Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[Cl:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21][C:22]([C:24](O)=[O:25])=[N:23][C:19]=2[CH:18]=1>>[CH3:7][N:6]([CH3:8])[C:4]([CH:3]([NH:2][C:24]([C:22]1[NH:21][C:20]2[CH:27]=[CH:28][C:17]([Cl:16])=[CH:18][C:19]=2[N:23]=1)=[O:25])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5]
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1nc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: CN(C)C(=O)C(Cc1ccccc1)NC(=O)c1nc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-N,N-dimethyl-3-phenyl-propionamide hydrochloride (2.0 mmol) and 5-chloro-1H-benzoimidazole-2-carboxylic acid (Crowther et al., J. Chem. Soc. 1949, p.1268, 2.0 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 1:1 ethyl acetate-hexanes (235 mg, 63%): HPLC (60/40) 4.92 min (91%); PBMS 371/373 (MH+, 100%); 1H NMR (CDCl3) δ11.25 (br, 0.6H), 10.9 (br, 0.4H), 8.36 (m, 1H), 7.78 (d, 0.4H, J=7.72 (d, 0.6H, J=8.8 Hz), 7.52 (d, 0.6H, J=2 Hz), 7.41 (d, 0.4H, J=8.4 Hz), 7.35-7.1 (m, 6H), 7.35 (m, 1H), 3.16 (m, 2H), 2.90 (s, 3H), 2.68 (s, ca. 2H), 2.67 (s, ca. 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:25])[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([C:22](O)=[O:23])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[O:10])[CH:7]=1.Cl.C[O:28][C:29](=[O:42])[C@H:30]([CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)[NH2:31].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:25][C:4]1[CH:5]=[C:6]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:20])([CH3:21])[C:22]([NH:31][CH:30]([CH2:32][C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][CH:34]=3)[C:29]([OH:28])=[O:42])=[O:23])=[CH:14][CH:13]=2)=[O:10])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)(C)C(=O)NC(Cc3c[nH]c4ccccc34)C(=O)O)cc2)c1

Procedure:
Using RSR13 acid (1.5 g, 4.4 mmol), tryptophan methyl ester hydrochloride (1.12 mg, 4.4 mmol) and 1-hydroxybenzotriazole hydrate (653 mg, 4.8 mmol), N-methylmorpholine (666 mg, 7.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.01 g, 6.0 mmol) in dimethylformamide (30 mL), the product was prepared in 2.3 g yield (96%)
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=1.[H-].[Na+]>CCOCC.CS(C)=O.O>[C:1]([C:2]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:22][NH:21][CH:20]=1)#[N:10]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: N#CC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: N#Cc1c[nH]cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of cinnamonitrile (16.53 g) and (para-toluenesulfonyl)methylisocyanide (25 g) in a mixture of ether and dimethyl sulphoxide (450 mL, 2:1) was added dropwise to a stirred suspension of sodium hydride (6.14 g, 60% dispersion in mineral oil) in ether (50 mL). An exothermic reaction took place. The reaction mixture was then stirred at room temperature for 2 hours, then diluted with water (500 mL) and this mixture was extracted three times with ether (250 mL). The combined extracts were washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to filter chromatography on a pad of silica eluting with a mixture of ethyl acetate and pentane (1 L, 1:4, v/v) and then with a mixture of ethyl acetate and pentane (2 L, 2:3, v/v). Fractions containing the required material were evaporated and the residue was suspended in pentane (500 mL) with stirring, then filtered to give the title compound as a solid, m.p. 120-122° C. MS: 167 (MH−).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:12]1([NH:11][C:8]([C:7]2[C:2]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)c1cccnc1Nc1ccccc1
Temperature: 190 °C
Yield: 26.3 %

