Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:18]([O:20][N:21]=[CH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])=[C:25]([CH3:36])[CH:24]=1)[CH3:19].C(N(CC)CC)C>CN(C=O)C.N1C=CC=CC=1>[CH2:18]([O:20][N:21]=[CH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][CH2:32][CH2:33][C:34]2[O:9][N:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:35]=2)=[C:25]([CH3:36])[CH:24]=1)[CH3:19]
Reactant: ON=Cc1ccccc1
Reactant: C#CCCCOc1c(C)cc(C=NOCC)cc1C
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCON=Cc1cc(C)c(OCCCc2cc(-c3ccccc3)no2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of benzaldehyde oxime (45 mg, 0.372 mmol) in DMF (0.5 ml) was added dropwise to a solution of N-chlorosuccinimide (50 mg, 0.374 mmol) and pyridine (1 drop) in DMF (0.5 ml), keeping the temperature between 25-30° C. The resulting solution was allowed to stir at room temperature for 90 minutes. To this was added a solution of 3,5-dimethyl-4-(4-pentyn-1-yloxy)benzaldehyde O-ethyl oxime (49 mg, 0.189 mmol) in DMF (0.5 mL, the resulting solution was then heated at 85-90° C. for 10 minutes. To this was added, dropwise over 10 minutes, a solution of triethylamine (54 μl, 0.386 mmol) in DMF (0.5 ml), the resulting solution was then heated at 85-90° C. for 1 hour. The reaction was cooled and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (15 ml). The organic phase was washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (Ethyl acetate/Hexane 5%) gave the product (Compound 127) as a clear oil (23 mg, 32%). The structure was confirmed by the 1H nmr spectrum which is given in Table 11 below.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(OC([O:12][CH2:13][CH3:14])OCC)C.[NH2:15][C:16]1[N:21]=[CH:20]C(O)=[CH:18][CH:17]=1>CC(O)=O>[N:21]1([C:16]2[N:15]=[CH:14][C:13]([OH:12])=[CH:18][CH:17]=2)[CH:20]=[N:3][N:2]=[N:1]1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(O)cn1
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccc(-n2cnnn2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
NaN3 (2.89 g, 44 mmol) and triethylorthoformate (7.4 ml, 44 mmol) were added to commercially available 6-amino-pyridin-3-ol (3.5 g, 32 mmol) in AcOH (50 mL). The reaction mixture was heated to 100° C. for 1-3 hours. The reaction was cooled to room temperature and left to stand overnight. The precipitate was filtered, washed with EtOAc (150 mL) and dried in vacuo. The crude product was obtained as a beige solid and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:22]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(N)nc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-propyl-pyrazolo[1,5-a]pyrimidine (99 mg, 0.25 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (30 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (48 mg, 50%). MS (ISP) 388.4 [(M+H)+]; mp 215–217° C.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:4]2[N:5]([CH:10]=[N:11][CH:12]=2)[C:6](=[O:9])[NH:7][N:8]=1.O>C(O)(=O)C>[Br:1][C:12]1[N:11]=[CH:10][N:5]2[C:4]=1[CH:3]=[N:8][NH:7][C:6]2=[O:9]
Reactant: BrBr
Reactant: O=c1[nH]ncc2cncn12
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]ncc2c(Br)ncn12
Reaction time: 1 h

Procedure:
A solution of bromine (8.0 gm., 0.05 mole) in acetic acid (10 ml.) is added to a mixture of imidazo[1,5-d]-as-triazin-4(3H)-one (6.8 gm., 0.05 mole) and acetic acid (500 ml.). The reaction mixture is stirred for 1 hour, poured into water and extracted with chloroform. The aqueous layer is separated, made slightly alkaline and extracted with ether. Evaporation of the chloroform and the ether layers yields 5.0 gm. of a solid (46.3%). This solid is recrystallized to afford the title product, a cream colored solid, m.p. 244°-245° C.(d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH2:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:29]([NH:36][C:37](=[O:38])[NH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
100 mg (0.26 mmol) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is mixed in 2.5 ml of methylene chloride with 37.9 mg (0.29 mmol) of benzyl isocyanate, and it is stirred overnight at room temperature. After concentration by evaporation, the residue is chromatographed. 66 mg (49% of theory) of 2-{[2-(3-benzyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-trifluoromethyl-phenyl)-benzamide with a melting point of 153° C. is obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[Cl:9][C:10]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([C:24]([Cl:28])=[C:25]([Cl:27])[Cl:26])[CH:23]=1)[CH2:17][N:18]=[N+:19]=[N-:20])=[C:11]([Cl:13])[Cl:12].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[N:18]([CH2:17][C:16]2[CH:21]=[C:22]([C:24]([Cl:28])=[C:25]([Cl:27])[Cl:26])[CH:23]=[C:14]([C:10]([Cl:9])=[C:11]([Cl:12])[Cl:13])[CH:15]=2)[N:19]=[N:20][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [N-]=[N+]=NCc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Reactant: N#CCC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1nnn(Cc2cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c2)c1N
