Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Cl:25])C(=O)C1>C1COCC1>[Cl:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[Cl:25]
Reactant: CCn1nccc1-c1cc(C(=O)OC)oc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1cc(C(=O)OC)oc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of methyl 5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate (800 mg, 3.14 mmol) and NCS (600 mg, 4.49 mmol) in THF (5 mL) was heated to 70° C. in a sealed tube. After 2 h, the reaction mixture was concentrated and purified via column chromatography (silica, 10-20% EtOAc/Hexane) affording the title compound (710 mg, 78%) as a white solid: LC-MS (ES) m/z 289 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)=O)(C)(C)C>>[CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:39][C:36]3[CH:37]=[CH:38][C:33]([N:30]4[CH2:29][CH2:28][NH:27][CH2:32][CH2:31]4)=[CH:34][N:35]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CNC(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: CNC(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 76.6 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide (500 mg, 1.80 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (550 mg, 1.98 mmol) gave 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide (580 mg, 77%). MS (ESI) m/z 421.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:3]=1)=[O:17]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CC1(O)CCCC1
Product: O=C(NCCC(O)c1cccc(C#CC2(O)CCCC2)c1)C(F)(F)F

Procedure:
Sonogashira reaction of bromide 25 with 1-ethynylcyclopentanol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((1-hydroxycyclopentyl)ethynyl)phenyl)propyl)-acetamide as brown oil. Yield (0.55 g, 55%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.28-7.35 (m, 3H), 4.85-4.87 (m, 1H), 3.66-3.70 (m, 1H), 3.38-3.44 (m, 1H), 2.41 (bs, 1H), 1.76-2.08 (m, 10H).
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[NH2:16][C:17]1([C:22]2[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1>ClCCl>[NH2:16][C:17]1([C:22]2[N:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=2[C:24]([F:7])=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: FC1=CC(F)=NN(F)N1
Reactant: NC1(c2nc(Cl)ccc2C(=O)O)CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC1(c2nc(Cl)ccc2C(=O)F)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
0.34 ml (4.15 mmol) of pyridine and 0.53 ml (6.23 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 1.0 g (4.15 mmol) of 2-(aminocyclopentyl)-6-chloronicotinic acid in 12 ml of dichloromethane. The mixture is stirred for 2 hours at ambient temperature and then diluted with dichloromethane. The organic phase is washed twice with an ice-cold solution of NaHCO3aq and then dried over Na2SO4, filtered, and concentrated under reduced pressure. 1 g of product is obtained in the form of a brown oil, which is used immediately in the next step. Quantitative crude yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1COCC1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[OH:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(-c2ccc(Cl)cc2)cc1)C1CCCCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC(c1ccc(-c2ccc(Cl)cc2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (4′-chlorobiphenyl-4-yl)(cyclohexyl)methanone (792.1 mg), THF (5.68 mL) and methanol (0.947 mL) was added sodium borohydride (120 mg) at 0° C. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate solution was added at 0° C. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH:13]=1)[C:11]#[N:12].[Br:18]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[Br:18][C:5]1[O:1][C:2]([C:6]2[CH:7]=[CH:8][C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH:13]=2)[C:11]#[N:12])=[N:3][CH:4]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CC(C)Oc1ccc(C2=NCCO2)cc1C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)Oc1ccc(-c2ncc(Br)o2)cc1C#N
Temperature: 25 °C
Yield: 55 %

