containing a small amount of toluene.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[NH:6][N:5]=[C:4]([SH:7])[N:3]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nc(S)n[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1nc(S)n[nH]1)c1ccccc1
Reaction time: 0.42 h

Procedure:
To a suitably equipped reaction vessel was charged 116 g (1.0 mole) of 5-amino-3-mercapto-1,2,4-triazole and 500 ml of pyridine. A total of 147.5 g (1.05 mole) of benzoyl chloride was added with vigorous stirring over 25 minutes, during which time the temperature rose from 24° to 59° C. The mobile, pale yellow slurry obtained was heated at reflux with stirring. The solid material dissolved and then, after about 40 additional minutes, a white solid began separating. An additional 200 ml of pyridine was added to aid mixing and the reaction was continued at 117°-122° for a total of 7 hours. The thick, white slurry obtained was filtered, washed with water and with methylene chloride, and dried to obtain 186 g (84 percent of theory) of the title compound, m.p. 311°-312° (dec.).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S([CH2:24][N+:25]#[C-])(=O)=O)=CC=1.O.[Cl-].[Na+]>COCCOC.C(O)C>[C:24]([CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)#[N:25]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ccc(C2CCC(=O)CC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CCC(c2ccc(N)cc2)CC1
Yield: 54.9 %

Procedure:
392 mg (3.5 mmol) of potassium t-butylate were added portionwise at -10° to a suspension of 278 mg (1.5 mmol) of 4-(4-oxo-cyclohexyl)-aniline and 370 mg (1.9 mmol) of toluene-4-sulfonylmethylisocyanide in 5 ml of 1,2-dimethoxyethane and 0.15 ml of ethanol. After stirring at -5° for 1 hour and at room temperature for a further 70 hours 25 ml of water and 10 ml of saturated sodium chloride solution were added and the mixture was extracted three times with 40 ml of dichloromethane each time. The organic phase was dried with sodium sulfate and concentrated. Chormatography over silica gel with ethyl acetate/hexane 1:2 gave 165 mg (56%) of 4-(4-cyano-cyclohexyl)-aniline with m.p. 132°-140°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:15][CH2:14]1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.[OH-].[K+]>O1CCOCC1.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>[CH2:22]([S:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:5]2[C:4]3[C:8](=[C:9]([C:11]#[N:12])[CH:10]=[C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])[CH:3]=3)[NH:7][N:6]=2)[CH2:14][CH2:15]1)(=[O:21])=[O:20])[CH3:23]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccccc4F)cc23)CC1

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carbonitrile (Intermediate 10) (50 mg, 0.102 mmols), 2-fluorophenyl boronic acid (42 mg, 0.306 mmols), potassium hydroxide (84 mg, 0.612 mmol), and Pd(PPh3)4 (10 mg) in dioxane/water (6/1, 3.5 mL) were reacted to give the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[Cl:25][C:26]([Cl:31])([Cl:30])[C:27](Cl)=[O:28].CCOCC.O>CCOCC>[Cl:25][C:26]([Cl:31])([Cl:30])[C:27]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:28]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCOCC
Product: CC(C)[C@@H](C(=O)O)N(C(=O)C(Cl)(Cl)Cl)c1ccc(Cl)cc1

Procedure:
To the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine (1.19 mmole) in ether (4.5 ml), under nitrogen, is added dimethylaminopyridine (4.25 mmole) which is cooled in an ice-bath and then trichloroacetyl chloride (3.58 mmole) in ether added slowly. The reaction mixture is heated at 40° for 3 days. The reaction is worked up with ether/water. The aqueous phase is extracted with ether and then the combined ether phases are washed with water and brine and dried over sodium sulfate. The residue is subjected to prep. TLC eluting with 10% ether/hexane to yield the m-phenoxybenzyl ester of N-trichloroacetyl,N-(4-chlorophenyl)valine. MS m/e 553 (M+, 1.8), 183 (100).
Reaction SMILES: NN.[Si:3]([O:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].O.ClCCl>C(O)C>[Si:3]([O:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[CH2:15][NH2:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CN)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
At room temperature, a hydrazine solution (35% strength in water, 0.6 ml, 6.6 mmol) is added to a solution of 2-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)benzyl]-1H-isoindole-1,3(2H)-dione (1.7 g, 4.4 mmol) in ethanol (44 ml), the mixture is stirred at room temperature for 15 h and water is added. After addition of dichloromethane and phase separation, the aqueous phase is extracted with dichloromethane. The combined organic phases are dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product is used without further purification for the next reaction.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:33])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2)=[O:33]
Reactant: Cc1cc2cc(Nc3ncnc4ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc34)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2cc(Nc3ncnc4ccc(NC(=O)CCN)cc34)ccc2[nH]1
Yield: 85.2 %

Procedure:
150 mg of 2-[4-(2-methyl-1H-indol-5-ylamino)-quinazolin-6-ylcarbamoyl]-ethyl-carbamic acid t-butylester dissolved in 5 ml of methylene chloride was reacted with 5 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 50 ml of saturated aqueous sodium bicarbonate solution for 30 mins, filtered under a reduced pressure, and dried to obtain the title compound (100 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:12])[N:3]=1.Cl.[NH2:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16](=[N:19][OH:20])[CH2:17][OH:18].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:14][C:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16](=[N:19][OH:20])[CH2:17][OH:18])[N:7]=1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Reactant: CCC(N)(CC)C(CO)=NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(CC)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(CO)=NO
Yield: 48.8 %

