Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]([C:34]([O:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)=[O:35])[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].O>CN(C)C=O.C(OCC)(=O)C>[NH:25]([C:34]([O:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[O:12])=[CH:41][CH:40]=1)=[O:35])[NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)NNC(=O)OCCc1ccc(N)cc1
Reactant: CC(=O)Nc1nc(C(=O)O)cs1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a suspension of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (557.3 mg, 2.993 mmol) in anhydrous N,N-dimethylformamide (10 ml) was added 1,1′-carbonyldiimidazole (531.7 mg, 3.279 mmol), and the mixture was stirred at 50° C. for 2 hr. 2-(4-Aminophenyl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (1.065 g, 3.607 mmol) was added, and the mixture was stirred at room temperature for 16 hr. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture, and the mixture was stirred, stood still and partitioned. The organic layer was washed with 0.5M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was suspended in tert-butyl methyl ether (30 ml), filtered, washed 3 times with tert-butyl methyl ether, and dried under reduced pressure to give 2-[(4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)phenyl]ethyl tert-butyl hydrazine-1,2-dicarboxylate (1.098 g, 2.368 mmol, yield 79.1%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1C(C2NC=CN=2)=[CH:20][N:19]=[C:18]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[N:17]=1>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:20][N:19]=[C:18]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[N:17]=1
Reactant: Cc1nccn1C
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: Cn1ccnc1-c1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
[4-(2,4-dichlorophenyl)-5-(1-methylimidazol-2-yl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 1,2-dimethylimidazole using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:22]=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 75 °C
Reaction time: 60 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (2 g) in dimethylformamide (10 ml) at room temperature was added vinyltri-n-butyl tin (4.25 g) and tetra-kis-triphenylphosphinepalladium(0) (0.3 g). The mixture was heated at 75° C. for one hour and then cooled and left at room temperature for 60 hours. The reaction mixture was diluted with water and extracted with ether. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give the crude product as a black oil (6 g) which was purified by column chromatography on silica gel (200 g) eluted with dichloromethane:hexane (1:1). Combination and evaporation of appropriate fractions gave the title compound as a buff solid, m.p. 186-70° C.
Reaction SMILES: N[C@H:2](C)C(C1C=CC=CC=1)(C1C=CC=CC=1)O.[OH:18][C:19]1[CH:31]=[CH:30][C:22]2[C@@H:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][O:25][C:21]=2[CH:20]=1.S(=O)(=O)(O)O>CO>[OH:18][C:19]1[CH:31]=[CH:30][C:22]2[C@@H:23]([CH2:26][C:27]([O:29][CH3:2])=[O:28])[CH2:24][O:25][C:21]=2[CH:20]=1
Reactant: O=C(O)C[C@H]1COc2cc(O)ccc21
Reactant: C[C@@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C[C@H]1COc2cc(O)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
[(3R)-6-Hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetic acid (R)-2-amino-1,1-diphenylpropan-1-ol salt (100 g) and sulfuric acid (30.26 g) were added to methanol (120 mL), and the mixture was stirred at 60° C. for 2 hr. After allowing to cool to room temperature, the solvent was concentrated under reduced pressure. To the residue were added toluene (831 mL), tetrahydrofuran (415 mL) and 1M hydrochloric acid (500 mL), and the mixture was partitioned. The organic layer was washed with water (500 mL), 5% aqueous sodium hydrogen carbonate solution (500 mL) and water (500 mL). The organic layer was concentrated, and toluene (110 mL) was added to the residue. The mixture was heated to 50° C., dissolved, allowed to cool to room temperature, and solid precipitation was confirmed. Normal heptane (220 mL) was added, and the mixture was stirred at room temperature for 5 hr. After cooling to 5° C., the solid was collected by filtration, washed with a mixed solution (1:2, 24 mL) of toluene-normal heptane. The solid was dried at 50° C. under reduced pressure to give the title compound (45.19 g). 99.6% ee.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]>C(Cl)Cl>[Br:1][C:9]1[CH:8]=[CH:7][C:6]([NH2:11])=[C:5]([O:4][CH3:3])[CH:10]=1
Reactant: COc1ccccc1N
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(Br)ccc1N
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Add dropwise a solution of bromine (0.83 mL, 16.2 mmol) in CH2Cl2 (130 mL) to a solution of 2-methoxy-phenylamine (2.0 g, 16.2 mmol) in dichloromethane (100 mL) at 0° C. over a period of 45 min. Stir the mixture at 0° C. to RT overnight. Wash the mixture with water, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography eluting with 10% EtOAc/hexane to give 1.95 g (59%) of the title compound. GC m/z (81Br) 203 [M+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[N:12]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>ClCCCl>[Cl:24][C:10]1[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cc1ccc2c(O)ncnc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(Cl)ncnc2n1
Yield: 75.9 %