Reaction time: 0.33 h
Yield: 48.9 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (0.692 g) in 25 ml of ethanol, 8.2 ml of a 1N methanolic solution of NaOH was added and the resulting mixture stirred for 20 minutes. 3,5-Di(trichlorovinyl)benzyl azide (1.5 g) was added in one portion and the resulting mixture stirred at 60° C. for 1 hour. The pH of the mixture was adjusted to 6 with acetic acid. The reaction mixture was then concentrated to a reduced volume and diluted with 100 ml of water. The aqueous mixture was extracted with CH2Cl2 (3×100 ml). The combined organic layers were washed with water, dried with MgSO4 and concentrated to give 1.5 g of crude product. This material was chromatographed on silica gel (95:5 CH2Cl2 :CH3OH) to give 890 mg of a solid. Recrystallization from 5 ml of ethanol provided pure triazole, m.p. 167°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH2:26]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:10])=[O:9])=[N:13][CH:14]=[CH:15][N:16]=2)=[CH:23][CH:22]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CNc2ccccn2)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: O=S(=O)(Nc1nccnc1-c1ccc(CN(Cc2ccccc2)c2ccccn2)cc1)c1ccccc1Cl
Yield: 35 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro) benzenesulfonamide (Intermediate 8), and 2-benzylaminopyridine, the title compound was isolated as a yellow solid in 35% yield (94% purity by HPLC).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](O)=[C:4]([C:13]#[N:14])[C:3]=1[C:15]#[N:16].S([O:22][CH3:23])(OC)(=O)=O.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:22][CH3:23])=[C:4]([C:13]#[N:14])[C:3]=1[C:15]#[N:16]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: N#Cc1c(C#N)c(O)c2ccccc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C#N)c(C#N)c(OC)c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
42 g (0.2 mol) of 1,4-dihydroxy-2,3-dicyanonaphthalene and 200 ml of N,N-dimethylformamide (DMF) were introduced at room temperature as the initial charge. 55.4 g (0.44 mol) of dimethyl sulfate and 60.8 g (0.44 mol) of potassium carbonate were added. The batch was slowly heated to 100° C. and stirred at that temperature for 8 h. It was then poured onto water, and the resulting precipitate was filtered off with suction, washed With water and dried to leave 30 g of 1,4-dimethoxy-2,3-dicyanonaphthalene (theory: 64%; melting point: 190° C.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>>[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]3[O:18][C:14]([CH3:13])=[CH:15][CH:16]=3)=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COCCN
Reactant: Cc1ccc(CN)o1
Reactant: Clc1ccc2c(Br)cccc2n1
Product: COCCNc1cccc2nc(NCc3ccc(C)o3)ccc12

Procedure:
The title compound, MS: m/e=312.3 (M+H+), was prepared in accordance with the general method of example 3 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2-methoxy-ethylamine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[C:12]([CH2:18][C:19]#[N:20])(=O)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([C:12]1[CH:18]=[C:19]([NH2:20])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[N:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cccc(NN)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 90.4 %

Procedure:
To a solution of commercially available 3-methoxyphenylhydrazine hydrochloride (1.0 g, 5.7 mmol) in toluene (5 mL) was added commercially available pivaloylacetonitrile (0.70 g, 5.5 mmol). The reaction mixture was heated at reflux for 5 h, filtered and washed with hexane to obtain 3-t-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-amine (1.22 g, 89% yield) as its hydrochloride salt as a pale yellow solid which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 7.35 (t, J=8.4 Hz, 1H), 7.04 (t, J=2.1 Hz, 1H), 7.00 (dd, J=1.5 and 7.5 Hz, 1H), 6.95 (dd, J=2.1 and 8.4 Hz, 1H), 5.90 (brs, 2H), 5.83 (s, 1H), 3.81 (s, 3H), 1.89 (s, 9H); MS (EI) m/z: 246 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14])=[O:8])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH2:12][C:13]2=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)NCCCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
