Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=1.C([Mg]Cl)(C)C>C(Cl)Cl>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[N:31]([CH3:32])[C:30]([CH3:33])=[N:29][CH:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ncc(I)n1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Product: Cc1ncc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)n1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL DCM and 146 mg (0.66 mmol) of 5-iodo-1,2-dimethyl-1H-imidazole in 1 mL DCM with 0.34 mL 2M isopropylmagnesium chloride. Yield: 36 mg of a white powder. LC-MSD, m/z for C21H17BrN4O2 [M+H]+=437.0, 439.0; HPLC retention time: 0.4 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:7]=[O:8])=[CH:4][S:5][CH:6]=1.P([O-])(O)(O)=[O:10].[Na+].Cl([O-])=O.[Na+].[OH-].[Na+]>C(#N)C.O.OO>[Br:1][C:2]1[C:3]([C:7]([OH:10])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: O=Cc1cscc1Br
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cscc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-4-methylthiophene (8.85 g), N-bromosuccinimide (8.85 g), 2,2'-azobis(isobutyronitrile) (0.16 g) and carbon tetrachloride (100 ml) was stirred under reflux for 6 hours. The mixture was concentrated under reduced pressure to give a crude product of 3-bromo-4-bromomethylthiophene. A suspension of this crude product of 3-bromo-4-bromomethylthiophene and potassium acetate (30 g) in acetone (100 ml) was stirred at room temperature for 5 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 4-acetoxymethyl-3-bromothiophene. This crude product was dissolved in tetrahydrofuran (50 ml), and 1N aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-4-hydroxymethylthiophene (5.33 g) as oil. 3-Bromo-4-hydroxymethylthiophene was dissolved in methylene chloride (100 ml), and manganese dioxide (15 g) was added. The mixture was stirred at room temperature for 6 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 4-bromo-3-thiophenecarbaldehyde. The crude product of 4-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added. Further, sodium chlorite (3.7 g) in water (40 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-bromo-3-thiophenecarboxylic acid (3.40 g) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20](I)([CH3:22])[CH3:21]>>[CH:20]([CH:13]1[C:12](=[O:19])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[O:15][CH2:14]1)([CH3:22])[CH3:21]
Reactant: CC(C)I
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Product: CC(C)C1COc2ccc(OCc3ccccc3)cc2C1=O

Procedure:
By the method of Example 8, 6-benzyloxy-4-chromanone and isopropyl iodide are converted to present title product.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH:48][CH2:49][CH2:50][NH:51][CH2:52][CH2:53][OH:54]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([N:51]([CH2:52][CH2:53][OH:54])[CH2:50][CH2:49][OH:48])=[O:44])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: OCCNCCO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCO)CCO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-(2-hydroxy-ethylamino)-ethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O5 [(M+H)+] 753.3293, observed 753.3294.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=1)[CH:13]=O.[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:27][CH2:28][CH:29]([NH:32][CH2:13][C:12]2[CH:15]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[F:1])[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[CH2:30][CH2:31]1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc(-c2ccncc2F)cc1C=O
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N)CC1
Product: COc1ccc(-c2ccncc2F)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic protocol described in Method C′; {4-[5-(3-Fluoro-pyridin-4-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester is prepared starting from 5-(3-Fluoro-pyridin-4-yl)-2-methoxy-benzaldehyde and (4-Amino-cyclohexyl)-methyl-carbamic acid tert-butyl ester. The desired product is isolated in 67%.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(CN2CCCC2)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCc1ccc(CN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
Dissolve 4-(pyrrolidin-1-ylmethyl)-benzonitrile (918 mg, 4.93 mmol) in methanol (32 mL). Add cobalt(II) chloride hexahydrate (2.7 g, 9.87 mmol) and stir for 20 min. Cool the mixture to 0° C., and carefully add sodium borohydride (1.86 g, 49.3 mmol) in small batches. Stir the mixture for 1.5 h at room temperature. Quench the mixture with water and partition between water and chloroform. Extract the aqueous phase three times with chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (80 g) eluting with a gradient of DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15; 50 mL/min) to give the title compound (421 mg, 45%). MS (ES+) m/z: 191 (M+H)+,
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=[CH:10][CH:11]=1>[Ni].O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cccc(OCCCBr)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc(OCCCBr)c1

Procedure:
1 g of Raney nickel is added to a solution of 4 g of 3-(3-bromopropoxy)-nitrobenzene in 40 ml of tetrahydrofuran and the starting substance is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. Evaporation of the filtrate gives 3-(3-bromopropoxy)-aniline as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[CH2:23]([N:25]([CH2:33][CH3:34])[C:26]([CH2:28][CH2:29][C:30](O)=[O:31])=[O:27])[CH3:24].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[CH2:33]([N:25]([CH2:23][CH3:24])[C:26]([CH2:28][CH2:29][C:30]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1])=[O:31])=[O:27])[CH3:34]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: CCN(CC)C(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCN(CC)C(=O)CCC(=O)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 3-(diethylcarbamoyl)-propionic acid with N,N'-dicyclohexylcarbodiimide and 4-pyrrolidino-pyridine as the catalyst in methylene chloride there is obtained 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenyl 3-(diethylcarbamoyl)propionate, m.p. 91°-93° C.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:21])([F:20])[C:8]1[N:13]=[C:12]2[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[NH:16][C:11]2=[CH:10][CH:9]=1.[CH2:22](O)[CH3:23]>>[F:21][C:7]([F:6])([F:20])[C:8]1[N:13]=[C:12]2[CH:14]=[C:15]([C:17]([O:19][CH2:22][CH3:23])=[O:18])[NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: CCO
Reactant: O=C(O)c1cc2nc(C(F)(F)F)ccc2[nH]1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2nc(C(F)(F)F)ccc2[nH]1