Procedure:
To a solution of 7-Methyl-pyrido[2,3-d]pyrimidin-4-ol (0.78 g, 4.84 mmol) in DCE (30 mL) was added DIEA (1.0 mL, 1.19 mmol), followed by POCl3 (2.4 mL, 26.1 mmol). The mixture was refluxed overnight. After cooling, the solvent was removed and the residue was dissolved in water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (2:1) to give 4-Chloro-7-methyl-pyrido[2,3-d]pyrimidine (0.66 g, 76%). 1H NMR (CDCl3, 400 MHz) δ 9.22 (s, 1H), 8.49 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 2.88 (s, 3H). MS (APCI+) [M+H]+180.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12]O.P(Br)(Br)([Br:16])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][Br:16]
Reactant: Cc1c(CCO)cccc1[N+](=O)[O-]
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: Cc1c(CCBr)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitrophenyl ethyl alcohol (100 g) is added to toluene (500 ml). POBr3 (190 g) is added to the reaction mixture and refluxed for 2 to 3 hrs. Toluene is distilled off completely to give 2-Methyl-3-nitro phenylethyl bromide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([C:23]([O:25][CH2:26]C)=[O:24])[CH:22]=1)[CH2:18]Br)=[O:14])C>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:18][C:17]2[CH:16]=[C:15]([C:13]([O:12][CH3:10])=[O:14])[CH:22]=[C:21]([CH:20]=2)[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cc(CBr)cc(C(=O)OCC)c1
Product: COC(=O)c1cc(COc2ccc(Cl)c(Cl)c2)cc(C(=O)OC)c1
Yield: 90 %

Procedure:
The title compound was prepared in a manner similar to that described for dimethyl 3-(3,4-dichlorobenzyloxy) isophthalate (Scheme I-A), from 3,4-dichlorophenol and 3,5-bis(ethoxycarbonyl)benzyl bromide. Yield 90%. 1H NMR (CDCl3, 400 MHz), δ8.53 (s, 1H); 8.27 (s, 2H); 7.53 (d, J=8.0 Hz, 2H); 7.38 (s, 1H); 7.08 (d, J=8.0 Hz, 1H); 5.32 (s, 2H); 4.46 (q, J=7.0 Hz, 4H); 1.45 (t, J=7.0 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]([O-])=[O:16])=[C:13]([CH3:18])[N:12]=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:18])[N:12]=[C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:10]=1
Reactant: Cc1nc(-c2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1CO
Reaction time: 1 h
Yield: 108.6 %

Procedure:
To a stirred solution of 4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate (75 mg, 0.2 mmol) in THF (6 mL) was added DIBAL (0.4 mL, 1.5 M in PhCH3, 0.6 mmol). The reaction was kept for 1 hr and was quenched by saturated aqueous potassium sodium tartrate solution (5 mL). The reaction was diluted with EtOAc (10 mL) and the organic layer was washed with 1N NaOH (10 mL), saturated Na2CO3 solution (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product as a white solid (75 mg). The crude reaction product was moved onto next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH:12]=[CH2:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>C(O)C.[C].[Pd]>[CH2:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[CH3:13]
Reactant: C=Cc1ccc(C(=O)OC)c(O)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(C(=O)OC)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of methyl 2-hydroxy-4-vinylbenzoate (2.31 g) in ethanol (25.0 mL) was added palladium-carbon (1.38 g), and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.43 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CN1CCCC1=O>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:10]1[N:11]=[C:4]2[CH:3]=[C:2]([O:24][C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=1
Reactant: Nc1cc(Br)cc2nc(-c3ccco3)nn12
Reactant: Cc1ccc(O)cc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2cc(N)n3nc(-c4ccco4)nc3c2)cc1