20.0 g. of 4-(p-methoxybenzoylamino)butyric acid, 50 ml. of toluene and 9.2 ml. of thionyl chloride are heated at reflux for 2 hours and then the mixture is treated with decolorizing charcoal and evaporated. The residue is dissolved in methylene chloride and chromatographed over neutral aluminum oxide. The 1-(p-methoxybenzoyl)-2-pyrrolidinone, which is eluted with methylene chloride, is recrystallized from alcohol and has a melting point of 119°-120° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[NH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O.O>O1CCCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16](=[S:2])[NH2:15]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
43 g of phosphorus pentasulfide were added slowly to 46.8 g of the amide of Stage A in 700 ml of tetrahydrofuran and the mixture was stirred for 4 hours at ambient temperature. The reaction mixture was poured into water and extracted with ether. The extracts were dried and the solvent was evaporated under reduced pressure. After chromatography on silica (eluant: CH2Cl2 --AcOEt 8-2), 10 g of expected product melting at 137° C. were obtained.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:22]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:21]=2[C:20]([F:37])([F:38])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(F)cc1C(F)(F)F
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: Fc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2)c(C(F)(F)F)c1

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (9.8 mmol) and 2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydrol (123) (19.7 mmol) using the procedure described for compound (3) (2.31 g, 45%).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O.Br[C:21]1[CH:22]=[C:23]([NH2:27])[CH:24]=[N:25][CH:26]=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.O>[CH:1]1([C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[N:25][CH:26]=2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: Nc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cncc(C2CC2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
Cyclopropylboronic acid (360 mg), cesium carbonate (1.4 g), and Pd(PPh3)4 (166 mg) were added to a 1,4-dioxane/water (4.5 ml/0.5 ml) solution containing 5-bromopyridin-3-amine (500 mg) in a nitrogen atmosphere, followed by stirring in a sealed tube at 100° C. for 5 hours. The reaction solution was adjusted to room temperature and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:MeOH=1:0 to 30:1). A brown solid of 5-cyclopropyl pyridin-3-amine (314 mg) was thus obtained.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Triethyl orthoformate (2 ml, 12 mmol) and p-Toluenesulfonic acid (20 mg, 0.10 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (2 g, 5.81 mmol) in ethanol (20 ml). The mixture was stirred at room temperature for 1 h. Potassium carbonate (1.1 g, 8.06 mmol) in solution in water (20 ml) was added and the mixture was heated under reflux for 2 h, cooled to 10° C. and water (20 ml) was then added. The precipitate was filtered, washed with water and dried under vacuum, to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (1.3 g, yield: 78%). mp and 1H-NMR were in accordance with those obtained for example 2. HPLC analysis was as shown in FIG. 1b.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC([O-])(C)C.[K+].[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][C:39]=1[CH3:46]>C1C=CC=CC=1>[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:40][C:39]=1[CH3:46]
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C=O)ccc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1cc(C=CCCCCCC(=O)O)ccc1F
Temperature: 25 °C
Yield: 107 %

Procedure:
To a suspension of 7-Carboxyheptanyltriphenylphosphonium bromide (9.240 g, 19.602 mmol) in 100 mL of benzene, was added t-BuOK (58.8 mL, 58.8 mmol, 1M in THF). The resulting mixture was refluxed for 1 h and then 4-fluoro-3-methylbenzaldehyde (1.43 mL, 11.761 mmol) was added via a syringe. The mixture was refluxed under N2 for an additional 63 h. After cooling to room temperature, the reaction mixture was washed with water (80 mL) and the aqueous layer was acidified with concentrated HCl to pH=2 and extracted with ethyl acetate (30 mL×3). The combined organic extracts dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (3.150 g, >99% yield). LC-MS: tR=9.6 min, m/z 251 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[C:10]=2[CH:9]=[N:8]1.OS(O)(=O)=O.