Procedure:
1 ml (18.71 mmol) of concentrated sulphuric acid is added to a solution of 0.2 g (0.87 mmol) of 5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid, obtained in step 23.2, in 10 ml of ethanol. The solution is stirred at reflux for 20 hours and then cooled and concentrated under reduced pressure. The resultant residue is subsequently taken up with 50 ml of dichloromethane and then washed successively with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate, 40 ml of water and 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulphate and then concentrated under reduced pressure. 0.19 g of product is obtained, which product is used as it is in the subsequent step.
Reaction SMILES: Br[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1COCC1.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]2[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>[Zn].C(OCC)(=O)C>[F:8][CH:2]([CH:29]([OH:30])[CH:26]1[CH2:25][CH2:24][CH:23]([CH:20]2[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]2)[CH2:28][CH2:27]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC1CCC(C2CCC(C=O)CC2)CC1
Reactant: CCOC(=O)C(F)Br
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(C(O)C(F)C(=O)OCC)CC2)CC1
Reaction time: 1 h
Yield: 127.7 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 1.1 g of well-dried zinc, 2.6 g of ethyl bromofluoroacetate (e-2) and 10 ml of THF were added, and the resultant mixture was cooled to 0° C. and stirred for 1 hour. The solution was slowly added dropwise in a temperature range of 20° C. to 25° C. to another reaction vessel under a nitrogen atmosphere in which 2.0 g of 4′-propyl-[1,1′-bi(cyclohexane)]-4-carboaldehyde (e-1) and 10 ml of THF were put, and the resultant mixture was further subjected to heating reflux for 4 hours. After cooling the resultant reaction mixture to 25° C., 100 ml of 1 N HCl aqueous solution and 100 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 3.7 g of ethyl 2-fluoro-3-hydroxy-3-(4′-propyl-[1,1′-bi(cyclohexane)]-4-yl)propanoate (e-3) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])=[C:6]([Cl:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH2:30]([N:13]([C:14]1[N:15]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:16]=[C:17]2[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]2)[C:11](=[O:12])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=1[Cl:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(NC(=O)N(Cc2ccccc2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)N(Cc2ccccc2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, 4-{3-benzyl-3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-ureido}-3-chloro-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 3 days at ambient temperature to give the title compound as colorless oil. MS: m/e=530.0 [M−H−].
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[N:4][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]2)=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1[C:2]1[C:3]([CH3:14])=[N:4][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Reactant: Cc1cn(-c2ccc(Br)c(C)n2)nn1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)c(C)n2)nn1
Temperature: 80 °C

Procedure:
3-Bromo-2-methyl-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridine (196 mg, 0.773 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (300 mg, 0.773 mmol), potassium carbonate (320 mg, 2.31 mmol), and tetrakis(triphenylphosphino) palladium(0) (89 mg, 0.077 mmol) were combined and suspended in DMF (3 ml) and water (0.3 ml). The mixture was heated at 80° C. for 2 hours, then diluted with water to 7 ml. The solids were collected, rinsed with water and resuspended in warm DMSO (3 ml). The suspension was diluted with dichloromethane (5 ml) and ether (4 ml). The solid was collected, rinsed with ether and methanol, and dried in vacuo to give the pure product as a white solid, 110 mg.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Ce+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[N+]([O-])([O-])=O.[Y+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])c1cccnc1O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Agent: [Ce+4]
Product: O=C(O)c1cccnc1O

Procedure:
With an aqueous solution of sodium 2-hydroxynicotinate there were mixed aqueous solutions of yttrium nitrate, lanthanum nitrate, cerium (III) nitrate, ammonium cerium (IV) nitrate and neobium nitrate, to obtain 2-hydroxynicotinic acid-rare earth metal complex colloids. The mixing speed was varied during mixing of the ammonium cerium (IV) nitrate aqueous solution, giving colloid solutions with mean particle sizes of 0.96 μm, 0.41 μm and 0.18 μm.
Reaction SMILES: [C:1](SC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)(=[O:18])[S:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.O.[NH2:36][NH2:37]>ClCCl>[NH:36]([C:1](=[O:18])[S:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)[NH2:37]
Reactant: NN
Reactant: CC(C)(C)c1cc(SC(=O)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(SC(=O)NN)cc(C(C)(C)C)c1O
Reaction time: 48 h
Yield: 92.7 %