Procedure:
To a suspension of 31.5 g (0.2 mole) of 2-chloro-3-pyridinecarboxylic acid in 75 mL of xylene was added 18.6 g (0.2 mole) of aniline, and the reaction mixture was heated at 190° C. (oil bath) for 45 min; then cooled. The xylene was filtered, and the reaction melt that had formed was crushed and partitioned between 100 mL of aqueous NaHCO3 (pH 8) and CH2Cl2 (150 mL). The solid that remained suspended in the two-phase system was filtered and discarded. The filtrate was concentrated to 200 mL, and the solid that precipitated from the two-phase system was filtered to give 7.6 g (13%) of N-phenyl-2-(phenylamino)-3-pyridinecarboxamide. Acetic acid was added to the filtrate to acidify the aqueous layer to pH 6 and the CH2Cl2 layer was separated. The aqueous solution was extracted with CH2Cl2 and the combined extracts were concentrated to 100 mL; the solid that precipitated was filtered and washed sequentially with water and CH2Cl2 to give 15.6 g of the product. An additional 5.3 g of the product was obtained from the filtrate for a total yield of 20.9 g (49%). The combined product was triturated with CH2Cl2 and then filtered to give 19.6 (46%) of the product as a yellow solid; mp 152°-155° C.; TLC (C6H12 -EtAc; 4:1 and EtAc-MeOH-NH4OH, 16:3:1) showed a single component. MS (EI) m/e (relative intensity): 214 (M+, 100), 213 (94), 195 (70), 169 (45), 168 (70), 167 (22), 77 (37), 51 (26).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][NH:32][CH:33]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]([CH3:31])[CH:33]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:30])[F:29])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CCN(C)C1
Product: CN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and methyl-(1-methyl-pyrrolidin-3-yl)-amine following General Procedure B.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)=[O:38]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]3)=[O:38])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CN1CCN(C(=O)c2ccccc2N)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)N3CCN(C)CC3)n2)c(OC)c1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available (2-aminophenyl)-(4-methylpiperazin-1-yl)-methanone. MS (ES+): m/z 637.40 (100) [MH+]; HPLC: tR=0.69 min (UPLC, purity).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH2:13][N:12](CC4C=CC(OC)=CC=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:44]1[S:45][CH:46]=[CH:47][N:48]=1)CCC>>[S:45]1[CH:46]=[CH:47][N:48]=[C:44]1[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:13][NH:12][C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(Cl)n4)cc3C2=O)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: O=C1NCC2(CCNCC2)c2[nH]c(-c3ccnc(-c4nccs4)n3)cc21

Procedure:
The title compound was prepared following the general procedure reported for Example 9—1 using A5 and 2-(tributylstannyl)thiazole, purified by semi-preparative HPLC (Method A) and was isolated as TFA-salt. 1H NMR (400 MHz, DMSO-D6, 300K): δ=1.90 (2H, d, J=14.1 Hz), 2.27 (2H, dt, J1=4.3 Hz, J2=14.4 Hz), 3.12 (2H, q, J=11.7 Hz), 3.30 (2H, s), 3.52 (2H, d, J=2.3), 7.36 (1H, d, J=1.9 Hz), 7.44 (1H, br s), 7.92 (1H, d, J=5.5 Hz), 8.01 (1H, d, J=3.1 Hz), 8.10 (1H, d, J=3.1 Hz), 8.26 (1H, br d, J=10.2 Hz), 8.78 (1H, br d, J=9.4 Hz), 8.83 (1H, d, J=5.5 Hz), 11.84 (1H, s); MS (ES) C18H18N6OS requires: 366. found: 367.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:32]=[CH:31][C:19]([CH2:20][CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)=[C:18]([F:33])[CH:17]=2)=[C:4]([O:34]C)[CH:3]=1.B(Br)(Br)Br.C(Cl)[Cl:41]>>[ClH:41].[Br:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:32]=[CH:31][C:19]([CH2:20][CH2:21][NH:22][CH3:23])=[C:18]([F:33])[CH:17]=2)=[C:4]([OH:34])[CH:3]=1
Reactant: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)c(F)c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CNCCc1ccc(-c2c(O)cc(Br)c3[nH]c(=O)c4sccc4c23)cc1F
Product: Cl
Temperature: 25 °C
Yield: 21 %