Procedure:
A stirring solution of 5-(4,5-dihydrooxazol-2-yl)-2-isopropoxybenzonitrile INT-31 (420 mg, 1.82 mmol), N-bromosuccinamide (990 mg, 5.56 mmol) and azoisobutyronitrile (14.9 mg, 0.09 mmol) in carbon tetrachloride (20 mL) was heated at 80° C. under N2 for 18 h. The reaction mixture was cooled to room temperature and the solids were removed by filtration. The filtrate was washed with sodium thiosulfate (20 mL) and brine (20 mL), and dried over MgSO4. The product was purified by chromatography (EA/hexanes) to afford 300 mg (55%) of 5-(5-bromooxazol-2-yl)-2-isopropoxybenzonitrile INT-32 as a yellow solid. LCMS-ESI (m/z) calculated for C13H11BrN2O2: 307.1; found 309.0 [M+2]+, tR=3.79 min. 1H NMR (400 MHz, CDCl3) δ 8.19-7.93 (m, 2H), 7.08-6.85 (m, 2H), 4.81-4.47 (m, 1H), 1.38 (dd, J=6.6, 3.0 Hz, 6H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[N+:2]=[N-:3].[CH2:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]#[CH:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[C:18]([O:17][C:16](=[O:22])[NH:15][CH2:12][C:13]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=2)[CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: [N-]=[N+]=NCc1cccc(Br)n1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCc1cn(Cc2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Azidomethyl)-6-bromopyridine (Example 470 Step 1) (700 mg, 3.29 mmol) and tert-butyl prop-2-yn-1-ylcarbamate (510 mg, 3.29 mmol) were combined in t-BuOH (6.0 mL) and water (3.0 mL). CuSO4.5H2O (41 mg, 0.16 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (130 mg, 0.66 mmol) in water (2.0 mL). The reaction was stirred at room temperature for 2 h. The solution was subsequently diluted with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Purification by flash chromatography (40-100% EtOAc/hexanes) afforded the title compound as a colorless solid.
Reaction SMILES: C[Si](C)(C)CCOC(=O)NC[C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:23]=1.[F-].[CH2:28]([N+:32](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:28][NH:32][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14][C:13]=2[CH:23]=1
Reactant: C[Si](C)(C)CCOC(=O)NCc1ccc2oc(-c3ccccc3)nc2c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNc1ccc2oc(-c3ccccc3)nc2c1
Yield: 27 %

Procedure:
Dissolve (2-phenyl-benzoxazol-5-yl-methyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (0.4, 0.99 mmol) in anhydrous THF (5 mL) and treat with 1M tetrabutylammonium fluoride in THF (1.5 mL, 1.54 mmol). Heat the mixture at reflux for 30 min, evaporate the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.1 g, 27%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@:12]([CH3:16])([C:13]([OH:15])=O)[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:52]([O:60][C:61]1[CH:70]=[CH:69][C:64]([C:65]([NH:67][NH2:68])=[O:66])=[CH:63][C:62]=1[C:71]([F:74])([F:73])[F:72])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH3:17][C:9]1([CH3:18])[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@:12]([CH3:16])([C:13]([NH:68][NH:67][C:65](=[O:66])[C:64]2[CH:69]=[CH:70][C:61]([O:60][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[C:62]([C:71]([F:72])([F:74])[F:73])[CH:63]=2)=[O:15])[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)O
Reactant: CCCCCCCCOc1ccc(C(=O)NN)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCCCCCCCOc1ccc(C(=O)NNC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid (4) (210 mg, 0.81 mmol) was stirred with HATU (372 mg, 0.98 mmol) and diisopropylethyl amine (DIEA) (0.705 mL, 4.1 mmol) in CH2Cl2-DMF (2:1, 6 mL) for 10 min followed by addition of 4-(octyloxy)-3-(trifluoromethyl)benzohydrazide (12a) (270 mg, 0.81 mmol) in CH2Cl2 (2 mL). The reaction was stirred at room temperature for 1 hour and then was concentrated under vacuum. The residue was diluted with ethyl acetate (20 mL) and washed with water (5 mL), brine (2×10 mL) and dried over Na2SO4. The organic layer was concentrated in vacuo and chromatographed on a silica gel column (ethyl acetate-hexane, 0-33%, as eluent) to afford the title compound (428 mg, 82% yield). MS (ESI): 573.84 (MH+); 1H NMR (400 MHz, CDCl3) δ 9.43 (br, 2H), 8.06 (d, 1H, J=2.0 Hz), 7.94 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 6.96 (d, 1H, J=8.8 Hz), 4.52 (br, 1H), 4.07 (t, 2H, J=6.4 Hz), 3.76 (br, 1H), 1.82 (m, 2H), 1.67 (s, 6H), 1.57 (s, 3H), 1.51 (s, 9H), 1.51-1.43 (m, 4H), 1.38-1.24 (m, 6H), 0.88 (t, 3H, J=7.2 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:6]1[N:7]=[C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)[S:9][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cccc(F)c1F
Product: COc1cc2ncn(-c3nc(-c4cccc(F)c4F)c(C(=O)O)s3)c2cc1OC
Yield: 39 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 2,3-difluorophenylboronic acid (23.7 mg, 0.15 mmol) gave 4-(2,3-Difluoro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (16.2 39%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.81 (br.s., 1 H); 8.83 (s, 1 H); 7.74 (s, 1 H); 7.52-7.64 (m, 2 H); 7.40 (s, 1 H); 7.33-7.39 (m, 1 H); 3.85 (s, 3 H); 3.83 (s, 3 H). MS m/z 418 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])C=1CCl>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=3[Cl:43])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Fc1cccc(Cl)c1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(F)cccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-chloro-2-(chloromethyl)-3-fluorobenzene and isolated as white solid (6.8 mg, 39%). MS (m/e): 425.4 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:12](=O)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([NH:27][NH2:28])([NH2:26])=[NH:25].[ClH:29].Cl.O>C(O)C>[ClH:29].[CH2:1]([N:8]1[C:16]2[CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][C:12](=[N:28][NH:27][C:24]([NH2:26])=[NH:25])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)Cc2c1ccn2Cc1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2c1ccn2Cc1ccccc1
Yield: 64.1 %

