Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>>[Cl:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: C[C@@H]1CNC(=O)c2cc3cc(O)ccc3n21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H]1CNC(=O)c2cc3cc(OCCCCl)ccc3n21
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 2, intermediate, from (R)-8-hydroxy-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, potassium carbonate and 1-bromo-3-chloropropane, to give the title compound as a light yellow solid (56%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of methyl 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionate (1.75 g) in methanol (15 ml) is added potassium hydroxide (1.0 g) in water (10 ml). The resulting mixture is stirred at RT until a clear solution is obtained (~20 min). Most of the methanol is removed, and the aqueous solution is acidified with dilute HCl and extracted with ether. The combined ether extracts are dried and concentrated to dryness to give 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-phenoxy]propionic acid.
Reaction SMILES: C(O)/C=C\CO.[CH2:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:8].CS(Cl)(=O)=O.C(N)[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:7]([N:9]1[CH2:12][CH:13]=[CH:11][CH2:10]1)[C:8]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: OC/C=C\CO
Solvent: CCOC(C)=O
Product: C1=CCN(Cc2ccccc2)C1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution containing 35.4 g (0.4 mol) of cis-2-butene-1,4-diol, 83.8 g (0.8 mol) of triethylamine, and 416.6 g of ethyl acetate in a round flask reactor, methanesulfonyl chloride was added dropwise with stirring for 30 min. at about 5° C. using an ice-bath. After addition, the mixture was allowed to react with stirring for 2 hours at room temperature. To the mixture, 171.7 g (1.6 mol) of benzylamine was added continuously dropwise with stirring for 30 min. at ambient temperature. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 52.2 g of 1-benzyl-3-pyrroline (yield 82.0%) was obtained.
Reaction SMILES: C[Si](Cl)(C)C.Cl[C:7]([F:18])([F:17])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9].[I:19]I.O>C(#N)C.[Zn]>[F:17][C:7]([F:18])([I:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:9]
Reactant: Cc1ccccc1C(=O)C(F)(F)Cl
Reactant: II
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1C(=O)C(F)(F)I
Temperature: 55 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
To a suspension of zinc (1.6 g) in acetonitrile (40 mL) were added trimethylsilyl chloride (3.1 mL) and 2-chloro-2,2-difluoro-1-(2-methylphenyl)ethanone (4.0 g), and the mixture was stirred at 55° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, iodine (3.5 g) was added, and the mixture was further stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane) to give the title compound as a yellow oil (yield 2.6 g, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1NCCn2c1cc1cc(O)ccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Temperature: 0 °C
Yield: 47.7 %

Procedure:
To the solution of 0.5 g (2.5 mmol) 8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1, intermediate a)) in 10 mL tetrahydrofuran, 0.6 g (3.0 mmol) 1-(tert-butoxycarbonyl)-4-hydroxypiperidine and 0.78 g (3.0 mmol) triphenylphosphine were added. The solution was cooled to 0° C., 0.68 g (3.0 mmol) di-tert-butyl azodicarboxylate were added and the cooling bath was removed. After 18 hours the reaction mixture was evaporated and the residue was flash-chromatographed on silica gel with dichloromethane: methanol: ammonia (9:1:0.1 v/v) as eluant to give 0.46 g (49%) of the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11](O)[CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(Cl)C(=O)C([Cl:55])=C(Cl)C(=O)C=1Cl.O>C(#N)C>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([Cl:55])[CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CC(O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(Cl)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
0.50 g (1.2 mmol) of 3-[4-chloro-2-(1-hydroxyethyl)-6-fluorobenzofuran-7-yl]-1-methyl-6-trifluoromethyluracil and 0.64 g (2.5 mmol) of triphenylphosphine were dissolved in 20 ml of acetonitrile, and 0.60 g (2.5 mmol) of chloranil was added thereto at room temperature. After stirring at room temperature for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a 5% potassium carbonate aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.50 g (yield: 96.2%) of the desired product as a pale brown glassy substance. Refractive index: 1.5639 (20° C.).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:42])[NH2:28])=[CH:25][CH:26]=4)[N:16]([CH3:29])[C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1

