Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1([F:20])[CH2:8][CH2:7][CH:6]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[F:20][C:3]1([F:2])[CH2:4][CH2:5][CH:6]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:31][CH3:32])=[O:33])[CH2:7][CH2:8]1
Reactant: COC(=O)C1CCNC(CC2CCC(F)(F)CC2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(CC2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
Methyl 2-((4,4-difluorocyclohexyl)methyl)piperidine-4-carboxylate hydrochloride (5.1 g, 16.36 mmol) was dissolved in DCM (150 mL), then DIPEA (7.14 mL, 40.89 mmol) was added. Methyl carbonochloridate (1.803 mL, 22.90 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 2 h. The mixture was washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), then dried through a phase separator and evaporated yielding crude dimethyl 2-((4,4-difluorocyclohexyl)methyl)piperidine-1,4-dicarboxylate (5.7 g, 105%)
Reaction SMILES: N1C=CC=CC=1.F.[C:8]([O:13][C:14]1[CH2:27][C@@H:26]([O:28][Si](C(C)(C)C)(C)C)[C@H:25](/[CH:36]=[CH:37]/[C@@H:38]([O:44][Si](C(C)(C)C)(C)C)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])(=[O:12])[CH2:9][CH2:10][CH3:11]>>[C:8]([O:13][C:14]1[CH2:27][C@@H:26]([OH:28])[C@H:25](/[CH:36]=[CH:37]/[C@@H:38]([OH:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:15]=1[S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1C(SCCCCCC(N)=O)=C(OC(=O)CCC)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: CCCCC[C@H](O)/C=C/[C@@H]1C(SCCCCCC(N)=O)=C(OC(=O)CCC)C[C@H]1O
Yield: 90.7 %

Procedure:
Using as the material and reagent a hydrogen fluoride-pyridine solution (0.2 ml) and (11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienamide (169 mg), the same procedure was followed as in Example 2 to obtain (11R,12S,13E,15S)-9-butyryloxy-11,15-dihydroxy-7-thiaprosta-8,13-dienamide (101 mg, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:14])[S:7][C:6]=2[CH:15]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:23]=[C:24]([C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[S:25][C:18]=12.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:14][C:8]1[S:7][C:6]2[CH:15]=[C:2]([O:1][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[CH:23]=[C:24]([C:26]5[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=5)[S:25][C:18]=34)[CH:3]=[CH:4][C:5]=2[C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: COC(=O)c1c(C)sc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc12
Yield: 61.2 %

Procedure:
This material was prepared from the reaction of methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (200 mg, 0.90 mmole) with 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (188 mg, 0.75 mmole) and Cs2CO3 (1.22 g, 3.75 mmole) in a manner as previously described for example 1 to give a yellow solid (200 mg, 51%). 1H NMR (DMSO-d6, 300 MHz) δ8.52 (1H, d, J=5.46 Hz), 8.38 (1H, d, J=9.04 Hz), 8.02 (1H, d, J=2.26 Hz), 7.89 (1H. s), 7.40 (2H, s), 7.02 (1H, s), 6.73 (1H, d, J=5.46 Hz), 3.98 (3H, s), 3.91 (3H, s), 2.82 (3H, s).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=[N+:2]=[N-:3].[CH3:14][CH:15]([CH3:20])[C:16]#[C:17][Mg]Cl.CC(C)C#C.C([Mg]Cl)(C)C>C1COCC1>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([N:1]2[C:16]([CH:15]([CH3:20])[CH3:14])=[CH:17][N:3]=[N:2]2)[CH:9]=1
Reactant: CC(C)C#C[Mg]Cl
Reactant: [N-]=[N+]=Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: C#CC(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cnnn1-c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A 30 mL scintillation vial was charged with 2-azido-4-chloro-1-nitrobenzene (200 mg, 1.0 mmol) and 0.75 M 3-methyl-1-butynylmagnesium chloride in THF (1.6 mL, 1.2 mmol; prepared by mixing 3-methyl-1-butyne (120 L, 1.2 mmol) and iPrMgCl (1.5 mL, 1.0 M in THF) at room temperature, heating to 40° C. for 30 minutes then cooling to room temperature). The reaction was allowed to stir at room temperature for 1 hour after which the reaction was quenched with SiO2 and the solvent removed. The product (adsorbed to SiO2) was then loaded on a SiO2 column and purified to give 1-(5-chloro-2-nitro-phenyl)-5-isopropyl-1H-[1,2,3]triazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15](OS(C)(=O)=O)[CH2:16][C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](/[CH:15]=[CH:16]/[C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(CC#N)OS(C)(=O)=O)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(/C=C/C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 99.4 %

