Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:34]=[CH:33][C:32]([S:35][CH3:36])=[C:31]([CH3:37])[CH:30]=1)[CH:7]=[CH:6]2.Cl.B(Br)(Br)Br.O>C(OCC)(=O)C.C(OCC)C>[CH3:37][C:31]1[CH:30]=[C:29]([C:8]2[C:9]([O:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH:34]=[CH:33][C:32]=1[S:35][CH3:36]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(SC)c(C)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Dissolve the product of Example 47 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (5 mL, 10.0 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with external ice bath and add BBr3 (0.3 mL, 3.2 mmol). After 1 hour, add water (1.0 mL) and ethyl acetate (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a column eluting the material with a step gradient of methanol in dichloromethane (0 to 0.5%) to give 330 mg of the title compound (92%): mass spectrum (ion spray): m/z=500.3 (M+H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[C:9]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])#[N:10]>ClCCl>[C:19]([O:18][C:17](=[O:23])[NH:16][C:12]1[S:13][C:14]([I:1])=[CH:15][C:11]=1[C:9]#[N:10])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1sccc1C#N
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(I)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Iodosuccinimide (9.28 g, 41.2 mmol, 1.0 eq) was added to a stirred mixture of tert-butyl (3-cyano-2-thienyl)carbamate (9.25 g, 4.1.2 mmol, 1.0 eq) in dichloromethane (82 ml, 0.5 M) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane and washed with 1N sodium hydroxide (300 mL), sodium thiosulfate (2×300 mL), water (2×300 mL), and brine. The organic layers was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a solid.
Reaction SMILES: C([O:3][C:4](=[O:33])/[C:5](/[F:32])=[C:6](\[CH3:31])/[CH:7]=[CH:8]/[C:9](/[F:30])=[C:10](\[C:12]1[C:21]([O:22][CH2:23][CH2:24][CH3:25])=[CH:20][C:19]2[C:18]([CH3:27])([CH3:26])[CH2:17][CH2:16][C:15]([CH3:29])([CH3:28])[C:14]=2[CH:13]=1)/[CH3:11])C.[OH-].[Na+].Cl>CCO>[F:32]/[C:5](=[C:6](/[CH3:31])\[CH:7]=[CH:8]\[C:9](\[F:30])=[C:10](/[C:12]1[C:21]([O:22][CH2:23][CH2:24][CH3:25])=[CH:20][C:19]2[C:18]([CH3:27])([CH3:26])[CH2:17][CH2:16][C:15]([CH3:29])([CH3:28])[C:14]=2[CH:13]=1)\[CH3:11])/[C:4]([OH:33])=[O:3]
Reactant: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C(/F)C(=O)O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Yield: 71.9 %

Procedure:
To a solution of (2Z,4E,6E)-2,6-difluoro-3-methyl-7-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid ethyl ester (Compound 10, 82 mg, 0.18 mmol) in EtOH (2 mL) was added 1M NaOH (1.0 mL). The mixture was heated to 60° C. for 2 h and was cooled to ambient temperature, acidified with 1M HCl, and extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50% EtOAc-hexane) to give the title compound as a pale yellow solid (56 mg, 73%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH:23]([CH2:27][NH:28][CH3:29])[O:22]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:25]3[CH2:26][CH:21]([CH3:20])[O:22][CH:23]([CH2:27][NH:28][CH3:29])[CH2:24]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CNCC1CNCC(C)O1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)OC(CNC)C3)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 6-methyl-2-(methylaminomethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-[6-methyl-2-(methylaminomethyl)morpholino]-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]([C:67]1[S:71][C:70]2[CH:72]=[CH:73][C:74]([NH2:76])=[CH:75][C:69]=2[CH:68]=1)=[O:66]>>[CH3:63][O:64][C:65]([C:67]1[S:71][C:70]2[CH:72]=[CH:73][C:74]([NH:76][C:30]([C@@H:20]3[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]4([C:12]5[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=5)[NH:15][C:16]4=[O:38])[C@H:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])=[O:32])=[CH:75][C:69]=2[CH:68]=1)=[O:66]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1cc2cc(N)ccc2s1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@@]4(C(=O)Nc5cc(Cl)ccc54)[C@H]3c3cccc(Cl)c3F)ccc2s1
Yield: 43.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (111 mg, 0.86 mmol), diphenylphosphinic chloride (106 mg, 0.446 mmol), then reacted with 5-Amino-benzo[b]thiophene-2-carboxylic acid methyl ester (Maybridge, 41 mg, 0.190 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzo[b]thiophene-2-carboxylic acid methyl ester (49 mg, 43%). MS (ES+) m/z [(M+H)+]: 654
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[C:4](=[O:17])[C:5]=1[NH:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.N1([CH:28]([NH:39][C:40](=[O:48])[C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[C:29]([CH3:38])([CH3:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[K+].[K+]>>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]([NH:39][CH:28]([NH:1][C:2]2[C:3](=[O:18])[C:4](=[O:17])[C:5]=2[NH:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=2)[C:29]([CH3:37])([CH3:38])[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:48])=[CH:42][CH:43]=1
Reactant: Nc1c(Nc2cncc(C(F)(F)F)c2)c(=O)c1=O
Reactant: CC(C)(Cc1ccccc1)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(Cc1ccccc1)C(NC(=O)c1ccc(Cl)cc1)Nc1c(Nc2cncc(C(F)(F)F)c2)c(=O)c1=O

