Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O)(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48]C)=[O:47])=[CH:44][CH:43]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)(=[O:29])=[O:28])=[C:5]2[CH2:39][CH2:40][CH2:41][C:42]1[CH:51]=[CH:50][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3C=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccccc3CN3CCOCC3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To methyl 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate (Example 16, Step 5, 58 mg, 0.081 mmol) in DCE (2 mL) at 0° C. were added morpholine (0.0092 mL, 0.105 mmol) and NaBH(OAc)3 (27 mg, 0.13 mmol) and the reaction mixture was allowed to warm to rt overnight. The reaction was quenched with sat. NaHCO3, extracted with EtOAc, and dried over MgSO4. Purification by silica gel chromatography (35% to 50% EtOAc/hexanes) gave the desired product as a white solid (41 mg, 64%).
Reaction SMILES: CC[O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:5].[OH-].[Na+]>O.CO>[NH:7]1[C:8]2[C:13](=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
Solution of 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester# (20.0 g, 85.75 mmole) and NaOH (100 mmole) in a mixture of water/MeOH (1/1) (200 ml) was stirred at 50° C. for 4 h and then overnight at ambient temperature. The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in water (200 ml) and acidified with 1M HCl up to pH=3. The precipitates were collected on the filter and washed with water (3×50 ml) and dried over phosphorus pentoxide in dessicator to give indole-2,5-dicarboxylic acid 1 (10.38 g, 59%) of compound 1 as white crystals. MS: 203.7 (M−2H); 204.7 (M−H). 1H-NMR (DMSO-d6): 8.32 (m, 1H, H-4, indole); 7.80 (m, 1H, H-6, indole); 7.45 (d, 1H, H-7, indole); 7.22 (s, 1H, H-3, indole).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[C:13]([SH:21])=[N:14][C:15]([N:18]([CH3:20])[CH3:19])=[N:16][CH:17]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II>>[CH3:20][N:18]([CH3:19])[C:15]1[N:14]=[C:13]2[S:21][N:9]([CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:10](=[O:11])[C:12]2=[CH:17][N:16]=1
Reactant: CN(C)c1ncc(C(=O)NCCN2CCCCC2)c(S)n1
Agent: II
Product: CN(C)c1ncc2c(=O)n(CCN3CCCCC3)sc2n1
Yield: 85.9 %

Procedure:
Using the procedure of Example 20, 6.2 g (20.1 mmol) of 2-dimethylamino-4-mercapto-pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide were treated with 5.08 g (20.0 mmol) of iodine to give 5.31 g of the title compound after recrystallization from ethyl acetate, mp 128-129° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:10])[CH:5]=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C[O-].[Na+].C(OCC)(=O)C>O1CCCC1.CO>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(S)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a solution of 3-mercaptobenzoic acid methyl ester (504 mg, 3 mmol) and 1-chloro-4-nitrobenzene (473 mg, 3 mmol) in tetrahydrofuran (4 mL) was added at 0° C., in a dropwise manner, a solution of sodium methoxide in methanol (3.3 mL, 1M). The mixture was heated at reflux for 2 hours with stirring, then cooled to room temperature. Ethyl acetate (25 mL) was added and the mixture was washed consecutively with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (2×10 mL), and brine (10 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a solid that was recrystallised from ethanol to give the title compound (518 mg, 60%) as a solid, mp 98-100° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=[S:25]>C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:27][N:26]=[C:24]([C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([F:20])[CH:22]=2)[S:25]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=S)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Reaction time: 72 h
Yield: 89.8 %

Procedure:
To a solution of (4-oxo-4-phenylbutyl)-carbamic acid tert-butyl ester (2.2 g, 8.5 mmol) in ethanol/DCM (30 mL/10 mL) was added 3-fluorothiobenzoic acid hydrazide (Takasugi, J. J.; Buckwalter, B. L. European patent EP 1004241, 2004) (1.2 g, 7.1 mmol) at room temperature. After stirring for 3 days, the reaction mixture was concentrated and purified by flash column chromatography (20:1 Hexanes/EtOAc) to provide the product (2.65 g, 90%).
Reaction SMILES: [NH2:1][C@H:2]([C@@H:5]([OH:22])[C@H:6]([OH:21])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][OH:4].C([O-])(O)=O.[Na+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(Cl)Cl.CO>O1CCOCC1.CCOC(C)=O>[CH2:32]([O:31][C:29]([NH:1][C@H:2]([C@@H:5]([OH:22])[C@H:6]([OH:21])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][OH:4])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@H](O)[C@@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCCC[C@@H](O)[C@H](O)[C@H](CO)NC(=O)OCc1ccccc1
Yield: 90 %