Procedure:
To 4-(2-cyano-1-hydroxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (4.24 g, 15.8 mmol) and pyridine (3.07 mL, 39.5 mmol) dissolved in dichloromethane (45 mL) at 0° C. is added methanesulfonyl chloride (3.45 mL, 42.6 mmol). After 1 hour, the reaction is not complete and is warmed to room temperature. After 18 hours at room temperature 1 equivalent of pyridine and 1 equivalent of methanesulfonyl chloride is added and stirred for 4 hours. The reaction mixture is diluted with EtOAc and washed several times with saturated NaHCO3. The organic layer is dried over Na2SO4, filtered and concentrated to give crude 4-(2-cyano-1-methanesulfonyloxy-ethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester. Assuming 100% yield, 4-(2-cyano-1-methanesulfonyloxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (5.47 g, 15.8 mmol) and triethylamine (11.0 mL, 79 mmol) are dissolved in MeOH (60 mL) and heated at 70° C. for 1 hour and concentrated. The residue is dissolved in EtOAc and washed with water, then concentrated and chromatographed using 100% dichloromethane to give cis/trans-4-(2-cyanovinyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (3.93 g, 99% yield) as a clear oil.
Reaction SMILES: [K].[SH:2][C:3]1[S:4][C:5]2[C:6]([N:16]=1)=[N:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=2.I[CH3:18]>CN(C=O)C>[CH3:18][S:2][C:3]1[S:4][C:5]2[C:6]([N:16]=1)=[N:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=2
Reactant: CI
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2nc(SC)sc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a stirred mixture of ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt (1.7 g, 6.6 mmol) from the previous step in DMF (10 mL) at 0° C. was added iodomethane (226 μL, 3.6 mmol). After the mixture was stirred at 0° C. for 2 h, it was allowed to warm slowly to rt. The mixture was partitioned between EtOAc (100 mL) and 0.5 M aq Na2CO3 (50 mL). The organic layer was separated and washed with brine (50 mL), dried over Mg2SO4, filtered, and concentrated under reduced pressure to afford ethyl 2-(methylthio)thiazolo[4,5-b]pyridine-6-carboxylate (724 mg, 82%) as a yellow solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 2.86 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=O)[NH:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>N1C=CC=CC=1>[OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[S:25])[NH:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 25 °C
Yield: 19 %