Procedure:
A suspension of the product from Example 52C, the product from Example 18B, and K2CO3 was processed as described in Example 1D to provide the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(O)c1ccc2snnc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4snnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzo[d][1,2,3]thiadiazole-5-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 8.51 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.57 (dd, J=8.5, 1.7 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H), 8.85 (dd, J=4.9, 1.5 Hz, 1H), 9.32 (dd, J=2.4, 1.0 Hz, 1H), 9.51 (dd, J=1.7, 0.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][O:13][CH2:12][CH2:11][N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1>C1COCC1.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:14][O:13][CH2:12][CH2:11][N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:8]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of tert-butyl (3R)-3-[4-(hydroxymethyl)phenyl]morpholine-4-carboxylate 10 (6 g, 20.45 mmol) in THF (121.4 mL) was added manganese dioxide (17.78 g, 204.5 mmol) and the resulting mixture stirred at rt overnight. The reaction mixture filtered through pad of celite, and washed with EtOAc (3×50 mL). The filtrate was concentrated in vacuo to leave product as a colourless oil (5.54 g, 93% yield), which was used directly in the next step without further purification; 1H NMR (400.0 MHz, DMSO) d 1.39 (9H, s), 3.05 (1H, m), 3.52 (1H, m), 3.71-3.87 (4H, m), 4.28 (1H, m), 5.06 (1H, s), 7.55 (2H, m), 7.93 (2H, m) and 10.00 (1H, s) ppm
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 4-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (18-4, 0.10 g, 0.31 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.50 mL, 3.6 mmol) followed by isonicotinoyl chloride hydrochloride (0.15 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-(4-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (18, 0.070 g) as light yellow solids in 52% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.81 (d, J=5.5 Hz, 2 H), 7.99 (dt, J=3.1, 1.5 Hz, 2 H), 7.92 (d, J=3.1 Hz, 1 H), 7.52 (dt, J=5.7, 3.2 Hz, 1 H), 7.20 (s, 1 H), 7.00 (d, J=8.8 Hz, 1 H), 6.81 (s, 2 H), 3.81 (s, 3 H), 2.08 (s, 6 H). ESI-MS: m/z 433.0 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[O:41][C:42]([CH3:53])=[C:43]([CH2:45][CH2:46][N:47]3[CH2:51][CH2:50][C@H:49]([F:52])[CH2:48]3)[N:44]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[F:52][C@@H:49]1[CH2:50][CH2:51][N:47]([CH2:46][CH2:45][C:43]2[N:44]=[C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=4)=[CH:35][CH:36]=3)[O:41][C:42]=2[CH3:53])[CH2:48]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CC[C@H](F)C1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CC[C@@H](F)C1

