Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Si:50]([O:67][CH2:68][CH2:69][N:70]([CH3:100])[CH2:71][CH2:72][C@@H:73]([NH:82][C:83]1[CH:88]=[CH:87][C:86]([S:89]([NH2:92])(=[O:91])=[O:90])=[CH:85][C:84]=1[S:93]([C:96]([F:99])([F:98])[F:97])(=[O:95])=[O:94])[CH2:74][S:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:50]([O:67][CH2:68][CH2:69][N:70]([CH3:100])[CH2:71][CH2:72][C@@H:73]([NH:82][C:83]1[CH:88]=[CH:87][C:86]([S:89]([NH:92][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)(=[O:90])=[O:91])=[CH:85][C:84]=1[S:93]([C:96]([F:98])([F:99])[F:97])(=[O:94])=[O:95])[CH2:74][S:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:63]([CH3:64])([CH3:66])[CH3:65])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](N[S@@](=O)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 130, 0.12 g, 0.23 mmol), DMAP (56 mg, 0.46 mmol), and EDC (88 mg, 0.46 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (3.0 ml) and DIPEA (0.08 ml, 0.46 mmol) were added and the solution was stirred at r.t for 15 min. A solution of (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 28, 0.178 g, 0.23 mmol) in DCM (1.5 ml) was added to the solution and the reaction mixture was stirred at r.t overnight. The reaction mixture was diluted with DCM and washed with sodium bisulfate (1N, aq.) followed by a sodium bicarbonate (saturated, aq.). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue which was dried under vacuum to provide N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzamide (EXAMPLE 11, STEP 1, 0.26 g) which was used in the preparation of EXAMPLE 11, STEP 2 without further purification.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:13].C(O)(=O)C>>[Br:13][CH2:11][CH2:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([OH:10])=[O:9]
Reactant: Br
Reactant: O=C1OCCC1c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)C(CCBr)c1ccccc1

Procedure:
The product of Example 3 (14.5 g, 90 mM) in 48% of HBr/acetic acid (100 ml) was left at room temperature overnight. The reaction was poured onto water (500 ml) and extracted with IPE 2x). The organic phase was washed with water, dried and evaporated to give the crystalline product (22 g) m.p. (cyclohexane).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]12([CH2:23][CH2:24][NH:25][CH3:26])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(N(C(C)C)CC)(C)C.[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>ClCCl.C(OCC)C>[C:13]12([CH2:23][CH2:24][N:25]([CH3:26])[C:5]([N:37]([CH3:36])[CH2:38][CH2:39][CH2:40][C:41]3[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=3)=[O:11])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: CNCCCc1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNCCC12CC3CC(CC(C3)C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CN(CCCc1ccncc1)C(=O)N(C)CCC12CC3CC(CC(C3)C1)C2
Reaction time: 0.28 h
Yield: 141.6 %

Procedure:
A solution of triphosgene (190 mg, 0.640 mmol) in dichloromethane (6.0 ml) was stirred at room temperature under a nitrogen atmosphere. A solution of 2-(1-adamantyl)-N-methylethylamine (Intermediate No. 3-1) (330 mg, 1.71 mmol) and diisopropylethylamine (0.357 ml, 2.05 mmol) in dichloromethane (6.0 ml) was added dropwise thereto over 17 minutes. After eight minutes, a solution of N-methyl-3-(4-pyridyl)propylamine (Intermediate No. 3-3) (264 mg, 1.78 mmol) and diisopropylethylamine (0.357 ml, 2.05 mmol) in dichloromethane (5.1 ml) was added to the mixture at a stretch, and the whole was stirred for 20 hours. The reaction mixture was diluted with diethyl ether (40 ml), the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (40 ml) twice and a saturated aqueous sodium chloride solution (40 ml) successively, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 335 mg (54%) of the titled compound.