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-3-propyl-3,7-dihydro-purine-2,6-dione (500 mg, 1.57 mmol) was dissolved in 10 mL of pyridine. P4S10 (1.05 g, 1.5 eq) was added and the reaction mixture was stirred under reflux for 6 h. The reaction mixture was then cooled to rt and quenched slowly with 5 mL of H2O. The mixture was then acidified at 0° C. to pH 5 with 6 N HCl. The aqueous layer was extracted with EtOAc. The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by preparative HPLC afforded 100 mg of the titled compound.
Reaction SMILES: C(N(CC)CC)C.CN1CCN(C)C1=O.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:22][CH:21]=1.Cl[CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[CH:35]([S:36]([NH:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:24][CH:25]=1)(=[O:38])=[O:37])=[CH2:34]
Reactant: NCCCc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: C=CS(=O)(=O)NCCCc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
7.50 g of triethylamine was added to a 1,3-dimethyl-2-imidazolidinone suspension (75 ml) containing 7.51 g of 6-[4-(3-aminopropyl)phenyl]-4,5-dihydropyridazin-3(2H)-one, and the mixture was stirred at room temperature for 10 minutes. Then, a tetrahydrofuran solution (40 ml) containing 5.85 g of chloroethylsulfonyl chloride was added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and precipitated crystal was collected by filtration and recrystallized from acetonitrile to obtain 5.39 g of 6-[4-(3-vinylsulfonylaminopropyl)phenyl]-4,5-dihydropyridazin-3(2H)-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[C:25]([CH2:24][OH:23])[CH:26]=[CH:27][CH:28]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: OCc1cccc(B(O)O)c1
Product: CC(On1ccc2ncc(-c3cccc(CO)c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and [3-(hydroxymethyl)phenyl]boronic acid according to the procedure described in example 4.
Reaction SMILES: [CH2:1]([P:8]([CH2:11][CH:12]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([NH:23]C(OC(C)(C)C)=O)=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([OH:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[NH2:23][C:20]1[N:19]=[CH:18][C:17]([CH2:16][CH:12]([CH2:11][P:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([OH:10])=[O:9])[C:13]([OH:15])=[O:14])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(CP(=O)(O)Cc2ccccc2)C(=O)O)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(CC(CP(=O)(O)Cc2ccccc2)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
3-[Benzyl(hydroxy)phosphoryl]-2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)propanoic acid (46 mg; 0.11 mmol) was dissolved in EtOAc (2 mL) and 1 mL of EtOAc, which had been saturated with HCl (g), was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated to yield 25 mg (64%) of 3-(6-aminopyridin-3-yl)-2-{[benzyl(hydroxy)phosphoryl]methyl}propanoic acid.
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[OH-].[Na+].[O:23]1CCOCC1>O>[CH:17]1([C:3]2[C:2](=[O:23])[NH:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]n2c(-c3ccccc3)nnc2cc1C1CCC1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (2.0 g, 7.0 mmol), 2 N NaOH (50 ml) and 1,4-dioxane (10 ml) were heated at reflux for 16 hours. Cooled and water (150 ml) added. Precipitate filtered, suspended in H2O, acidified (2 N HCl), filtered and dried to give a white solid. 1H NMR (250 MHz, CDCl3) δ1.89-2.02 (1 H, m), 2.08-2.25 (3 H, m), 2.36-2.48 (1 H, m), 3.56-3.70 (1 H, m), 7.48-7.60 (3 H, m), 7.88 (1 H, s), 8.38 (1 H, m). Mass spec ES+ (M+1)=267.
Reaction SMILES: C[Si]([PH:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O-:9])[O:6][CH2:7][CH3:8])(C)C.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18].C(Cl)(Cl)Cl>O>[O:20]=[C:19]([CH3:21])[CH2:17][CH2:18][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: C=CC(C)=O
Reactant: CCOC(OCC)[PH]([O-])(OCC)[Si](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(OCC)P(=O)(CCC(C)=O)OCC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
15.0 g of ethyl trimethylsilyl(diethoxymethyl)phosphonite are added dropwise to a stirred solution of 3.9 g of methyl vinyl ketone under an atmosphere of nitrogen at room temperature. The mixture is then heated to 50° C. for a period of 1 hour. The mixture is then allowed to cool to room temperature, 25 ml of chloroform is then added followed by 10 ml water and this mixture is vigorously stirred for a period of 0.5 h. The organic layer is then separated, dried over magnesium sulphate and concentrated under reduced pressure and the crude product distilled under reduced pressure to give ethyl 3-oxobutyl(diethoxymethyl)phosphinate, b.p. 130°-135° C./0.02 mbar, 31P=+45.3 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11].C([O-])([O-])=O.[K+].[K+].ClC1C=C(C)C([N+]([O-])=O)=CC=1C>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c(Cl)c1
Agent: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Product: Cc1cc(Cl)c(C)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of commercially available 2-chloro-1,4-dimethylbenzene (5 mL, 37 mmol) in concentrated H2SO4 (5 mL) cooled to 0-5° C. was added dropwise concentrated HNO3 (4.7 mL, 74.6 mmol) over 20 min. After the addition, the reaction was stirred at 0-5° C. for 30 min, then poured carefully into a mixture of ice and saturated aqueous K2CO3 solution (40 mL), and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel), eluting with 10-30% EtOAc/hexane to give a mixture of the title compound and its regioisomer (1-chloro-2,5-dimethyl-4-nitrobenzene) (3.0 g). The mixture was further chromatographed (silica gel) eluting with 10% CH2Cl2 in hexane to afford pure compound 19A (0.2 g).
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][N:27]=1>>[NH2:25][C:26]1[N:27]=[CH:28][C:29]([C:12]#[C:11][C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:30][CH:31]=1
Reactant: Nc1ccc(I)cn1
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(N)nc2)c1)c1ccccc1
Yield: 84.4 %