Procedure:
Prepare using the method of Example 103 with palladium (II) acetate (0.002 g, 0.008 mmol), anhydrous acetonitrile (4 mL), triphenylphosphine (0.009 g, 0.034 mmol), distilled water (1 mL), 4-(methanesulfonyl)benzeneboronic acid (0.096 g, 0.45 mmol), 2-(4-bromophenyl)-4-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethyl}-5-methyl-1,3-oxazole (See Example 104) (0.150 g, 0.42 mmol) and potassium carbonate (0.176 g, 1.27 mmol) to give the title compound as a cream coloured solid (0.133 g): MS (m/e): 429(M+1).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH:21]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[CH:22]([CH3:24])[CH3:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH:21]([O:25][C:26]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:27])[CH:22]([CH3:24])[CH3:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (630 mg, 4.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl benzoate (500 mg, 1.5 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 49 (200 mg, 35% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.84-0.91 (br. m, 2H), 0.99 (d, J=6.8 Hz, 6H), 1.16-1.31 (br. m, 3H), 1.66-1.68 (br. m, 2H), 1.82-1.85 (m, 2H), 2.03-2.12 (br. m, 2H), 2.80 (t, J=6.4 Hz, 2H), 6.11 (d, J=4.4 Hz, 1H), 7.51 (t, J=6.0 Hz, 1H), 7.57 (t, J=6.0 Hz, 2H), 7.71 (t, J=7.2 Hz, 1H), 7.96 (dd, J=8.4, 1.6 Hz, 2H), 11.97 (br. s, 1H). MS (ESI) m/z 400.08 (M+Na)+; 376.10 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C(OCC)(OCC)OCC.CCCCCC>[F:20][C:19]1[C:2]2[N:1]=[CH:23][O:22][C:3]=2[C:4]2[NH:8][C:7](=[O:9])[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:5]=2[C:18]=1[F:21]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(I)cc2F)c1O
Solvent: CCOC(OCC)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(I)cc1F
Temperature: 120 °C
Yield: 535.3 %

Procedure:
A mixture of 5-amino-6,7-difluoro-1-(2-fluoro-4-iodo-phenyl)-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (I-13a: 550 mg, 1.3 mmol) in triethyl orthoformate (5 mL) and p-toluene sulfonic acid (20 mg, 0.13 mmol) were taken in a flask and the flask was heated to reflux at 120° C. for 30 minutes. The reaction was monitored by TLC (70% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure and the concentrate was triturated with diethyl ether and filtered. The residue was washed with diethyl ether and dried under reduced pressure to afford 300 mg of the product (54.5% yield). H1NMR (DMSO-d6, 300 MHz): δ 12.50 (s, 1H), 8.87 (s, 1H), 7.97 (dd, 1H), 7.78 (d, 1H), 7.50 (t, 1H). LCMS: 92.2%, m/z=431.9 (M+1).
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH2:3][SH:4].Cl[CH2:7][CH2:8][CH2:9][OH:10]>CO>[CH2:9]([OH:10])[CH2:8][CH2:7][S:4][CH2:3][CH2:2][S:5][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCCCCl
Reactant: SCCS
Agent: [Na]
Solvent: CO
Product: OCCCSCCSCCCO
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 300 ml of absolute methanol, was added 12.2 g of metallic sodium. To the resulting solution which was being stirred in an ice bath, was added dropwise 25 g of dithioglycol. After the dropwise addition, the stirring was continued for additional 30 minutes in the ice bath. Then, 52 g of 3-chloro-1-propanol was further added dropwise. At the conclusion of the dropwise addition, the temperature of the reaction system was raised to a room temperature, and the reaction system was allowed to stand for 10 hours at the room temperature. The thus produced sodium chloride was removed by filtration under reduced pressure, and the resulting filtrate was concentrated. Crystals thus obtained were recrystallized from acetone. Melting Point 52° C., Yield 20 g.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[N:3][CH:2]=1.[CH:14](OCC)=[O:15].[H-].[Na+]>C(COC)OC.C(OCC)(=O)C>[CH:14]([CH:8]([CH2:7][C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:15]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cncnc1
Reaction time: 24 h