Reaction SMILES: C(O)C.Cl.[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[NH:7])[NH2:6].[O-]CC.[Na+].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:12]([O:11][C:9]([C:8]1[CH:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=2)[NH:7][C:5]=1[NH2:6])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=N)N
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]c1N
Temperature: 25 °C
Yield: 103.1 %

Procedure:
After adding 700 ml of ethanol to 50.7 g of ethyl 2-amidinoacetate hydrochloride (a publicly known compound described in Liebigs Ann. Chem., 1895(1977)), the mixture was stirred at room temperature, 22.3 g of sodium ethoxide (1 equivalent with respect to ethyl 2-amidinoacetate hydrochloride) was added, and the mixture was stirred for 15 minutes under a nitrogen atmosphere. To this there was added 49.9 g of 1-(4-benzyloxyphenyl)-2-bromoethanone (publicly known compound described in Journal of Heterocyclic Chemistry, vol. 2, 310(1965) and Journal of Medicinal Chemistry, vol. 17, 55(1974)), and the mixture was stirred for 36 hours at room temperature under a nitrogen atmosphere. Water was added, ethyl acetate was used for liquid separation and extraction, and then the organic layer was dried over sodium sulfate and concentrated to dryness to obtain 56.7 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCc1ccc(C#Cc2cccc(O)c2)cc1
Reactant: BrCc1ccccc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(OCc3ccccc3)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-((3-hydroxyphenyl)ethynyl)phenyl)propanoate (98 mg, 0.45 mmol) and (bromomethyl)benzene (142 mg, 1.03 mmol) according to the general procedure IV to give 112 mg (68%) of a pure pale yellow solid. Rf=0.60 (EtOAc:PE, 1:1); 1H NMR (CDCl3): δ 7.46-7.32 (m, 7H), 7.46-7.22 (m, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.14-7.12 (m, 2H), 6.95 (ddd, J=8.3 Hz, 2.8 Hz, 1.0 Hz, 1H), 5.07 (s, 2H), 3.66 (s, 3H), 2.95 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3): δ 173.8, 158.6, 140.9, 136.7, 131.8, 129.4, 128.6, 128.3, 128.0, 127.5, 124.4, 124.4, 121.1, 117.3, 115.6, 89.2, 89.0, 70.0, 51.6, 35.4, 30.8; MALDI-MS m/z 393.4 (M+Na+).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: C#CCCCCO
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCCO)c21

Procedure:
Using general Method D above, 5-hexyn-1-ol (56 mg, 0.57 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (13 mg) (Aldrich) and CuI (7 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 14 h to yield (Z)-1,3-dihydro-4-(6-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1.N1C=CC=CC=1.[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)=[O:29].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH:17][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:38][CH:37]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: COCCCCCCOc1ccc(C(=O)NN)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of 4-(6-methoxy-n-hexyloxy)benzohydrazide (106.82 g) and pyridine (162 ml) in tetrahydrofuran (1 L) at 0°‥5° C. was treated portionwise with 4-methoxycarbonylbenzoyl chloride 83.75 g) over 30 minutes. After a further 1 hour at 0°-5° C., and 2 hours at room temperature, tlc indicated completed reaction and the reaction mixture was poured into water (7 L). The resulting precipitate was collected by filtration, washed thoroughly with water, and dried under hi-vacuum at 50° C. to give N-[4-(6-methoxy-n-hexyloxy)benzoyl]-N′-(4-methoxycarbonylbenzoyl)hydrazine (171.0 g) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4].[F:21][CH:22]([F:31])[O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([O:23][CH:22]([F:21])[F:31])=[CH:25][CH:26]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2cccc(Cl)c2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2cccc(Cl)c2)S1(=O)=O
Temperature: 160 °C
Yield: 73 %

Procedure:
2-Butyl-4-chloro-5-(3-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (0.250 g, 0.75 mmol) and 4-(difluoromethoxy)aniline (0.238 g, 1.50 mmol) were mixed in MeCN (2 mL) and heated in a microwave reactor at 160° C. for 60 mins. The reaction mixture was evaporated and the residue was purified on a Horizon TM flash system using Heptane and EetOAc as eluant giving the title compound (0.25 g, 72.9%). 1H-NMR (500 MHz, CDCl3): δ 7.25-7.1 (m, 4H), 7.0 (s, 1H), 6.9-6.7 (dd, 4H), 6.4 (t, 1H, J=Hz), 3.8 (t, 2H), 1.95-1.8 (m, 2H), 1.55-1.45 (m, 2H), 1.05 (t, 3H); 13C-NMR (125 MHz, CDCl3): δ179.6, 159.0, 134.4, 133.3, 132.0, 129.9, 129.6, 129.6, 127.3, 124.3, 120.4, 115.9, 40.6, 30.4, 23.6, 20.3, 13.7; Mass Spectrum: M−H+ 456.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:21]2[N:20]([CH:27]2[CH2:32][CH2:31][O:30][C:29]([CH3:34])([CH3:33])[CH2:28]2)[C:19](=[O:35])[C:18]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:39][CH:38]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:21]2[N:20]([CH:27]2[CH2:32][CH2:31][O:30][C:29]([CH3:33])([CH3:34])[CH2:28]2)[C:19](=[O:35])[C:18]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[NH:3][C:4](=[O:7])[O:5][N:50]=2)=[CH:41][CH:42]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)(C)C2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOC(C)(C)C2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.8 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[7-butyl-4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.39 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.15 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.25 g, 58%).
