Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[CH:5]=[C:4]([CH3:27])[N:3]=1.[CH3:28][NH2:29]>C1COCC1>[CH3:28][NH:29][C:2]1[N:3]=[C:4]([CH3:27])[CH:5]=[C:6]([S:8][CH2:9][C:10]2[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])[N:7]=1
Reactant: Cc1cc(SCc2cc3cccc(C)c3nc2-c2ccccc2)nc(Cl)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(C)cc(SCc2cc3cccc(C)c3nc2-c2ccccc2)n1
Yield: 10 %

Procedure:
A mixture of Example 85 (100 mg, 0.29 mmol), THF (1 mL) and 2M methylamine in THF (5 mL) was heated in a microwave at 120° C. for 1 h. The solvent was removed in vacuo. Purification by preparative HPLC (Method 1) gave the title compound as a white solid (12 mg, 10%). δH (DMSO-d6) 8.52-8.55 (m, 1H), 7.82 (dd, J 8.3, 0.4 Hz, 1H), 7.68-7.72 (m, 2H), 7.59-7.64 (m, 1H), 7.45-7.55 (m, 4H), 6.95-7.05 (m, 1H), 6.30 (s, 1H), 4.55-4.65 (m, 2H), 2.68-2.75 (m, 6H), 2.11 (s, 3H). LCMS (ES+) 387.3 (M+H)+, RT 3.26 minutes (Method 3).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:6](O)=[O:7].[NH2:18]C(N)=O>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:6](=[O:7])[NH:18][C:15]2=[O:17]
Reactant: NC(N)=O
Reactant: O=C(O)c1cc(I)c(C(F)(F)F)cc1C(=O)O
Product: O=C1NC(=O)c2cc(C(F)(F)F)c(I)cc21

Procedure:
Prepared in analogy to Example A15(b) from 4-Iodo-5-trifluoromethyl-phthalic acid and urea. Light brown solid. MS (m/e): 339.9 ([M−H]−, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28](O)=[O:29])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:65]([O:69][C:70]([N:72]1[CH2:77][CH2:76][N:75]([C:78](=[O:83])[C@@H:79]([NH2:82])[CH2:80][F:81])[CH2:74][CH2:73]1)=[O:71])[CH2:66][CH2:67][CH3:68]>CN(C=O)C>[CH2:65]([O:69][C:70]([N:72]1[CH2:73][CH2:74][N:75]([C:78](=[O:83])[C@@H:79]([NH:82][C:28]([C:19]2[CH:18]=[C:17]([O:16][CH2:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[O:31])[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=2)=[O:29])[CH2:80][F:81])[CH2:76][CH2:77]1)=[O:71])[CH2:66][CH2:67][CH3:68]
Reactant: Cc1ccc2c(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc(C(=O)O)nc2c1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)c2cc(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c3ccc(C)cc3n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 452 mg 4-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 15 ml DMF were added 0.54 ml DIPEA and 400 mg HATU. After 5 minutes 410 mg 4-((R)-2-Amino-3-fluoro-propionyl)-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate were added and the mixture stirred for 24 h. The mixture was concentrated, diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and 0.1 M HCl. The crude product thus obtained after evaporation of the solvent was used in the next step without further purification. Yield: 1.28 g.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[C:29]([Br:30])=[C:28]([Br:31])[C:27]([Br:32])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[C:29]([Br:30])=[C:28]([Br:31])[C:27]([Br:32])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1cc(Br)c(Br)c(Br)c1Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1cc(Br)c(Br)c(Br)c1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,4,5-Tetrabromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,4,5-tetrabromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:23][NH2:24].O>CCO>[NH:23]([C:16]([C:15]1[CH:20]=[CH:21][C:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)=[O:17])[NH2:24]
Reactant: NN
Reactant: COC(=O)c1ccc(NC(=O)COc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(NC(=O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
To a suspension of methyl 4-[(phenoxyacetyl)amino]benzoate (843 mg, 2.95 mmol) in EtOH (10 mL) was added hydrazine hydrate (2.15 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt. Water (10 mL) was added to the reaction mixture and a white solid precipitated out. Filtration, washing with EtOH/water (2×2 mL) and water (3×1 mL), and drying under vacuo at 70° C. for 6 hrs gave 389 mg of the title compound (46%) as a white solid in 95.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]=O)[CH3:2].[CH3:14][NH2:15].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][NH:15][CH3:14])[CH3:2]
Reactant: CCc1c(C=O)oc2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1c(CNC)oc2ccccc12
Reaction time: 8 h
Yield: 89 %