Procedure:
A mixture of 1-benzyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.32 g), concentrated hydrochloric acid (0.13 ml), water (0.13 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water and dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid-ethyl acetate (1 ml), and the mixture was concentrated. The residue was recrystallized from ethanol to give 1-benzyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 10) (0.67 g) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[C:9](=[O:10])[C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]#[N:26])#[N:18]>ClC1C=CC=CC=1>[OH:10][C:9]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:21]2[C:22]=1[CH:23]=[C:24]([C:25]#[N:26])[C:19]([C:17]#[N:18])=[CH:20]2
Reactant: N#Cc1ccncc1C#N
Reactant: O=c1c(-c2ccccc2)c1-c1ccccc1
Solvent: Clc1ccccc1
Product: N#Cc1cc2c(O)c(-c3ccccc3)c(-c3ccccc3)n2cc1C#N
Reaction time: 2 h

Procedure:
Diphenylcyclopropenone (0.319 g, 1.55 mmol) and 3,4-dicyanopyridine (0.200 g, 1.55 mmol) were mixed in a dry, argon filled reaction flask. Chlorobenzene (2.5 mL) (oxygen free) was added, and the reaction was heated to 130C. After 2 h the heating was stopped and the reaction was allowed to reach room temperature. Petroleum ether 40-60C (2.5 mL) was added in order to obtain a complete precipitate of the product. The solvent was filtered off and the precipitate was washed with petroleum ether. The crude product was stirred with chloroform (30. mL) for lb. The dark chloroform solution was filtered off leaving the title product as a yellow precipitate.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[CH3:21].B(Br)(Br)Br>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4]([CH3:21])=[C:3]([OH:2])[CH:12]=[CH:11]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc3c(C)c(OC)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Cc1c(O)ccc2cc(-c3ccc(O)cc3)ccc12

Procedure:
The title compound was prepared by reacting 2-methoxy-6-(4-methoxyphenyl)-1-methylnaphthalene (0.35 g, 1.26 mmol) with boron tribromide 3.8 mL of 1 N solution, 3.8 mmol) according to method D to yield 0.15 g (48%) of a white solid: mp>170° C. (dec.); 1H NMR (DMSO-d6): δ 2.42 (3H, s), 6.87 (2H,k d, J=8.33 Hz), 7.15 (1H, d, J=8.81 Hz), 7.59 (2H, d, J=8.35 Hz), 7.65 (1H; d, J=8.93 Hz), 7.71 (1H, dd, J=1.24 Hz, J=8.90 Hz), 7.88 (1H, d, J=8.87 Hz), 7.95 (1H, s), 9.49 (1H, s), 9.52 (1H, s); MS (ESI) 249 m/z (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)[CH:6]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(N2CCN(C)CC2)c1
Yield: 50 %

Procedure:
A solution of 5.56 g (30 mmol) 2-chloro-isonicotinic acid ethyl ester in 20 ml 1-methylpiperazine was heated for 5 hrs at 90° C. The solvent was evaporated and the residue purified by chromatography to give 3.72 g (50%) of the title compound as a yellow oil.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](F)[CH:16]=[C:15]([F:23])[C:14]=1[F:24].[C:25](OCC)(=[O:27])C>C1COCC1.CCCCCC>[F:24][C:14]1[C:15]([F:23])=[CH:16][C:17]([O:27][CH3:25])=[C:18]([N+:19]([O-:21])=[O:20])[C:13]=1[NH:12][C:6]1[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:5]=1[F:4]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of sodium methoxide (32.0 g, 600 mmol) in dry THF (500 mL) at −78° C. was added to (2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine (25 g, 60 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was quenched with 200 mL of water and concentrated. The concentrate was acidified with cold 2N HCl (pH=2) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1-5% ethyl acetate in hexane) afforded 18 g of the product (70.6% yield). H1NMR (CDCl3, 300 MHz): δ 7.42 (dd, 1H), 7.34 (d, 1H), 6.9 (s, 1H), 6.64-6.54 (m, 2H), 3.92 (s, 3H). LCMS: 94.1%, m/z=422.9 (M−1). HPLC: 98.8%.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:22])=O>CN(C)C=O.ClCCCl>[ClH:22].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:1])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1

