Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9]C=2OC)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH:17]1(NN)CCCC1.COC(=C(C#N)C#N)C>>[NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH3:17])[C:3]=1[C:15]#[N:16]
Reactant: NNC1CCCC1
Reactant: COc1ccccc1-n1ncc(C#N)c1N
Agent: COC(C)=C(C#N)C#N
Product: Cc1nn(C2CCCC2)c(N)c1C#N

Procedure:
Following the procedure for the preparation of 5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile but substituting 1-cyclopentylhydrazine and 2-(1-methoxyethylidene)malononitrile provided the title compound. 1H NMR (300 MHz, CDCl3): δ 4.24 (m, 3H), 2.24 (s, 3H), 2.01 (m, 4H), 1.90 (m, 2H), 1.67 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:16]([F:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:30][O:31][NH2:32]>>[CH3:30][O:31][NH:32][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([C:12]2[C:16]([F:17])=[C:15]([O:18][CH:19]([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)[C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1]
Reactant: CON
Reactant: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2Cl)c(F)c1OC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CONC(=O)c1cc(-c2nn(C)c(OC(F)F)c2F)c(Cl)cc1Cl

Procedure:
Using 5.2 g (14 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-4-fluoro-1-methyl-1H-pyrazol-3-yl)benzoyl chloride, 19.2 g (0.14 mol) of potassium carbonate and 9.2 g (28 mmol) of a 25% strength aqueous methoxyamine hydrochloride solution and following the procedure described for Precursor 1.2, a crude product was obtained whose purification by means of silica gel chromatography (eluent:hexane/ethyl acetate=4:1) gave 1.5 g of the desired product of value.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]2[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:16]=3)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41](S([O-])(=O)=O)C>>[C:1]1([CH:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([NH:22][C:23]([C:25]2[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=4)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:16]=3)=[O:11])[CH2:8][CH3:41])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Reactant: CCS(=O)(=O)[O-]
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1

Procedure:
(R)-7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1-phenyl-ethyl)-amide, ethanesulfonate;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:8](=[O:12])[CH:9]([CH3:11])[CH2:10]2
Reactant: C=C(C)C(=O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1Cc2cc(F)ccc2C1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Fifty grams (0.30 moles) of 4'-fluoro-2-methylacrylophenone is added to a slurry of 60.1 g. (0.45 moles) of anhydrous aluminum chloride in 27 ml. of carbon disulfide at 20° to 25°C over 1 hour. The mixture is heated to 45°C over 1 hour and stirred at 45°C for 1 hour. The reaction is quenched in ice. The oily aqueous layer is extracted with toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[N:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>C(#N)CCC.C(Cl)(Cl)Cl.[Cu-]=O>[C:11]1([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=[N:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1ccccc1
Reactant: c1cc2[nH]nnc2cn1
Agent: O=[Cu-]
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCCC#N
Product: c1ccc(-n2nnc3cnccc32)cc1
Temperature: 110 °C
Yield: 15.6 %