Procedure:
3-Ethyl-benzofuran-2-carbaldehyde (1.16 g, 6.65 mmol) was added to a solution of methylamine (26 mL of a 2M solution in MeOH, 52 mmol) and the resulting mixture was stirred overnight. The mixture was concentrated under reduced pressure. The residue was taken up in ethanol (20 mL) and then cooled in an ice-bath. NaBH4 (370 mg, 9.90 mmol) was added in one portion. The mixture was concentrated under reduced pressure and the residue taken up in 1 M NaOH. The mixture was extracted with Et2O (3×). The combined organics were washed with brine, dried and concentrated under reduced pressure to give the title compound (1.12 g, 89%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.58 (dd, J=8.4, 6.6 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.30-7.25 (m, 2H), 3.75 (s, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.26 (s, 3H), 2.05 (br s, 1H), 1.21 (t, J=7.5 Hz, 3H); ESI MS m/z 190 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:59])[CH2:43][N:44](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:38][C:37]=1[NH:60][S:61]([CH3:64])(=[O:63])=[O:62])C1C=CC=CC=1>>[OH:59][CH:42]([C:39]1[CH:40]=[CH:41][C:36]([OH:35])=[C:37]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH:38]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.60 (m, 2H), 1.90-2.10 (m, 2H), 2.06 (s, 3H), 2.50-3.00 (m, 5H), 3.16 (s, 3H), 3.55-3.70 (m, 2H), 4.65-4.80 (m, 1H), 6.00 (brs, 1H), 6.70-7.25 (m, 7H), 7.58 (d, J=9.0 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H), 10.39 (s, 1H); MS (ES) m/z: 618.1 (MH+); HRMS Calcd. for C28H36N5O7S2 (MH+): 618.2056. Found: 618.2036.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[BH4-].[Na+]>C(O)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([CH:12]([CH3:16])[CH:13]([OH:15])[CH3:14])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: CC(=O)C(C)c1cc(C(F)(F)F)cc2ccoc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)C(C)c1cc(C(F)(F)F)cc2ccoc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of 0.09 gm (0.35 mMol) 3-(5-trifluoromethylbenzofur-7-yl)-2-butanone in ethanol was cooled to 0° C. To this solution was added 0.013 gm (0.35 mMol) sodium borohydride and the resulting mixture stirred for 30 minutes. The reaction mixture was then allowed to warm to room temperature and was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed sequentially with 0.1 N hydrochloric acid, water, and saturated aqueous sodium chloride. The remaining organic phase was concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 30% ethyl acetate in hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.041 gm (45%) of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[CH:19][N:20]=4)[CH:17]=3)=[CH:9][N:10]=2)[N:7]=1.[CH2:21]([N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[CH:14][C:15]5[N:16]([CH:18]=[CH:19][N:20]=5)[CH:17]=4)=[CH:9][N:10]=3)[N:7]=2)[CH:25]=[N:24]1)[CH3:22]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc2ncc(Cc3ccc4nccn4c3)n2n1
Product: CCn1cc(-c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)cn1

Procedure:
The title compound was prepared in analogy to Example 9 using chloro-3-imidazo[1,2-a]pyridin-6-ylmethyl-imidazo[1,2-b]pyridazine (Example 74) instead of (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanol (Stage 9.1) and 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (tR 2.88 min (conditions 3), MH+=344.1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([NH:30][S:27]([CH:24]2[CH2:26][CH2:25]2)(=[O:29])=[O:28])=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NS(=O)(=O)C2CC2)cn1
Yield: 56 %

Procedure:
As described for example 233, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (128 mg, 0.41 mmol) was converted, using cyclopropanesulfonic acid amide instead of butane-1-sulfonic acid amide, to the title compound (96 mg, 56%) which was obtained as an off white solid. MS: m/e=412.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[F:11][C:12]([F:41])([F:40])[CH2:13][NH:14][C:15]([C:17]1([CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16]>ClCCl.C(O)C>[F:40][C:12]([F:11])([F:41])[CH2:13][NH:14][C:15]([C:17]1([CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[CH2:38][CH2:39]2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:16]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCNCC2)c2ccccc2-c2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4[nH]3)CC2)c2ccccc2-c2ccccc21
Temperature: 150 °C