Procedure:
(Ozinskas et al., J. Org. Chem. 1986. 51: 4057-5050). To a suspension of starting material 31 (Cosmoferm B.V., Delft, Netherlands) (6.35 g, 20 mmol) in aqueous NaHCO3 (1 N, 80 ml, 4 equiv.) and 1,4-dioxane (30 ml) was added benzyl chloroformate (3.31 ml, 1.1 equiv.). The reaction mixture was stirred at rt overnight, whereupon t.l.c (only ethyl acetate or DCM-MeOH 5:1) indicated the reaction was finished. The suspension was diluted with EtOAc and poured onto water. After separation, the aqueous phase was extracted with EtOAc (3×). The combined organic solutions were washed aqueous NH4Cl, brine, dried over Na2SO4, and concentrated to afford a residue. The residue was purified by flash column chromatography (Petroether-EtOAc, 2:1 to only EtOAc) to provide compound 32 (8.13 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[CH3:7]/[C:8](/[CH2:16][OH:17])=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)C=C>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([O:17][CH2:16]/[C:8](/[CH3:7])=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]=[CH2:1]
Reactant: C/C(=C\c1ccccc1)CO
Reactant: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: C=CCCl
Solvent: C1CCOC1
Product: C=CCOC/C(C)=C/c1ccccc1
Temperature: 5 °C
Yield: 67.4 %

Procedure:
Solid potassium tert-butylate (110 g, 0.960 mol) was added portion-wise (1 hour) to a solution of trans-2-methyl-3-phenyl-2-propen-1-ol (100 g, 0.950 mol) in dry THF (1 liter) at room temperature under nitrogen. After 1 more hour at room temperature, the reaction was cooled to 5° C. and tetra butyl ammonium iodide (12.1 g, 0.032 mol) was added followed by allyl chloride (100 g, 1.280 mol) drop-wise. The reaction was warmed up to room temperature overnight and poured onto water (2 liters). The reaction was extracted twice with ethyl acetate. Each organic phase was washed with water and brine. Combined extracts are dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether and the solvents were removed under vacuum. The product was purified by distillation through a 20-cm Widmer column. 120.5 g of the desired compound was obtained (97% pure, 0.620 mol, 97%). B.P.=70° C./0.067 mbar
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.Cl>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Product: COc1ccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Yield: 10 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 4-methoxy-phenylhydrazine×HCl according to the method described for Example 1 in 10% yield. MS: M=413.5 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([Br:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:14][C:15]([NH:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26])=[O:16].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.CO>C1(C)C=CC=CC=1.CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15](=[O:16])[NH:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[C:8]([Br:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Cc1cc(C)c(NC(=O)CBr)c(C)c1
Reactant: CCOC(=O)c1[nH]c(Br)nc1C
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1c(C)nc(Br)n1CC(=O)Nc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-bromo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester (1.00 g, 4.291 mmol) and 2-bromo-N-(2,4,6-trimethyl-phenyl)-acetamide (1.209 g, 4.720 mmol) in a mixture of toluene (16 mL) and acetone (8 mL) was added diazabicycloundecene (0.71 mL, 4.720 mmol). The resulting solution was stirred at room temperature for 24 h. Methanol (10 mL) was added to dissolve the precipitate formed, followed by the addition of silica gel (25 g). The solvent was removed under reduced pressure to dryness and the residue was applied to a silica gel-packed column. The isolation of the product was achieved by column chromatography (hexanes-ethyl acetate 4:1 to 1:2). Yield—0.736 g (42%). 1H NMR (DMSO d-6, 500 MHz) δ 9.52 (s, 1H), 6.86 (s, 2H), 5.15 (br s, 2H), 4.25 (q, J=7.1 Hz, 2H), 2.38 (s, 3H), 2.21 (s, 3H), 2.11 (s, 6H), 1.30 (t, J=7.1 Hz, 3H); LC/MS: tR=1.46 min., MS: [M+H]=408.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-chlorobenzene-1-sulfonyl chloride. 1H NMR (DMSO-d6) δ: 7.56-7.62 (m, 2H), 7.63-7.68 (m, 2H), 7.72-7.81 (m, 5H), 7.92 (d, 1H), 8.10 (d, 1H), 9.06 (s, 1H), 10.75 (s, 1H); MS (ES): 444.0 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([OH:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3cnn4CC(C)(C)C(=O)O)no2)cc1C#N
Temperature: 80 °C
Yield: 5.3 %