Procedure:
1.8 g (3.7 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]-imidazo[4,5-b]pyridine-6-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were stirred into 100 l of ethanol saturated with hydrogen chloride for 16 hours first at 0° C. and then at room temperature until no more starting material could be detected by thin layer chromatography. Then the solvent was distilled off, the oily residue was taken up in 50 ml of absolute ethanol and mixed with 3.6 g (37 mMol) of ammonium carbonate. After 4 hours the solvent was distilled off in vacuo, the crude product obtained was purified by flash chromatography (silica gel; gradient:dichloromethane/ethanol 19:1 to 4:1) and evaporated down again. Yield: 1.6 g of beige solid (80% of theory), Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia=90:5:5)
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[C:21]([NH2:22])=[CH:20][C:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C)C(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:22][C:21]1[C:16]([Cl:15])=[CH:17][CH:18]=[C:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=1)=[O:5]
Reactant: Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution containing 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (2.00 g) in N,N-dimethylacetamide (40 mL) cooled to -20° C. was added thionyl chloride (1.50 g) and the mixture was stirred for 1.0 hour. 6-chloro-3-phenylsulfonylaniline (2.42 g) was added in one portion and mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into aqueous sodium hydroxide (1.0N, 250 mL) and extracted with ethyl acetate. The combined ethyl acetate extracts were washed (aqueous sodium hydroxide, brine) and evaporated. Chromatography, with hexane:ethyl acetate as the eluent (4:1 then 2:1) yielded the title compound as a white solid (1.25 g); mp: 79°-80° C.; NMR (250 MHz): 1.61 (s,3), 7.69 (m,3), 7.82 (m,2), 7.94 (d,1, J=9), 7.98 (m,2), 8.52 (s,1), 9.93 (s,1); MS: m/z=408(M+1). Analysis for C16H13ClF3NO4S: Calculated: C, 47.11; H, 3.19; N, 3.44; Found: C, 47.10; H, 3.28; N, 3.38.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].Br[CH:14]([C:16]1[N:21]2[N:22]=[CH:23][N:24]=[C:20]2[N:19]=[CH:18][CH:17]=1)[CH3:15]>COCCOC>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:14]([C:16]2[N:21]3[N:22]=[CH:23][N:24]=[C:20]3[N:19]=[CH:18][CH:17]=2)[CH3:15])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(O)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCSc1ccc(OC(C)c2ccnc3ncnn23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(ethylthio)phenol (1.54 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 above) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of diethylether and ethyl acetate (in the ratio 6:4 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.28 g, (m.p. 65°-67° C.).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][N:18]=1)#[N:16]>CN(C=O)C>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:20]2[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[N:18][CH:19]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(F)cn1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(O[C@@H]2CC[C@H](N)c3ccccc32)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.2 %