Reaction SMILES: I[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[CH3:16])=[CH:5][N:6]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1.CN1C(=O)CCC1.CO>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:2]2[O:3][C:4]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[CH3:16])=[CH:5][N:6]=2)=[CH:21][CH:20]=1
Reactant: Cc1n[nH]c2ccc(-c3cnc(I)o3)cc12
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc(CNc2ncc(-c3ccc4[nH]nc(C)c4c3)o2)cc1
Temperature: 165 °C
Yield: 1026.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2-iodooxazol-5-yl)-3-methyl-1H-indazole (0.40 g, 123 μmol), (4-methoxyphenyl)methanamine (1.13 mL, 8620 μmol) and NMP (2.0 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 165° C. for 10 minutes. The crude product was adsorbed onto a plug of silica gel and chromatographed through two stacked Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 10% 2 M NH3.MeOH in DCM, to give N-(4-methoxybenzyl)-5-(3-methyl-1H-indazol-5-yl)oxazol-2-amine (422 mg, 98% yield). LCMS (API-ES) m/z (%): 355 (100%, M++H); 1H NMR (400 MHz, MeOH-d4) 7.76 (s, 1H) 7.52 (s, 1H) 7.48-7.57 (m, 1H) 7.38-7.46 (m, 1H) 7.26-7.34 (m, 2H) 6.96-7.02 (m, 1H) 6.80-6.91 (m, 2H) 4.42 (s, 2H) 3.75 (d, J=6.06 Hz, 3H) 3.30 (s, 3H).
Reaction SMILES: [C:1]1([N:7]([C:14]2[C:24]3[C:25]4[C:17]([CH2:18][CH2:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:35]=[O:36]>O>[CH:35]([C:4]1[CH:3]=[CH:2][C:1]([N:7]([C:14]2[C:24]3[C:25]4[C:17]([CH2:18][CH2:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=1)=[O:36]
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
32.14 g (0.1 mol) of the above prepared 5-(N,N-diphenylamino)acenaphthene was dissolved in 300 ml of N,N-dimethylformamide, and 22.73 g (0.15 mol) of phosphorus oxychloride was dropwise added thereto at room temperature for 30 minutes. After raising the temperature to 50° C., the reaction mixture was stirred for 14 hours. The reaction was determined to be finished when disappearance of 5-(N,N-diphenylamino)acenaphthene was identified. The reaction product was poured into an aqueous solution having 45 g (1.05 mol) of 93% sodium hydroxide dissolved in 1000 ml of water. The resultant mixture was cooled to precipitate a crystal, and the crystal was filtrated, washed with water and dried to obtain 30.27 g (yield: 86.6%, melting point: 138.0°-141.0° C.) of 5-[N-(4-formylphenyl)-N-phenylamino]acenaphthene.