Procedure:
A solution of S,S-bis[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] carbonodithioate (5.0 g, 9.9 mmol) in dichloromethane (50 mL) is added dropwise to a 0° C. solution of hydrazine monohydrate (1.1 g, 22.0 mmol) in dichloromethane (60 mL). The ice bath is removed and the reaction is stirred vigorously for 48 hours. The reaction mixture is diluted with ethyl acetate and washed four times with water and once with brine. The organic phase is dried over magnesium sulfate and the solvents are evaporated in vacuo. The residue is chromatographed on a 100 g silica column with ethyl acetate/hexane (1/9 then 1/1). The hydrazide is crystallized from isopropyl ether to give 2.72 g (92%) of S-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] hydrazinecarbothioate, mp 130.0-131.0° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N:17]=[O:18])=[C:12]1[OH:19])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N:17]=[O:18])=[C:12]1[O:19][CH3:3])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=NC1=C(O)C(=Cc2ccccc2)NC1=O
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Yield: 90 %

Procedure:
An excess of an ethereal diazomethane solution was added to a suspension of 5-benzylidene-4-hydroxy-3-nitroso-1,5-dihydro-pyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol. After the vigorous evolution of nitrogen has subsided, the reaction solution is concentrated in vacuo and the residue thus obtained is recrystallized from methanol. Red crystals of 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one with a melting point of 172° C. were obtained in a yield of 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[C:12]([C:23]([O:25]C)=[O:24])[CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[C:12]([C:23]([OH:25])=[O:24])[CH:13]=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=3)[N:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)cc3)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)cc3)nc12
Yield: 63.9 %

Procedure:
A solution of methyl 2-(4-fluorophenyl)amino-4-hydroxy-6-nitroquinazoline-8-carboxylate (1.89 g) and lithium hydroxide monohydrate (5.182 g) in tetrahydrofuran (500 mL) and water (350 mL) was stirred at room temperature for 24 h. The reaction was acidified to pH 2 with 2 N hydrochloric acid, then was concentrated to ca. 400 mL. The yellow precipitate which formed was isolated by filtration, washed with water and dried to afford the title compound as a tan solid (1.16 g). 1H NMR (300 MHz, DMSO-d6 (w/TFA (50 uL)): 8.90 (d, J=2.6 Hz, 1H), 8.84 (d, J=2.6 Hz, 1H), 7.59 (dd, J=8.1, 4.9 Hz, 2H), 7.31 (t, J=8.8 Hz, 2H). HPLC (Method F): 5.97 min. MS (APCI+): m/z 345.
Reaction SMILES: O1CCCC1.[C:6]([CH2:9][CH2:10][C:11](=[N:22][NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)(=[O:8])[NH2:7].C([BH3-])#N.[Na+].Cl>CO>[C:6]([CH2:9][CH2:10][CH:11]([NH:22][NH:23][C:24]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=1)=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)(=[O:8])[NH2:7]
Reactant: NC(=O)CCC(=NNC(=O)Nc1ccc(OC(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)CCC(NNC(=O)Nc1ccc(OC(F)(F)F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
In a mixed solvent of 15 ml of tetrahydrofuran and 15 ml of methanol was dissoved 0.46 g (1.0 mmole) of 2-[3-carbamoyl-1-(3-trifluoromethylphenyl)propylidene]-N-(4-trifluoromethoxyphenyl)hydrazinecarboxamide, after which to the resulting solution were added 0.46 g (7.7 mmoles) of sodium cyanoborohydride and then 5 drops of a saturated methanolic solution of hydrochloric acid, and the reaction was carried out for 36 hours.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:28])[CH2:26][OH:27])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[F:29][C:30]1[CH:31]=[C:32]([CH:39]=[CH:40][C:41]=1F)[C:33]([N:35]1[CH2:38][CH2:37][CH2:36]1)=[O:34]>C(#N)C>[N:35]1([C:33]([C:32]2[CH:39]=[CH:40][C:41]([O:7][C:8]3[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:28])[CH2:26][OH:27])[CH:23]=3)[C:11]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:12])=[C:30]([F:29])[CH:31]=2)=[O:34])[CH2:38][CH2:37][CH2:36]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)cn1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO)c2)cn1
Temperature: 160 °C
Yield: 10.7 %

Procedure:
Potassium carbonate (182 mg, 1.32 mmol) was added to a mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (200 mg, 0.66 mmol) and 1-(3,4-difluorobenzoyl)azetidine (137 mg, 0.69 mmol) in acetonitrile (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 4 hours. The mixture was allowed to reach ambient temperature and pressure and reduced in vacuo. The residual oil was partitioned between ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (34 mg).
Reaction SMILES: C[S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(=O)(=O)[NH:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=CC=1C(O)=O.N1CCCC1>>[CH:32]1([CH2:31][NH:30][S:2]([C:5]2[CH:6]=[CH:7][C:8]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:34][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1Cl
Solvent: C1CCNC1
Product: O=C(O)c1cc(S(=O)(=O)NCC2CC2)ccc1N1CCCC1
Yield: 38 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-(cyclopropylmethyl-sulfamoyl)-benzoic acid and pyrrolidine and obtained in 38% yield.