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. p-methyl-phenol and a catalytic amount of CSCO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 306 M+H+ (100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([N:11]([CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:10].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:36][CH2:35][CH2:34][CH2:33][CH2:32][O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([N:11]([CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:10]
Reactant: ClCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCN(C)C(=O)c1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)c1ccccc1COCCCCCl

Procedure:
[2-(Hydroxymethyl)phenyl]-N-methyl-N-octadecylformamide is reacted with 1-bromo-4-chlorobutane in acetone in the presence of potassium carbonate at the reflux temperature of the solvent to obtain [2-(4-chlorobutoxymethyl)phenyl]-N-methyl-N-octadecylformamide.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Br)C.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[C:22]([C:24]2[N:28]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[N:26][CH:25]=2)=[O:23])[CH:15]=[CH:14][CH:13]=1>ClCCl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:22]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[N:12]=[CH:13][CH:14]=[CH:15]2)([C:24]1[N:28]([C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[N:26][CH:25]=1)[OH:23]
Reactant: Ic1ccccn1
Reactant: O=C(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: OC(c1ccccn1)(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-iodo-pyridine (commercially available) (307 mg, 1.5 mmol) in dichloromethane (20 mL) at room temperature was treated with ethyl magnesium bromide (0.50 mL, 1.5 mmol, 3M in ether) and allowed to react for 45 m. A solution quinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanone, (Intermediate 13) (465 mg, 1.00 mmol) in dichloromethane was added via syringe at room temperature and the reaction mixture was then stirred at room temperature for 16 h. The mixture was quenched with water (20 mL) and a sat. solution of ammonium chloride (20 mL). The residue was isolated in a typical aqueous to give pyridin-2-yl(quinolin-8-yl)(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 14) (385 mg, crude).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.Cl[C:21]1[N:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:21]1[N:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: N#Cc1cccnc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1ccc(CNc2ncccc2C#N)c(OC)c1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
2,4-Dimethoxybenzylamine (2.90 g, 17.3 mmol) and triethylamine (1.75 g, 17.3 mmol) were added sequentially to a solution of 2chloronicotinonitrile (2.0 g, 14.4 mmol) in N,N-dimethylacetamide (29 mL). The reaction was heated at 80° C. for 4 h, quenched with water and extracted with diethyl ether (3×). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0-5% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (2.80 g). MS 270.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([NH:16][N:17]=[C:18]([C:20]2[C:24]([OH:25])=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[S:22][CH:21]=2)[CH3:19])=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])([O-:3])=[O:2].[OH-].[Na+]>>[N+:1]([C:4]1[CH:13]=[C:12]([C:14]([NH:16][N:17]=[C:18]([C:20]2[C:24]([OH:25])=[C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)[S:22][CH:21]=2)[CH3:19])=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(F)(F)F)cc3)c2O)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(F)(F)F)cc2)c1O

Procedure:
From methyl 2-nitro-4-[(2-{1-[5-(4-trifluoromethylphenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)carbonyl]benzoate (60.9 mg (0.12 mmol) and 0.2 M sodium hydroxide aqueous solution (1.26 mL, 0.25 mmol), 38.2 mg of the desired product was obtained in the same manner as in Synthetic Example 70 as a pale yellow solid (yield 65%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:18])=[O:17])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:11]([O:35][CH3:36])[N:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].[OH-:37].[Na+]>CCO>[CH3:36][O:35][C:11]1[C:12]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)(=[O:18])=[O:17])[N:14]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:37])[CH:8]=2)[N:10]=1
Reactant: [OH-]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C#N)c2)nc1OC
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(N)=O)c2)nc1OC
Temperature: 0 °C