Procedure:
Intermediate A (300 mg, 1.84 mmol) was added to an ice cold stirred suspension of sodium hydride (60% in mineral oil, 221 mg, 5.52 mmol) in DMF (15 mL) and stirred for 15 min. 2-Cyano-5-fluoropyridine (224 mg, 1.84 mmol) was added and the reaction warmed to RT. After 90 min, the reaction was quenched by dropwise addition of water and the mixture partitioned between EtOAc (75 mL) and water (150 mL). The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound (255 mg, 0.96 mmol, 52%). LCMS (Method 4): Rt 0.28, 1.73, m/z 266.1 [MH+].
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11](N3C[C@H](CNC(=O)C)OC3=O)=[CH:10][C:9]=2[F:26])[CH2:4][CH2:3]1.[N+:28]([O-:31])(O)=[O:29].O>C(O)(=O)C>[F:14][C:13]1[CH:12]=[C:11]([N+:28]([O-:31])=[O:29])[CH:10]=[C:9]([F:26])[C:8]=1[N:5]1[CH2:4][CH2:3][S:2](=[O:27])(=[O:1])[CH2:7][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a suspension of the product of example 1 (300 g, 1.21 mol) in 3 L of acetic acid, nitric acid (255 mL, ca. 6 mol, fuming, 90%) is added over 30 min at room temperature. Yellow precipitate is formed within minutes and increases over time. The reaction is kept at room temperature for 18 hours, before it is poured into 6 L of water. After stirred for 2 hours, the yellow suspension is filtered. The precipitate is washed with water (1.5 L×3) and EtOH (0.5 L×2) and dried in oven at 50° C. overnight to give 333 g (94%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8]C(C#N)(O[Si](C)(C)C)[C:6]=2[CH:18]=1.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][CH:20]([C:19]([OH:22])=[O:21])[C:6]=2[CH:18]=1
Reactant: C[Si](C)(C)OC1(C#N)CCSc2ccc(Cl)cc21
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C1CCSc2ccc(Cl)cc21

Procedure:
Following the procedure of Example 2, 6-chloro-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-1-benzothiopyran (5.8 g.) was reacted with stannous chloride dihydrate in glacial acetic acid (25 ml.) and concentrated hydrochloric acid (25 ml.). Recrystallization from benzene:cyclohexane gave 6-chloro-3,4-dihydro-2H-1-benzothiopyran-4-carboxylic acid (2.59 g.), m.p. 153°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24](=[O:30])[N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([O:31][CH3:32])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24](=[O:30])[N:25]5[CH2:26][CH2:27][CH2:28][CH2:29]5)=[C:18]([O:31][CH3:32])[CH:17]=4)[CH2:35][CH2:34][N:11]3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCC(=O)N1CCCC1
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCC(=O)N1CCCC1

Procedure:
Following the procedure described in Example 1 step D, 4-(4-chlorophenyl)-N-(3-methoxy-4-(2-oxo-2-(pyrrolidin-1-yl)ethoxy)phenyl) 1H-pyrrole-2-carboxamide (11 mg) was alkylated with 1,2-dibromoethane to yield 9.2 mg of the title compound. MS (ESI) 480 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.63 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.88 g, 4.6 mmol). The resulting free base was obtained as a yellow foam. Yield 1.2 g (64%). mp 95°-100° C. FDMS m/e=405 (M+ of free base). α[D]589 =5.15 (c=1.01, dimethylsulfoxide).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:20])[CH2:18]O)[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:33][CH2:18][C@@H:17]([CH3:20])[C@@H:16]1[C@:21]2([CH3:27])[C@H:13]([C@H:12]3[C@H:24]([CH2:23][CH2:22]2)[C@:25]2([CH3:26])[C:9]([CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6][C@@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[CH:10][CH2:11]3)[CH2:14][CH2:15]1
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A solution of 0.54 g of (20S)-1α,3β-diacetoxy-21-hydroxy-20-methyl-pregn-5-ene and 0.825 g of carbon tetrabromide in 10 ml. of ether was treated with 0.625 g of triphenylphosphine and the mixture was left at room temperature for 16 hours. After dilution with ether, insoluble material was filtered off. The filtrate was concentrated in vacuo and the residue was chromatographed on 15 g of silica gel using hexane/ether (9:1) for the elution. There was obtained 0.55 g of uniform (20S)-21-bromo-1α,3β-diacetoxy-20-methyl-pregn-5-ene in the form of a colourless powder of melting point 75°-76° C.; [α]D =-13.8° (c=0.5 in chloroform).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].CC(=CC)C.C([OH:18])(C)(C)C.[O-]Cl=O.[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:18])=[O:8]
Reactant: O=Cc1scnc1Cl
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: O=C(O)c1scnc1Cl
Reaction time: 0.33 h