Procedure:
A mixture of 0.05 g (0.328 mmol) of 2-chloro-1H-benzimidazole and 0.21 g (0.487 mmol) of 9-(4-piperazin-1-yl-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide is heated to 150° C. for two hours. After cooling, the reaction mixture is dissolved in dichloromethane/ethanol. The product is purified by column chromatography on silica gel (eluant: dichloromethane/ethanol=20:1).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:8](=[N:12][O:13][CH3:14])[C:9](Cl)=[O:10])=[C:4]([F:23])[CH:3]=1.[NH3:24]>C1COCC1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:8](=[N:12][O:13][CH3:14])[C:9]([NH2:24])=[O:10])=[C:4]([F:23])[CH:3]=1
Reactant: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(N)=O

Procedure:
The title compound is prepared from 3-(4-bromo-2-fluorobenzyl)-2-methoxyimino-4-oxooctanoyl chloride (from Step G) according to the method of Example 4, Step E, except that instead of bubbling ammonia into the cold reaction mixture, it is preferable to prepare a saturated solution of ammonia in THF (at about -50° C.) and add this cold solution gradually (under protection from moisture) to a stirred solution of the acid chloride in THF at -50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2/[C:14](=[CH:22]/[C:23]2[NH:24][CH:25]=[CH:26][C:27]=2[O:28][CH3:29])/[C:15](=[O:21])[NH:16]3)=[CH:5][CH:4]=1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1

Procedure:
Using general Method D above, 4-methoxyphenyl acetylene (0.49 g, 3.68 mmol) (from Step A above) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (0.47 g, 1.47 mmol) using DPPFPdCl2 (0.12 g) (Aldrich) and CuI (28 mg) (Aldrich) as catalyst in DMF (10 mL) and Et3N (15 mL) as solvent and was heated at reflux for 1 day, yielding (Z)-1,3-dihydro-4-[(4-methoxyphenyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 0.31 g, 57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>Cl.O>[CH3:8][C:6]1[CH:7]=[C:2]([N:11]([CH2:12][CH2:13][OH:14])[CH3:10])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1cc(Cl)cc(C)n1
Reactant: CNCCO
Agent: Cl
Solvent: O
Product: Cc1cc(N(C)CCO)cc(C)n1
Yield: 88.8 %

Procedure:
A solution of 4-chloro-2,6-dimethylpyridine (849 mg, 6 mmol), (J. Het. Chem. 1990, 1841), in 2-(methylamino)ethanol (1.35 g, 18 mmol) and 3M ethereal hydrogen chloride (3 drops) was heated at 140° C. for 1 hour. The reaction mixture was allowed to cool and was diluted with water. The insolubles were removed by filtration and the aqueous filtrate was poured onto a suspension of magnesium sulphate (50 g) in ethyl acetate (100 ml). The insolubles were removed by filtration and the filtrate dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with ether, collected by filtration and dried under vacuum at 50° C. to give 2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (960 mg, 90%).
Reaction SMILES: C=[C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:21].[Na+].O>O1CCOCC1.O.[Os](=O)(=O)(=O)=O.O>[O:21]=[C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1
Reactant: C=C1CCOC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of Compound 29a (1.6 g, 5.99 mmol) in a mixture of dioxane-water (32.9 mL and 11 mL respectively) under stirring at r.t. was added a 4% sol. of osmium tetroxide in water (0.762 μL, 0.125 mmol). After 2 h, was added portionwise milled sodium metaperiodate (2.56 g, 12 mmol) affording a suspension that tended to become clear gray from brownish. After 4 h H2O was added, extracting with EtOAc, washing with H2O, drying over Na2SO4, evaporating the solvent to dryness. The residual tawny semi-solid was purified by means of automated flash chromatography (SP1®TM-Biotage; Petroleum Ether-EtOAc 7:3) to give 0.96 g of the title compound as a grey solid. Yield: 59.5%
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([F:23])=[C:11]2[C:15]=1[N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12]2.[C:24](=[O:26])=[O:25]>C1COCC1>[CH3:20][C:19]([O:18][C:16]([N:14]1[C:15]2[C:11](=[C:10]([F:23])[CH:9]=[CH:8][C:7]=2[C:24]([OH:26])=[O:25])[CH2:12][CH2:13]1)=[O:17])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2c(F)ccc(Br)c21
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(F)ccc(C(=O)O)c21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1.6 M tert-BuLi (1.2 mL, 1.92 mmol) was added to a solution of 1,1-dimethylethyl 7-bromo-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (260 mg, 0.92 mmol) in THF (52 mL) at −78 (bath temp). The reaction was stirred for 5 min, and dry ice (CO2) powder was added. The reaction was stirred for 10 min, and was allowed to warm slowly to room temperature. The reaction mixture was washed with EtOAc, and the organic layer was evaporated. The crude product was purified by flash chromatography, giving the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si](C)(C)C(C)(C)C(C)C)[C:5]=1[CH2:23][S:24][CH2:25][C@H:26]([NH:33][C:34]#[N:35])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1.[OH:37][CH2:38][C:39](=O)[CH3:40]>O1CCCC1.[OH-].[Na+].O>[CH3:1][O:2][C:3](=[O:36])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH2:23][S:24][CH2:25][C@@H:26]([C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1)[NH:33][C:34]1[O:37][CH:38]=[C:39]([CH3:40])[N:35]=1
Reactant: CC(=O)CO
Reactant: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](NC#N)c1nc(C)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C)c(OC)cc(O)c1CSC[C@H](Nc1nc(C)co1)c1nc(C)no1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 260 mg of (R)-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-2-[2-cyanoamino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-5-methoxy-6-methyl-benzoic acid methyl ester in 50 ml of tetrahydrofuran were added 0.1 ml of 25% aqueous hydroxyacetone and 0.09 ml of IN sodium hydroxide solution. The suspension was stirred for 12 h at 40° C. After cooling, the mixture was diluted with 100 ml water and subsequently extracted with 200 ml ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent, and the purified product was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1 to yield (R)-3-hydroxy-5-methoxy-6-methyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(4-methyl-oxazol-2-ylamino)-ethylsulfanylmethyl]-benzoic acid methyl ester as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[CH3:16][N:17]([CH:19]=[C:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7])[CH3:18]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1C(=O)C(C)(C)OC1(C)C
Temperature: 60 °C
Yield: 84 %