Procedure:
0.356 g of 5-methyl-pyridine-2-sulfonic acid [2-(2-cyano-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 19, dissolved in EtOH (5 ml) were treated at RT with 2N NaOH (0.7 ml) and the solution was refluxed for 30 minutes until the transformation was complete according to TLC analysis. The reaction mixture was cooled to 0° C., the pH adjusted to pH=1. The crystalline solid was filtered off, washed with water and dried in a high vacuum to provide the desired 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid amide as an off-white solid. ISN mass spectrum, m/e 521.1 (M−1 calculated for C24H22N6O6S: 521).
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=O)=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN.C(P(=O)([O-])OCC)#N.Br.Br[CH2:36][CH2:37][NH2:38]>ClCCl>[O:23]1[CH2:36][CH2:37][N:38]=[C:21]1[C:20]1[N:19]=[CH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9][C:10]=12
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reactant: NCCBr
Agent: Br
Agent: CCOP(=O)([O-])C#N
Agent: CN
Solvent: ClCCl
Product: O=C(N1CCCC1)N1Cc2c(C3=NCCO3)ncn2-c2ccccc21
Reaction time: 0.67 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 322, 1.03 g) and 25 ml of dichloromethane cooled at 0° in an ice bath are added 1.15 ml of Methylamine and 0.650 ml) of ethyl cyanophosphonate, followed immediately by 0.811 g of 2-bromoethylamine hydrobromide. The ice bath is then removed and the reaction is stirred for 40 min. Aqueous sodium bicarbonate is then added. The mixture is stirred for 10 min and then partitioned with dichloromethane. The organic layers are dried over sodium sulfate and concentrated. The resulting mixture is stirred in 20 ml of THF and 3.3 ml of 1M potassium tert-butoxide is added dropwise over 2-3 min and the reaction is stirred an additional 10 min, at which time the reaction mixture is partitioned between ethyl acetate, water, and saline. The organic layers are dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (300 ml) eluting with methanol/methylene chloride (4/96), the appropriate fractions are pooled and concentrated to give the title compound, mp 217°-220°; MS (m/z) at 337; IR (mineral oil) 1651, 1512, 1416, 1357, 1396 cm-1 ; NMR (CDCl3) 1.81, 3.27, 4.05, 4.42, 4.99, 7.11-7.18, 7.26, 7.51, 8.03 δ.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[O-][CH2:23]CCC.[K+].CI>>[CH3:23][C:15]1[C:16](=[O:17])[CH2:18][CH2:19][C@@:20]2([CH3:21])[C:14]=1[CH2:13][CH2:12][C@@H:6]1[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:11]
Reactant: CCCC[O-]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: [K+]
Solvent: CI
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O

Procedure:
testosterone (XII) is reacted with potassium butoxide and methyl iodide to form 4-methyl-17β-hydroxyandrost-4-en-3-one
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]1.Cl.[N:16](OCCC(C)C)=[O:17].[OH-].[NH4+]>CCOC(C)=O.CCO.CC(O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:13]([NH2:14])=[C:12]([N:16]=[O:17])[CH:11]=[N:10]1
Reactant: CC(C)CCON=O
Reactant: Nc1ccnn1-c1c(F)cccc1F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCO
Product: Nc1c(N=O)cnn1-c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
To a solution of (2,6-difluorophenyl)-1H-pyrazol-5-amine (2.60 g, 13.3 mmol) in 8 mL of EtOAc and 4 mL of EtOH was added 8 mL of HCl in 2-propanol (5-6 N). The heterogeneous mixture was cooled with an ice-NaCl bath, and isopentyl nitrite (1.83 mL, 13.6 mmol) was added drop wise (within 10 min) to prevent the temperature from exceeding 10° C. After stirring for 15 min, the reaction mixture became homogeneous. Stirring was continued for a total of 40 min. The brown homogeneous solution was diluted with 150 mL of EtOAc, and neutralized with ammonium hydroxide. The EtOAc layer was separated and washed with brine to afford a rusty crystalline solid which was triturated with 15 mL Hexanes. The rusty solid was collected and dried in a vacuum oven at 45° C. for 2 h to afford 1-(2,6-difluorophenyl)-4-nitroso-1H-pyrazol-5-amine This crude material was used without further purification. MS (ES+): 225.1 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1.[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH2:33])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:18]([O:22][C:23](=[O:35])[NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][NH:33][C:13]([C:11]2[N:10]=[N:9][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:17][CH:16]=3)[CH:12]=2)=[O:15])=[C:27]([CH3:34])[N:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1cn(Cc2ccc(CO)cc2)nn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CO)cc2)nn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-hydroxymethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid (0.95 g, 4.07 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.024 g, 4.07 mmol), HATU (2.013 g, 5.30 mmol) and DIPEA (2.85 mL, 16.29 mmol) in 50 mL DMF was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with 1 n HCl solution and saturated sodium bicarbonate solution. The organic solution was dried over MgSO4, filtered and concentrated to yield the crude product which was used in the next step without further purification. LCMS (Method A) RtA=1.279; [M+H]+=467.0.