Procedure:
To a stirring mixture of 10.3 g (69.8 mmol) 4-chloro-thiazole-5-carbaldehyde (Journal of the Chemical Society, Perkins Transactions, 1992, 973-978), 296 ml (2792 mmol) 2-methyl-2-butene, and 200 mL tertiary butanol was added a solution of 50.5 g (558 mmol) NaClO2, 50.2 g (419 mmol) NaH2PO4 in 300 mL of water, dropwise over 20 minutes. The reaction was stirred for 1 hour then concentrated to 1/3 volume via rotary evaporation. The remaining solution was acidified with 6N HCl with rapid stirring. The precipitated solid was filtered and air dried under high vacuum overnight to give 10.6 g of white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](SC)=[N:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1.Cl.[NH2:20][OH:21].C(N(CC)C(C)C)(C)C>C(O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:20][OH:21])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Br:16])[CH:10]=2)=[N:4][S:5][N:6]=1
Reactant: CSC(=Nc1ccc(F)c(Br)c1)c1nsnc1N
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nsnc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
A solution of methyl 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carbimidothioate (78 mg, 0.22 mmol) in ethanol (2.3 mL) was treated with hydroxylamine hydrochloride (62 mg, 0.9 mmol) followed by N,N-diisopropylethylamine (180 μL, 1.0 mmol) and stirred at 90° C. for 16 h. The reaction mixture was purified by preparative HPLC to give the desired product (58 mg, 78%). LCMS for C9H8BrFN5OS (M+H)+: m/z=331.9, 333.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:40]=[CH:41][N:42]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:40]=[CH:41][N:42]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:38][CH:39]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(N3CCCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nn3ccnc23)nc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCCC(C(=O)Nc4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.7 %

Procedure:
A mixture of tert-butyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxamido)benzoate (150 mg, 0.26 mmol) and TFA (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 2 h. The residue was concentrated in vacuo. The crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxamido)benzoic acid (5 mg, 4%) as yellow solid. 1H NMR (300 MHz, DMSO): δ 10.36 (s, 1H), 10.25 (s, 1H), 8.14 (brs, 2H), 7.90-7.74 (m, 5H), 7.44 (s, 1H), 6.97 (s, 1H), 4.25-4.15 (m, 4 h), 3.91 (s, 3H), 3.77 (s, 3H), 2.67 (brs, 2H), 2.04-1.57 (m, 3H). LC-MS: [M+H]+, 517.9, tR=1.366 min, HPLC: 95.06% at 214 nm, 95.20% at 254 nm, tR=4.927 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([CH3:13])[C:11]=2[N:12]=1.C(OC([C:27]1[NH:28][CH:29]=[CH:30][CH:31]=1)=O)(C)(C)C>>[CH3:19][N:6]1[C:7](=[O:18])[C:8]2[CH:17]=[CH:16][CH:15]=[N:14][C:9]=2[N:10]([CH3:13])[C:11]2[N:12]=[C:2]([C:27]3[NH:28][CH:29]=[CH:30][CH:31]=3)[CH:3]=[CH:4][C:5]1=2
Reactant: CC(C)(C)OC(=O)c1ccc[nH]1
Reactant: CN1C(=O)c2cccnc2N(C)c2nc(Cl)ccc21
Product: CN1C(=O)c2cccnc2N(C)c2nc(-c3ccc[nH]3)ccc21

Procedure:
The title compound (mp 158°-160° C.) was prepared from 2-chloro-5,11-dihydro-5,11-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and (t-butoxycarbonyl)pyrrole in a manner analogous to that described in Example 23.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[CH2:21]([O:23]CCO)[CH3:22].[H-].[Na+].[H-]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH2:20][O:23][CH2:21][CH3:22])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Reactant: CCOCCO
Agent: [H-]
Agent: [Na+]
Product: CCOCCOC(=O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
To a mixture of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate and 2-ethoxyethanol is added sodium hydride. After the hydride is reacted, the mixture is heated on a steam bath for 12 hours. The solvent is removed and the residue is acidified with dilute acetic acid to give the product of the example.