[Cl:27]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[Cl:27][C:12]1[CH:13]=[CH:14][C:15]2[N:7]([CH2:6][C:5]3[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)[N:8]=[CH:9][C:10]=2[C:11]=1[NH2:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)ccc2c1cnn2Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-(3-(trifluoromethyl)benzyl)-1H-indazol-4-amine (0.056 g, 0.192 mmol) in THF (1.0 mL) was cooled to −78° C. under N2. H2SO4 (0.00512 mL, 0.0961 mmol) was added and the mixture was stirred for 5 minutes. N-chlorosuccinimide (0.0257 g, 0.192 mmol) was added in one portion and the reaction was stirred at −78° C. for 1 hour. Sodium carbonate (0.0204 g, 0.192 mmol) was added and the mixture was warmed to ambient temperature. The mixture was diluted with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were then washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (40% EtOAc/hexane) in which two major bands were observed. The higher band was determined to be the title compound (0.028 g, 44%) and was isolated as a dark yellow/green solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C[O-].[Na+]>CO>[NH2:13][C:11]([C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[C:5]2[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1cc(Br)cc2cc[nH]c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Yield: 514.8 %

Procedure:
To a solution of 5-bromo-1H-indole-7-carboxamide (10 g, 41.84 mmol) in methanol (5 mL), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (684 mg, 3.42 mmol) and sodium methoxide (0.5 M in THF, 13.7 mL, 6.84 mmol) were added. The reaction mixture was stirred at reflux temperature for 16 hours. All solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure, and purified by flash column chromatography (ethyl acetate/hexanes, 1/1) to give the desired product (7.4 g, 43%).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[N:18]=[C:17]2[C:12]([C:13](=[O:24])[C:14]([C:21]([OH:23])=[O:22])=[CH:15][N:16]2[CH2:19][CH3:20])=[CH:11][C:10]=1[F:25].[CH2:26]([I:28])[CH3:27].C(N(CC)CC)C>CN(C)C=O>[IH:28].[CH2:19]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([F:25])=[C:9]([N:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][CH:1]3[CH2:6][N:5]4[CH2:26][CH3:27])[N:18]=2)[C:13](=[O:24])[C:14]([C:21]([OH:23])=[O:22])=[CH:15]1)[CH3:20]
Reactant: CCI
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)nc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CC2CCC1CN2c1nc2c(cc1F)c(=O)c(C(=O)O)cn2CC
Product: I
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A solution of 0.35 g (1.0 mmole) of 7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.32 ml (4.0 mmole) of ethyl iodide, 0.56 ml (4.0 mmole) triethylamine and 10 ml of N, N-dimethylformamide was heated at 100° for 17 hours. The reaction mixture was evaporated to dryness and the residue was stirred with 25 ml of 1 N sodium hydroxide for one hour. The solution was neutralized to pH 7 with 1 N hydrochloric acid, filtered and evaporated the filtrate to dryness. The residue was recrystallized from ethanol to give 0.29 g of the title compound, mp>300°.
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:44])[N:9]=[C:10](SC)[C:11]([C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH2:37][CH2:38][O:39][CH3:40])[C:29]=1[F:41])=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.[N+:45]([C:48]1[C:49]([NH:54][NH2:55])=[N:50][CH:51]=[CH:52][CH:53]=1)([O-:47])=[O:46]>C(N(CC)CC)C>[F:41][C:29]1[C:30]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=1[CH:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[O:21][N:20]=2)=[CH:15][CH:14]=1)[C:10]1[NH:9][C:8](=[O:44])[N:54]([C:49]2[C:48]([N+:45]([O-:47])=[O:46])=[CH:53][CH:52]=[CH:51][N:50]=2)[N:55]=1
Reactant: NNc1ncccc1[N+](=O)[O-]
Reactant: COCCOc1cc(OC)cc(C(=Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)C(=NC(=O)OC)SC)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1cc(OC)cc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2nn(-c3ncccc3[N+](=O)[O-])c(=O)[nH]2)c1F
Temperature: 85 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
To 3 ml of a DMF solution containing 86 mg of {2-[2-fluoro-5-methoxy-3-(2-methoxyethoxy)phenyl]-1-methylsulfanyl-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]ethylidene}carbamic acid methyl ester, 25 mg of (3-nitropyridin-2-yl)hydrazine and 0.023 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours and concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 66 mg of sodium cyanotrihydroborate and 0.085 ml of acetic acid were added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 50 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (55 mg).