Procedure:
Following General Procedure F, tert-butyl 4-(6-bromo-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)-2-fluorophenethyl(methyl)carbamate (90 mg, 0.16 mmol) in CH2Cl2 at 0° C. was added BBr3 (1.0 M in CH2Cl2, 6 mL, 6 mmol) and the reaction was warmed to room temperature for 4 h. The reaction was quenched by pouring onto water or ice-water and the resulting mixture was concentrated and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired product was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a white solid (15 mg, 21%): ESI MS m/z 447 [C20H16BrFN2O2S+H]+; HPLC >99% (AUC), tR=9.26 min.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([CH3:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[F:23])=[C:6]([CH3:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Cc1ccc(O)c(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 2-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-4-methyl-phenol (300 mg, 0.87 mmol, 1 eq) in DMF (6 mL) was added Cs2CO3 (425 mg, 1.31 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 1 h, then ethyl 2-bromoacetate (174 mg, 1.04 mmol, 1.2 eq) was added. The reaction mixture was stirred for 1 h then the reaction quenched by pouring into water. The mixture was extracted with EtOAc and the organic extract washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (260 mg, 70%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:20]2C=CC=C[C:19]=2N=N1.C(Cl)Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:8]1[CH:19]=[CH:20][N:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=12
Reactant: Nc1cccc(N)n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: c1ccn2ccnc2c1

Procedure:
In Scheme 3, 2,6-diaminopyridine 15 is reacted with an alpha halocarbonyl 16 to give the imidazo[1,2-a]pyridine 17. The resulting amino group can be reacted with a carboxylic acid 18 using a coupling reagent such as chloro-1,3 dimethyl-4,5-dihydro-3H imidazolium chloride in the presence of a base such as TEA in a solvent such as ACN or alternatively by reacting amine 17 with an acid chloride 18 at elevated temperature in a solvent such as dichloroethane to give compound 19. Alternatively, the 2,6-diaminopyridine 15 is reacted with acid 20 using a coupling agent such as, but not limited to, BOP or DMC in an organic solvent such as DCM or DMF in the presence of an organic base such as Hunig' s base. The resulting amide 21 is reacted with alpha halocarbonyl 22 to give the imidazo[1,2-a]pyridine 23.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:8][C:7]=1[N+]([O-])=O)#[N:5].O.Cl>CO>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=[O:23])=[CH:8][C:7]=1[O:2][CH3:1])#[N:5]
Reactant: C[O-]
Reactant: N#Cc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1C#N

Procedure:
Sodium methanolate solution (2.8 g of a 30 percent strength solution in methanol) was added to a solution of 3-[4-cyano-3-nitrophenyl]-6-trifluoromethyl-1,2,3,4-tetrahydro-pyrimidine-2,4-dione (2.4 g) in 50 ml of anhydrous methanol. The reaction mixture was subsequently refluxed for 5 hours. After cooling, water (50 ml) was added first, followed by 10% strength aqueous hydrochloric acid to a pH of 3-4. The precipitate formed was subsequently separated off, washed with water and petroleum ether and dried. Yield: 1.1 g; m.p.: >230° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH:6]([S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:8])[CH3:7].[CH:17]1([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[ClH:2].[CH:17]1([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:1][CH:3]([OH:5])[CH2:4][O:16][C:13]2[CH:14]=[CH:15][C:10]([S:9][CH:6]([CH3:8])[CH3:7])=[CH:11][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: ClCC1CO1
Reactant: NCCCCC1CCCCC1
Reactant: CC(C)Sc1ccc(O)cc1
Product: CC(C)Sc1ccc(OCC(O)CNCCCCC2CCCCC2)cc1
Product: Cl
Yield: 11.4 %