Procedure:
A solution of ethyl 3-[4-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoate (D109) (100 mg, 0.21 mmol) in ethanol (2 ml) was treated with 2M sodium hydroxide aqueous solution (1 ml, large excess) and heated at 80° C. for 2 hours. The reaction mixture was cooled and most the ethanol was removed in vacuo. The residue was diluted with water (3 ml) and acidified with a concentrated.HCl aqueous solution and extracted with EtOAc (3×10 ml). The combined extracts were dried and concentrated in vacuo. Purification of the residue by MDAP gave the desired product (5 mg, 5%) as a colourless solid. MS (ES) C24H23N5O4 requires 445; found (MH+) 446.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH:35][CH2:34][C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:38])[F:39])=[CH:37][CH:36]=1)=[O:7]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.2 %

Procedure:
Publicly known [e.g. De.Paulis et al, J. Med. Chem., 1022(1922)]2-methoxy-5-nitrobenzoic acid (9.00 g, 45.7 mmol) was dissolved in 450 ml of dichloromethane and, after triethylamine (8.11 ml, 58.4 mmol) and ethyl chlorocarbonate (4.70 ml, 49.3 mmol) were added, the mixture was stirred for 45 minutes at room temperature. Next, 4-trifluoromethylbenzylamine (9.59 g, 54.8 mmol) was added dropwise, which was stirred for 30 minutes at room temperature. The reaction mixture was poured into water. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to obtain 12.5 g of the aimed compound as yellow powder. Further, the filtrate was concentrated and recrystallized from ethyl acetate to obtain 2.13 g of the second crystals. Total 14.6 g (91%).
Reaction SMILES: [N:1]([C@@H:4]([CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:5]([N:7]1[CH2:11][CH2:10][S:9][CH2:8]1)=[O:6])=[N+]=[N-].C(NC(C)C)(C)C.[I:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[I:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:14]2[CH2:15][CH2:16][CH:12]([C@H:4]([NH2:1])[C:5](=[O:6])[N:7]3[CH2:11][CH2:10][S:9][CH2:8]3)[CH2:13]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)N1CCSC1)C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: N[C@H](C(=O)N1CCSC1)C1CCN(S(=O)(=O)c2ccc(I)cc2)C1
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 28 mg (0.1 mmol) of 3-[(2S)-2-azido-2-pyrrolidin-3-ylethanoyl]-1,3-thiazolidine in methylene chloride (1 mL) was added 0.030 mL of diisopropylamine and 29 mg (0.12 mmol ) of 4-iodobenzenesulfonyl chloride. The mixture was stirred for 18 h and subjected directly to preparative TLC on silica gel (eluent: 60% ethyl acetate in hexanes) to give the desired sulfonamide (40 mg) as an off white solid. This solid was dissolved in wet THF (10%) and 25 mg (0.1 mmol) of triphenyl phosphine was added and stirred at 60° C. for 5 h and concentrated. A mixture of diastereomers were separated by preparative TLC on silca gel (10% methanol in CH2Cl2). Diastereomer I (faster moving isomer) 1H NMR (500 MHz, CDCl3) δ 7.9 (d, 2H, J=8.1 Hz), 7.52 (d, 2H, J=8.1 Hz), 4.65–4.47 (m, 2H), 3.86 (m, 1H), 3.78 9 (dd, 1H, J=6 and 8 Hz), 3.43 (m, 1H), 3.25–3.02 (m, 4H), 2.4 (m, 1H), 1.95 (m, 2H). Diastereomer II (slower moving isomer) 1H NMR (500 MHz, CDCl3) δ 7.91 (d, 2H, J=8.2 Hz), 7.56 (d, 2H, J=8.2 Hz), 4.63–4.41 (m, 2H), 3.86 (m, 1H), 3.79 (m, 0.5H), 3.64 (m, 0.5H), 3.37 (m, 3H), 3.25 (dd, 1H, J=10 and 14 Hz), 3.12 (m, 2H), 3.01 (t, 1H, J=4.4 Hz), 2.4 (m, 1H), 1.94 (m, 1H), 1.61 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13]([CH2:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:20](=[O:27])[NH:21][C:22]1([C:25]#[N:26])[CH2:24][CH2:23]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[C:25]([C:22]1([NH:21][C:20]([C@@H:9]2[CH2:10][C@@H:11]([S:13]([CH2:16][CH:17]3[CH2:18][CH2:19]3)(=[O:15])=[O:14])[CH2:12][NH:8]2)=[O:27])[CH2:24][CH2:23]1)#[N:26]
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)CC2CC2)C[C@H]1C(=O)NC1(C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)CC3CC3)CN2)CC1