Procedure:
A mixture of 2,2,5,5-tetramethyl-dihydro-furan-3-one (2.84 g, 20.0 mmol, 1.0 equiv; commercially available) and tert-butoxy-bis(dimethylamino)methane (3.65 g, 20.9 mmol, 1.05 equiv; commercially available) was heated to 60° C. for 24 h (in analogy to a procedure described in H. H. Wasserman and J. L. Ives J. Am. Chem. Soc. 1976, 98, 7868-7869). The residue was purified by flash column chromatography on silica eluting with diethyl ether to yield 3.3 g (84% yield) of the title compound. MS (EI): 197 [M]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccncc2)cc1-c1nc(-c2ccccn2)no1
Yield: 10 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), 4-pyridylboronic acid (48.8 mg, 0.4 mmol), and Pd(PPh3)4 (23 mg, 0.02 mmol) in a solution of 2M sodium carbonate (2 mL) and ethylene glycol dimethyl ether (2 mL) was heated overnight at 105° C. Standard work up, afforded 6.6 mg (10%) of 3-(2-pyridyl)-5-[2-methoxy-5-(4-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].C1C[O:14][CH2:13]C1.C1N=CN(C(N2C=NC=C2)=O)C=1>CCOC(C)=O>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]2[O:10][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: C1CCOC1
Reactant: Nc1cc(Br)c(F)cc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Br)c(F)cc2o1
Temperature: 60 °C

Procedure:
A flask was charged with 2-amino-4-bromo-5-fluorophenol (3.3 g, 18.84 mmol) and THF (200 mL), and CDI (3.05 g, 18.84 mmol) was added. The mixture was heated to 60° C. for 2 h. The mixture was diluted with EtOAc and washed with 1N HCl in water. The organic phase was dried over Na2SO4 and concentrated to give 5-bromo-6-fluorobenzo[d]oxazol-2(3H)-one. 1H NMR (400 MHz, DMSO-d6) δppm 7.38 (d, J=6.06 Hz, 1H) 7.56 (d, J=8.34 Hz, 1H) 11.88 (br. s., 1H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH:9]=2)[NH:1][CH:2]=1)=[O:20]
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Product: O=C(c1c(F)cccc1Cl)c1c[nH]c2cnc(NC(=O)C3CC3)cc12

Procedure:
N-[3-(2-Chloro-6-fluorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-5-yl]cyclopropanecarboxamide was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2-chloro-6-fluoro benzoyl chloride (Compound No. 19).