Procedure:
An acylating agent, in acid chloride form, was prepared by combining 26.3 g of 4-(2-piperidino-ethoxy)benzoic acid, hydrochloride, 36.5 g of thionylchloride and 1 drop of dimethylformamide in 200 ml. of 1,2-dichloroethane, and stirring the mixture under reflux for 2 hours under a nitrogen atmosphere. The mixture was then evaporated to dryness under vacuum to obtain the desired 4-(2-piperidinoethoxy)benzoyl chloride, hydrochloride, which was dissolved in 1 liter of 1,2-dichloroethane. To the solution was added 20 g of 6-acetoxy-2-(4-acetoxyphenyl)benzo B!thiophene and the mixture was stirred vigorously. To it was then added, over about 3 minutes, 73.4 g of aluminum chloride. During the addition, the reaction mixture turned dark brown and hydrogen chloride evolved. The mixture was then stirred for one hour, and was poured over 1 liter of ice-water. The layers were separated, and the aqueous layer was extracted three times with 200 ml. portions of warm chloroform. The organic layers were combined and dried over magnesium sulfate, and were then filtered and evaporated under vacuum to obtain a brownish-yellow oil, which was not purified. The presence of the desired product was confirmed by thin layer chromatography (TLC) on silica gel, eluting with 9/1 chloroform/methanol, which showed that the major constituent ran at the same R, as authentic 6-acetoxy-2-(4-acetoxyphenyl)-3- 4(2-piperidinoethoxy)benzoyl!-benzo B!thiophene.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[C:15]2[CH:22]=[CH:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:16]=2[N:17]=[CH:18][N:19]=1.I[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>C1COCC1.CCCCCC.[Cl-].[Zn+2].[Cl-].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>[Cl:13][C:14]1[C:15]2[CH:22]=[C:21]([C:41]3[C:42]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:38]=[CH:39][CH:40]=3)[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ncnc21
Reactant: Ic1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(-c2cccc3ccccc23)cc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a stirred solution of N,N-diisopropylamine (265 μL, 1.89 mmol) in THF (3.00 mL) was added dropwise 1.60 M n-butyllithium in hexane (1.17 mL) at −78° C. under an atmosphere of Argon, and the mixture was stirred for 20 minutes at −78° C. To this mixture was added dropwise a solution of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.70 mmol) in THF (5.00 mL), and the mixture was stirred for 1 h at −78° C. A solution of zinc chloride (278 mg, 2.04 mmol) in THF (2.00 mL) was added dropwise, and the resulting mixture was taken out the cooling bath and allowed to stir for 1 h. To a suspension of tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.08 mmol) in THF (2.00 mL) was added 1-iodonaphthalene (0.30 mL, 2.06 mmol), and the resulting yellow solution was immediately added to the reaction mixture. The resulting mixture was heated at 80° C. for 1 h. After cooling to 23° C., the reaction mixture was quenched by the addition of water (70.0 mL) and the water layer was acidified with 1.00 M hydrochloric acid. The mixture was extracted with DCM (3×100 mL), and the organic layers were combined. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with 30% ethyl acetate in hexanes to afford the title compound (665 mg, 82%). LC/MS: Rt=11.11 min, ES+ 420.0 (FA long).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([NH:58][CH2:59][C@@H:60]2[CH2:65][CH2:64][CH2:63][NH:62][CH2:61]2)[CH2:57][CH2:56]1>CN(C=O)C>[CH:55]1([NH:58][CH2:59][C@@H:60]2[CH2:65][CH2:64][CH2:63][N:62]([C:30]([C:26]3[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])=[O:31])[CH2:61]2)[CH2:57][CH2:56]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: C1CNC[C@H](CNC2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H](CNC2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (200 mg, 0.4 mmol), HOBt (54 mg, 1 eq.), EDAC (77 mg, 1 eq.), TEA (0.17 mL) and cyclopropyl-(R)-1-piperidin-3-ylmethyl-amine (110 mg, 0.48 mmol) in DMF (3 mL) was stirred at rt for overnight. The reaction was concentrated and purified on a silica gel column to give 45 mg of the titled compound.