Procedure:
In analogy to the procedure described in example 409f, (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-cyclopropylmethanesulfonyl-pyrrolidine-1-carboxylic acid tert-butyl ester was treated with trifluoroacetic acid in dichloromethane to give the title compound which was used in next step without further purification. MS: m/z=299.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][OH:35])[CH:19]=1)=[O:17].O[Li].O>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34][OH:35])[CH:19]=1)=[O:17]
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3ccccc3CO)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3ccccc3CO)cc3ccccc23)c1

Procedure:
Compound 17e was synthesized from 16e (0.6 mmol) and LiOH.H2O (1.8 mmol) using the procedure according to Method E described above.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]=2)[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl>[C:33]([O:32][C:30]([NH:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:19]2[CH:18]=[C:13]([CH:12]=[C:11]([NH:10][C:6]3[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:28]=[CH:27][CH:26]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1cc(N)cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)cc(Nc2nc(Cl)ncc2Cl)c1
Yield: 71.6 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (0.371 mL, 3.24 mmol) and methyl 3-amino-5-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)benzoate (1.20 g, 3.24 mmol) in DMF (20 mL) and potassium carbonate (895 mg, 6.48 mmol) were stirred at 60° C. overnight. The reaction mixture was diluted with 1 N HCl and extracted with ethyl acetate three times. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.20 g, 72%). LCMS for C25H26Cl2N4O4Na (M+Na)+: m/z=539.3, 541.3.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH3:17][O:18][CH2:19][CH2:20][OH:21].C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:21][CH2:20][CH2:19][O:18][CH3:17])[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: COCCO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-methoxyethanol and DBU in THF. ES-MS m/e (%): 362 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([C:17](=O)[CH3:18])[C:14](=[O:16])[CH3:15])=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([CH3:20])[O:7]2.[NH2:22]/[C:23](/[CH3:32])=[CH:24]\[C:25]([O:27][CH:28]1[CH2:31][CH2:30][CH2:29]1)=[O:26]>CC(O)C>[C:14]([C:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:20])=[CH:5][C:4]3=[O:21])[C:24]([C:25]([O:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:26])=[C:23]([CH3:32])[NH:22][C:17]=1[CH3:18])(=[O:16])[CH3:15]
Reactant: C/C(N)=C/C(=O)OC1CCC1
Reactant: CC(=O)C(=Cc1ccc(F)c2c(=O)cc(C)oc12)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCC2)C1c1ccc(F)c2c(=O)cc(C)oc12

Procedure:
150 mg (0.52 mmol) of 3-[(5-fluoro-2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione are dissolved with 40.4 mg (0.26 mmol) of cyclobutyl 3-aminocrotonate in 5 ml of 2-propanol and heated under reflux under argon for 3 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: ethyl acetate/cyclohexane 2:1). 54.8 mg (50% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[O:36]=[C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[N:29][C:24]([C:23]([F:38])([F:22])[F:37])=[CH:25][CH:26]=2)[CH:35]=[CH:34][N:33]1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)ccn3c2C1
Yield: 55.2 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (212 mg, 0.602 mmol) and 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (145 mg, 0.604 mmol) were reacted according to Example 18 (step g) to provide the title compound (170 mg, 55%) as a white solid: ESI MS m/z 512 [M+H]+.