Procedure:
A mixture of ethyl 3-(5-pyrimidyl)propionate (2.28 g) and ethyl formate (1.41 ml) dissolved in dry dimethoxyethane (5 ml) was added dropwise over 30 min to a suspension of sodium hydride (60%, 4.0 g) in DME (5 ml) under nitrogen, keeping the temperature below 0° C. Stirring was continued for a further 24 h, then the mixture was poured onto ice and washed with ether. The aqueous layer was adjusted to pH 7, then evaporated and the residue extracted with acetone. Filtration and evaporation gave crude product, which was taken up in ethyl acetate, charcoaled, dried and evaporated to give ethyl 2-formyl-3-(5-pyrimidyl)propionate. Like other compounds of this type, this proved difficult to characterise and was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[CH:11]=[C:12]([CH3:20])[C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[CH:11]=[C:12]([CH3:20])[C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2CC2)nn2c(N)nnc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (2.99 ml) was initially charged in DMF (30 ml), admixed under argon with sodium hydride (907 mg) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 2.0 g) were dissolved in DMF (30 ml) and one equivalent of the alkoxide solution was added. After stirring at 50° C. for one hour, two further equivalents of alkoxide solution were added and the mixture was stirred further at 50° C. The reaction mixture was then dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-10% in 40 min). 620 mg of the title compound were obtained. LC-MS rt: 0.57 min [M+H]+: 220.1 (met. b)
Reaction SMILES: ClC1C=CC([C:8]2[N:9]=C3C=CC=CN3C=2CC2N=C(C(NN)=O)ON=2)=CC=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34]([CH2:44][C:45]3[N:49]=[C:48]([C:50]([O:52]CC)=O)[O:47][N:46]=3)=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:36]=2)[CH:33]=1.CN>>[F:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34]([CH2:44][C:45]3[N:49]=[C:48]([C:50]([NH:9][CH3:8])=[O:52])[O:47][N:46]=3)=[C:35]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[N:36]=2)[CH:33]=1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)no1
Reactant: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Agent: CN
Product: CNC(=O)c1nc(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)no1

Procedure:
The title compound was prepared in the same fashion as that for compound 215 from ethyl 3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate and methylamine. m/e+=370 (M+H−). 1H NMR (400 MHz, in DMSO-d6): δ 9.23 (H, D, brd, NH), δ 8.66-8.65 (1H, D, dd, J=5.2, 2.0 Hz, ArH), δ 7.81-7.78 (2H, D, m, ArH), δ 7.45-7.40 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ 7.32-7.28 (2H, D, m, ArH), δ 4.72 (2H, D, s, CH2), and 2.76 (3H, D, s, CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1.[C:17](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH2:18].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([O:19][C:17](=[O:24])[NH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(N)=O
Reactant: Brc1ccc2nc(-c3cccnc3)nn2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Reaction time: 18 h
Yield: 72.3 %

Procedure:
A mixture of 6-bromo-2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.65 g, 6.00 mmol), tert-butyl carbamate (843 mg, 7.2 mmol) and cesium carbonate (2.74 g, 8.4 mmol) in 1,4-dioxane (37.8 ml) was purged with argon. Then tris(dibenzylideneacetone)dipalladium(0) (330 mg, 360 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (416 mg, 720 μmol) were added and the purging was repeated. The mixture was heated to reflux and stirred for 18 hours under argon atmosphere. After evaporation to dryness under reduced pressure, the crude material was purified by flash chromatography (50 g silicagel column using heptane/ethyl acetate 20-100% as eluent). Final evaporation of the solvents afforded (2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-carbamic acid tert-butyl ester (1.35 g, 72.5%) as yellow solid. Mp.: 296° C. MS: m/z=312.3 (M+H+).
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:23])[CH:5]3O[C:6]43[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]4.S(=O)(=O)(O)O.[N-:29]=[N+:30]=[N-:31].[Na+].Cl>CS(C)=O.O>[CH2:1]1[C@@H:3]2[C:4](=[O:23])[C:5]([N:29]=[N+:30]=[N-:31])=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC45OC4C(=O)[C@H]4CC4[C@]35C)[C@@H]1CCC2=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C(N=[N+]=[N-])C(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Temperature: 85 °C
Yield: 70 %

Procedure:
To a stirred solution of 1,2β-methylen-4,5-epoxyandrostane-3,17-dione (0.50 g, 1.59 mmole) in dry dimethylsulfoxide (7.5 ml) is added conc. sulfuric acid (0.11 ml) and sodium azide (1.4 g). The resulting reaction mixture is heated at about 85° C. during 3 hours, cooled, poured into a mixture of water (50 ml) and conc. hydrochloric acid (4 ml), and extracted with ethyl acetate (3×50 ml). The combined organic extracts are dried over sodium sulfate, filtered and evaporated in vacuo to yield a solid which is purified by flash column chromatography eluting with n-hexane-diethyl ether 6:4. There are obtained 0.378 g (70% yield) of 1,2β-methylen-4-azidoandrost-4-ene-3,17-dione [I, R=--N, R1 =R2 =H; (a) and (b)=single bonds]