Reaction SMILES: Br[C:2](=[C:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+].CCO>COCCOC>[C:3]1([C:2](=[C:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]3[C:26]4[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=4[O:27][CH3:28])[NH:20][CH:19]=3)=[O:17])[CH2:11][CH2:10]2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(Br)c4ccccc4)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4ccccn4)CC3)c[nH]c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
To a solution of 1-[4-(1-bromo-1-phenyl-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.030 g, 0.062 mmole), pyridine-3-boronic acid (0.011 g, 0.093 mmol) in 4 mL of DME was added 2M sodium carbonate (0.12 mL, 0.24 mmol) and EtOH (1 mL) and the resulting mixture was degassed with a stream of Ar bubbles for 10 min. To this mixture was added Pd(dppf)2Cl2 (0.003 g, 5 mol %) and the reaction mixture was heated with stirring at 90° C. for 18 h. The cooled mixture was then filtered (C-18 cartridge and 0.45 μm filter), the residue was washed with MeOH and the filtrate was evaporated. Purification of the residual material by preparative HPLC afforded the title compound (0.011 g, 37%) as a light gray solid:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]=O)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH2:15][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C=O)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(CN3CCN(C)CC3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-formyl-1H-indazole-4-carboxamide (0.1 g, 0.255 mmol) in methanol (2 mL) was added acetic acid (0.015 g, 0.255 mmol) and 1-methylpiperazine (0.077 g, 0.765 mmol) and stirred it at room temperature for 3 h. NaBH3CN (0.016 g, 0.255 mmol) was then added. The resulting reaction mixture was stirred at room temperature overnight. After completion of reaction, the solvent was removed under reduced pressure and water was added. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-indazole-4-carboxamide (0.027 g, 28.8%). LCMS: 477.25 (M+1)+; HPLC: 99.71% (@ 254 nm) (Rt; 4.649); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 8.39 (t, 1H, J=4.8 Hz), 8.27 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 5.89 (s, 1H), 5.19-5.14 (m, 1H), 4.35 (d, 2H, J=5.2 Hz), 3.58 (s, 2H), 2.39-2.33 (m, 8H), 2.21 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.00 (m, 2H), 1.99-1.96 (m, 2H), 1.91-1.86 (m, 2H), 1.69-1.68 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1[CH:24]=[CH:23]N=C1)(N1C=CN=C1)=O.C(O[Si](C)(C)CCC)(=O)[CH2:26][C:27]([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1.[N-]1C=CN=C1.Cl>O1CCCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](=[O:6])[CH2:26][C:27]([O:29][CH2:23][CH3:24])=[O:28]
Reactant: CCC[Si](C)(C)OC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cc(I)cc(F)c1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
2,3-Difluoro-5-iodobenzoic acid (Preparation 19, 18.2 g) in tetrahydrofuran (100 mL) at room temperature is treated with 1,1′-carbonyldiimidazole (12.46 g) portion-wise over a one minute period under a nitrogen atmosphere and the mixture is stirred for 6 h. In a separate flask, ethyltrimethylsilyl malonate (14.38 g) in tetrahydrofuran (40 mL) is cooled to 0-5° C. and DBU (11.20 g) is added dropwise over a period of 15 minutes. After 5.5 h, this solution is cannulated into the ice cooled imidazolide solution over a 7 minute period with vigorous stirring. The mixture is allowed to slowly warm to room temperature overnight. The reaction mixture is poured into 600 mL of ice/water containing 41 mL of 6N HCl. The mixture is extracted 3 times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated in vacuo. The crude product is purified by chromatography, using 600 g of silica gel, packed and eluted with methylene chloride/heptane/ethyl acetate/acetic acid (3/7/0.5%/0.5%), to afford the title compound in 65% yield as an orange oily solid. Physical characteristics: 1H NMR (CDCl3) δ12.65, 8.00, 7.94, 7.73, 7.58, 5.81, 4.35-4.19, 3.96, 1.35, 1.28; IR (diffuse reflectance) 2986, 1647, 1622, 1573, 1489, 1420, 1383, 1293, 1275, 1240, 1215, 1037, 958, 882, 801 cm−1; MS (EI) m/z 354 (M+); HRMS (FAB) m/z 354.9648 (C11H9F2IO3+H). Anal. Found: C, 37.34; H, 2.50; N, 0.15.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:15]=[CH:19][CH:18]=[CH:17]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(-n2cccc2)c1
Reaction time: 0.03 h

Procedure:
To 60 ml of stirred glacial acetic acid was added 25.0 grams (0.15 mole) of ethyl 3-aminobenzoate. The mixture was stirred for two minutes and 19.6 grams (0.15 mole) of 2,5-dimethoxytetrahydrofuran was added during a five minute period. Upon complete addition the red solution was heated under reflux for 1.5 hours. The acetic acid solvent was removed by distillation. Higher boiling volatiles were also removed by distillation, under reduced pressure (80°-110° C./55 2 mm). Pure ethyl 3-(pyrrol-1-yl)benzoate was obtained by distillation under reduced pressure; bp 143°-145° C./2 mm. The product solidified on standing; mp 62°-64° C. The yield was 25.4 grams of white solid.