Procedure:
In a manner similar to that described in Example 443, (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (100 mg, 0.28 mmol) and 2-amino-5-iodopyridine (69.3 mg, 0.31 mmol) were reacted to give the title compound as light yellow solid (89 mg).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]1([CH3:27])[CH2:26][CH2:25][NH:24]1>>[CH3:22][C:23]1([CH3:27])[CH2:26][CH2:25][N:24]1[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CC1(C)CCN1
Product: CC1(C)CCN1c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 100 °C
Yield: 59 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 93 mg, 0.329 mmol) and 2,2-dimethylazetidine (84 mg, 0.988 mmol; FCH Group, Chernigov, Ukraine), heating at 100° C. for 4 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(2,2-dimethylazetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66 (s, 6H) 2.27 (t, J=7.53 Hz, 2H) 2.87 (t, J=6.85 Hz, 2H) 3.42 (td, J=6.75, 2.15 Hz, 2H) 4.14 (br. s., 2H) 6.95 (br. s., 1H) 7.12 (d, J=2.15 Hz, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.64 (d, J=8.02 Hz, 1H) 7.95 (d, J=7.43 Hz, 1H) 8.35 (br. s., 1H) 12.09 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3N)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]3[C:11](=[CH:12][CH:13]=2)[C:20]2[C:19](=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:16](=[O:18])(=[O:17])[NH:15]3)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3N)cccc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccnc2c3c(ccc12)-c1ccccc1S(=O)(=O)N3
Yield: 23.5 %

Procedure:
In a similar fashion using route 16 general procedure 61, 8-(2-amino-benzenesulfonylamino)-quinoline-4-carboxylic acid methyl ester (Intermediate 288) (270 mg, 0.75 mmol), t-butyl nitrite (0.14 ml, 1.13 mmol), AcOH (2.7 ml) and THF (2.7 ml) gave the title compound (60 mg, 23%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([CH:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7][CH2:6]1)=[O:4].CC([O-])(C)C.[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].OP([O-])(O)=O.[K+]>CN(C=O)C>[C:18]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]1[CH2:7][CH2:6][CH:5]([C:3](=[O:4])[N:2]([CH3:1])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][C:16]2=1)#[N:19]
Reactant: CCOC(=O)CBr
Reactant: CN(C(=O)C1CCc2[nH]c3ccc(C#N)cc3c2C1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(C#N)ccc31)CC(C(=O)N(C)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a stirred solution of (±)-6-cyano-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid methyl-phenyl-amide (0.14 g, 0.43 mmol) in dry DMF (1.5 ml) is added KOtBu (58 mg, 0.52 mmol) and ethyl bromoacetate (79 mg, 0.47 mmol). The reaction mixture is stirred at rt overnight, then poured into saturated aqueous KH2PO4 and extracted with CH2Cl2. The combined organic layers are washed with H2O and brine, dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography on silica gel (hexane/EtOAc 1:1) to provide subtitle compound (91 mg) as a beige solid in 51% yield. tR (LC-3) 1.15 min; ESI-MS (positive ion): m/z 416.09 [M+H]+ (calcd 415.19 for C25H25N3O3). 1H-NMR (CDCl3): 1.13 (t, J=7.0 Hz, 3H); 1.79 (m, 1H); 2.05 (m, 1H); 2.25 (m, 1H); 2.65 (m, 1H); 2.72 (m, 2H); 3.19 (s, 3H); 3.24 (m, 1H); 4.07 (q, J=7.0 Hz, 2H); 5.00 (d, J=3.3 Hz, 2H); 7.33 (m, 1H); 7.41 (m, 5H); 7.50 (d, J=8.0 Hz, 1H); 7.87 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Br:9]Br>C(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:9])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Solvent: ClCCl
Product: Nc1ncc(Cl)cc1Br

Procedure:
20 g (77.8 mmol) of 2-amino-5-chloropyridine dissolved in 160 ml of CH2Cl2 are reacted with 8 ml of bromine, which is added dropwise at 0° C. After the addition is complete, the mixture is left to react at 25° C. for 2 h. The suspension is washed with 10% strength sodium hydroxide solution, and the organic phase is washed with water and then dried over MgSO4, filtered and evaporated. The compound obtained is recrystallized in isopropanol. M.p. 82° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)(=[O:4])=[O:3].[NH2:15][C@@H:16]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([F:38])[CH:34]=1)[CH2:30][C@H:16]([NH:15][C:12]([CH:9]1[CH2:8][CH2:7][CH:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH2:11][CH2:10]1)=[O:14])[C@H:17]([OH:29])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[CH:22]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CS(=O)(=O)CC1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)C2CCC(CS(C)(=O)=O)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.4 %

Procedure:
To a stirred solution of acid from step 6 (100 mg, 0.5 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (190 mg, 0.5 mmol), and HATU (175 mg, 0.5 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (280 μL, 1.6 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 95:5 to 92:8 methylene chloride/methanol) provided the title compound (60 mg): mp 45–50° C.; ESI MS m/z 537 [M+H]+.