Procedure:
A suspension of 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (III) (Hal=Cl) (2.3 g) in dry ethanol was treated with 3-amino-1-hydroxy-3-spirocyclohexylpropan-2-one oxime hydrochloride (IV) (2.5g) and dry triethylamine (2.7 g) and the mixture was refluxed for 7 h. The reaction mixture was filtered and the solid washed with hot ethanol. The solvent was removed from the filtrate and the resulting yellow oil was triturated with cold water giving a yellow solid which on recrystallisation from water in the presence of charcoal gave the nitropyrimidine (II) (1.85 g; yield 47.4%) as an off-white powder, m.pt >300° (decomp.).
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]([C:6]([OH:8])=[O:7])[CH3:5].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[C:9]([NH:3][C@H:4]([C:6]([OH:8])=[O:7])[CH3:5])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 75 °C
Yield: 90.4 %

Procedure:
To a solution of sodium hydroxide (8.98 g, 224.49 mmol) in water (112.25 mL), was added at rt DL-Alanine (10 g, 112.25 mmol). The resulting solution was heated at 75° C. and the benzoyl chloride (15.77 g, 112.25 mmol) was slowly added. The reaction was heated for 30 minutes, and cooled down to 0° C. with an ice bath. Conc. HCl was added to adjust the pH to 1, then the white solid was filtrated through a fritted glass funnel and vacuum dried with P2O5 overnight. No purification was needed. This gave N-benzoylalanine (19.6 g, 90.4% yield) as white solid. 1H NMR (DMSO-d6) δ 12.61 (s br, 1H), 8.64 (d, 1H), 7.87-7.85 (m, 2H), 7.52-7.43 (m, 3H), 4.40 (q, 1H), 1.39 (d, 3H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].[OH-].[Na+:11]>O>[C:1]([O-:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].[Na+:11]
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(CC(=O)O)C(=O)[O-]

Procedure:
2600 grams of itaconic acid where dissolved in 1150 grams of water with 1600 grams of sodium hydroxide (50% w/w), at 60° C. to yield a clear solution of monosodium itaconate. Under mechanical stifling, 572 ml of sulfuric acid (93% w/w) where added at the rate of 10 ml/min, while the temperature was maintained at 60° C. The resulting slurry contained 2220 grams of crystalline itaconic acid, dispersed in a solution of sodium sulfate at 338 g/L, saturated in itaconic acid. Upon filtration, rinsing of the crystal with 30° C. water, and drying in a vacuum oven, high purity crystalline itaconic acid was recovered.
Reaction SMILES: [S:1](OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].C(OC=C)(=O)C.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1C=CC(O)=[CH:32][CH:33]=1>O>[CH2:32]([SH:1])[CH2:33][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [NH4+]
Solvent: C=COC(C)=O
Solvent: O
Product: CCCCCCCCCCCCS

Procedure:
As soon as the mixture has reached 80° C., a solution of 2 g of ammonium persulfate in 10 cm3 of water is added thereto. A mixture containing 1,251 g of vinyl acetate and 450 g of "Versatate VEOVA 10", and a solution containing 100 g of deionized water, 2 g of ammonium persulfate and 82.5 g of a 22% strength aqueous solution of polyoxyethyleneated nonylphenol (30 units of ethylene oxide), are then introduced simultaneously at a constant rate over 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])[CH:15]=1)=[O:13].CN(C(ON1N=NC2[CH:40]=[CH:41][CH:42]=[N:43]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:43][CH:42]2[CH2:40][CH2:41]2)=[O:8])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([C:21]2[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:27])[CH:15]=1)=[O:13]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Cl)c(NC(=O)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(C(=O)NC2CC2)ccc1Cl)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 4-chloro-3-({[1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]carbonyl}amino)benzoic acid (1.74 g) in DMF (17 mL) were added HATU (3.03 g), cyclopropanamine (680 mg) and iPr2NEt (3.08 g) successively at 0° C., and the mixture was stirred at room temperature for 16 hr under a nitrogen atmosphere. The mixture was partitioned between EtOAc (50 mL) and 1 M HCl (50 mL), and the precipitates produced were removed by filtration. The organic layer of the filtrate was separated and washed with 1 M HCl (50 mL), saturated aqueous NaHCO3 (50 mL×2) and brine successively, dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was triturated with a mixture of IPE and MeOH. The precipitates were collected by filtration, triturated with EtOH and collected by filtration to give N-{2-chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (890 mg).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
A solution of isobutylamine (1.10 mL, 11.14 mmol) and pyridine (600 μL, 7.42 mmol) in DCM (60 mL) was treated with 4-(bromomethyl)benzene sulfonyl chloride (2.00 g, 7.42 mmol) and stirred at room temperature for 1.5 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) gave 4-bromomethyl-N-isobutyl-benzenesulfonamide (1.08 g, 48%). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 4.50 (s, 2H), 4.43 (t, J=6.4 Hz, 1H), 2.78 (t, J=6.6 Hz, 2H), 1.81-1.65 (m, 1H), 0.88 (d, J=6.7 Hz, 6H). LCMS (m/z, Method A) ES+ 308.0 [M+Na]+.