Procedure:
Reaction of the epichlorohydrin derivative of 4-(isopropylthio)phenol (9.0 g., 0.04 mole) with cyclohexylbutylamine (6.7 g., 0.043 mole) according to procedure of Example 2(b) and crystallization of the crude product from ethanol affords an 11.4% yield of analytically pure 1-[(4-cyclohexylbutyl)amino]-3-[4-[(1-methylethyl)thio]phenoxy]-2-propanol hydrochloride, m.p. 179° with prior softening from 118°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:50])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10].I[CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCC1>[CH3:1][O:2][C:3](=[O:50])[CH2:4][N:5]([CH2:52][CH2:53][CH3:54])[CH2:6][CH2:7][NH:8][C:9]([C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:10]
Reactant: CCCI
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CCC)CC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 66.9 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-methoxy-2-oxoethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (28 mg, 0.041 mmol), 1-iodopropane (55.4 mg, 0.326 mmol) and potassium carbonate (11.27 mg, 0.082 mmol) in acetonitrile (2 mL) and dioxane (2.000 mL) was heated up for 8 hours. LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a white solid (20 mg, 67%). LCMS: m/e 729.47 (M+H)+, 2.96 min (method 1).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH2:24][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(F)ccc2F)c(=O)[nH]c1=O
Yield: 53.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (214 mg, yield: 53.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]#[N:17].[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=[O:26])(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][C:16]#[N:17])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=1
Reactant: N#CCNc1cnccc1-c1ccccc1Cl
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CS(=O)(=O)c1cc(C(=O)N(CC#N)c2cnccc2-c2ccccc2Cl)cc(C(F)(F)F)c1
Yield: 25 %

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-ylamino]-acetonitrile and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 6 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Another purification step using preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2) yielded the title compound as colorless solid (25%). MS (ESI): m/z=494.055 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:18](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[K+]>C(#N)C.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:16]#[N:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (9.0 g, 42 mmol) in acetonitril (125 mL) was added triethylamine (5.5 g, 54 mmol) followed by dropwise addition of methanesulfonyl chloride (5.7 g, 50 mmol). When addition was complete the mixture was stirred overnight. The mixture was filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate (100 mL) and the organic solution was washed with water (2×10 mL) and brine. The organic phase was dried (MgSO4) and the solvent was evaporated to give a residue that was dissolved in absolute ethanol (250 mL). Potassium cyanide (8.2 g, 125 mmol) was added and the mixture was heated at reflux overnight. The reaction mixture was allowed to cool to ambient temperature, filtered and the solvent was evaporated. The residue was dissolved in diethyl ether (200 mL) and the organic solution was washed with water (2×20 mL) and then dried (MgSO4) in the presence of activated carbon. The mixture was filtered and the solvent was evaporated to give 9.2 g of 4-(cyanomethyl)piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 1.20-1.33 (m, 2H), 1.46 (s, 9H), 1.77-1.88 (m, 3H), 2.32 (d, 2H), 2.66-2.78 (m, 2H), 4.10-4.23 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[C:16]12([NH:26][C:27]([NH2:29])=[S:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>C(O)CCC>[BrH:1].[C:16]12([NH:26][C:27]3[S:28][C:3]([C:5]4[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=4)=[CH:2][N:29]=3)[CH2:25][CH:20]3[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]3)[CH2:23]1)[CH2:17]2
Reactant: NC(=S)NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCCCO
Product: Br
Product: O=[N+]([O-])c1cc(-c2cnc(NC34CC5CC(CC(C5)C3)C4)s2)cc(O)c1O
Temperature: 25 °C

Procedure:
A suspension of 8.3 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is treated with 1-(1-adamantyl)-2-thiourea in 90 ml of n-butanol and the mixture is heated to boiling under reflux for 4 hours. After cooling to room temperature, the crystals are filtered under suction and recrystallized from n-butanol. There is obtained 5-[2-(1-adamantylamino)-5-thiazolyl]-3-nitropyrocatechol hydrobromide of m.p. 245°-247°.