Procedure:
A solution of 1H-[1,2,3]-triazolo-[4,5-C]-pyridine (200 mg, 1.7 mmol), iodobenzene (407 mg, 2.0 mmol), Cs2CO3, (1.08 g, 3.3 mmol), copper (I) oxide (17 mg, 0.12 mmol), 4,7-dimethoxy-[1,10]-phenanthroline (84 mg, 0.35 mmol), PEG 400 (0.3 ml) were combined in butyronitrile (3 ml) and heated to 110° C. overnight. The reaction was diluted with CHCl3, filtered through Celite© and then concentrated and purified on 16 g SiO2 with 0-3.5% NH3MeOH in CH2Cl2 to give 52 mg (16%) of 1-phenyl-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C11H8N4, 196.1. m/z found, 197.1 [M+H]+. 1H NMR δ (400 MHz, CDCl3) δ 9.58 (s, 1H), 8.66 (d, J=5.8 Hz, 1H), 7.83-7.75 (m, 2H), 7.72-7.62 (m, 3H), 7.62-7.52 (m, 1H).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1.[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.CO>ClCCl>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:36](=[O:37])[CH2:35][C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: C1=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CCNC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccccc1)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine tri-hydrochloride (73.6 mg, 0.2 mmol) and phenylacetyl chloride (31 mg, 0.2 mmol) in dichloromethane (1.5 mL) was added i-Pr2NEt (0.1 mL). The resulting mixture was stirred at rt for 3 h. MeOH (0.3 mL) was added to quench the reaction. Solvents were removed and the residue was dissolved in DMF (≈2 mL), which was purified by mass-directed HPLC to obtain the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=2.34 (m, 2H), 3.72 (t, J=5.6 Hz, 2H), 3.80 (d, J=17.6 Hz, 2H), 4.21 (d, J=35.6 Hz, 2H), 6.40 (s, 1H), 6.73 (d, J=38.4 Hz, 1H), 7.22-7.34 (m, 4H), 7.51 (d, J=8.8 Hz, 1H), 7.63 (m, 1H), 8.04 (s, 1H), 8.25 (d, J=4.4 Hz, 1H), 8.37 (t, J=7.2 Hz, 1H), 9.33 (d, J=13.6 Hz, 1H), 11.92 (d, J=14.8 Hz, 1H), 12.97 (s, 1H). MS (ES+): m/z 450.07 [MH+]. HPLC: tR=2.17 min (ZQ2000, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.FC1C=C(C=C(F)C=1)CN1C=C(C2C3C(=NC=C(C4C=CC(OC)=C(NS(C)(=O)=O)C=4)C=3)NC=2)C=N1.[F:71][C:72]1[CH:77]=[C:76](B2OC(C)(C)C(C)(C)O2)[CH:75]=[CH:74][C:73]=1[C:87]1[CH2:92][CH2:91][N:90]([C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[CH2:89][CH:88]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:76]4[CH:75]=[CH:74][C:73]([C:87]5[CH2:92][CH2:91][N:90]([C:93]([O:95][C:96]([CH3:98])([CH3:97])[CH3:99])=[O:94])[CH2:89][CH:88]=5)=[C:72]([F:71])[CH:77]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: COc1ccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)cc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 38.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 product of example 71) (200 mg, 0.368 mmol) was coupled with tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 70) (296 mg, 0.736 mmol) using potassium phosphate (234 mg, 1.104 mmol), tricyclohexyl phosphine (15 mg, 0.055 mmol) and Pd2(dba)3 (34 mg, 0.036 mmol) in dioxane/water (15/3 ml) to afford 104 mg (38.3% yield) of the pure product after column purification using 35% ethyl acetate in hexane as eluent. MS: m/z=740.7 (M+1).
Reaction SMILES: Br[C:2]1[CH:23]=[N:22][C:5]2[NH:6][C:7](=[O:21])[CH2:8][N:9]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:10][C:4]=2[CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:29]([O:28][C:24](=[O:27])/[CH:25]=[CH:26]/[C:2]1[CH:23]=[N:22][C:5]2[NH:6][C:7](=[O:21])[CH2:8][N:9]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])[CH2:10][C:4]=2[CH:3]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(Br)cc3C2)CC1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(/C=C/C(=O)OC(C)(C)C)cc3C2)CC1
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
A suspension of 7-Bromo-4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (1.39 g, 3.64 mmol) in propionitrile (32 mL) and DMF (8 mL) was de-oxygenated with Ar for 15 min. The mixture was treated with tert-butyl acrylate (2.1 mL, 14 mmol) and (i-Pr)2EtN (1.3 mL, 7.4 mmol) and then was de-oxygenated with Ar for 10 min. Pd(OAc)2 (83 mg, 0.37 mmol) and P(o-tol)3 (0.22 g, 0.73 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 10 min. The mixture was heated to reflux overnight, then allowed to cool. The resulting precipitate was isolated by filtration and dissolved in CH2Cl2. The solution was filtered through Celite and the solvent was removed in vacuo to give the title compound (1.13 g, 72%) as an off-white solid: MS (ESI) m/e 430 (M+H)+.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].Br[CH2:35][CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:22]([NH:24][N:25]([CH2:35][CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Product: CC(C)C[C@@H](C(=O)NN(CCc1c[nH]c2ccccc12)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and 3-(2-bromoethyl)indole.
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([CH:14]2[CH2:16][CH2:15]2)[CH:3]=1.[Li]C(C)(C)C.F[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[N:24]=1>C1COCC1>[CH:14]1([C:4]2[NH:5][N:6]=[C:2]([NH:1][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[N:24]=3)[CH:3]=2)[CH2:15][CH2:16]1
Reactant: Fc1ccc(F)c(F)n1
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)cc1N
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Fc1ccc(F)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A solution of tert-butyl 5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylate (1.00 g, 4.49 mmol) in THF (15 ml) was cooled to −78° C. t-BuLi (1.7 M in THF, 4.15 mmol) was added dropwise and the resulting solution was stirred for 30 min. at −78° C. A solution of 2,3,6-trifluoropyridine (0.46 g, 3.4 mmol) in THF (5 ml) was added, and the resulting solution was stirred for 5 min at −78° C., and then the reaction was warmed to 0° C., and stirred at that temperature for 30 min. The reaction was quenched with aq. NH4Cl and extract with EtOAc (2×20 ml). The organic fractions were dried over Na2SO4, filtered, and concentrated. The resulting oil was then placed in ACN (15 ml) at 0° C., and N-trimethylsilylimidazole (0.5 ml) was added. The reaction was stirred for 20 min, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.10 g, 12%). MS: Calcd.: 236. Found: [M+H]+ 237.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]([CH3:12])([CH2:10][OH:11])[CH2:8][OH:9].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[CH3:6][C:7]([CH3:12])([CH2:10][O:11][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH2:8][OH:9]
Reactant: CC(C)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(C)(C)CO
Yield: 54.9 %

Procedure:
To an N,N-dimethylformamide solution (50 ml) containing 2.500 g of 2,2-dimethyl-1,3-propanediol was added an about 60% oil suspension containing 2.112 g of sodium hydride. After the reaction mixture was stirred under cooling with ice for 1 hour, 9.930 g of 1-bromo-octadecane was added dropwise thereto. After the reaction mixture was stirred at room temperature for 16.5 hours, water was added thereto and this mixture was extracted with hexane and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=100:0 to 20:1). Thus, 4.700 g of the title compound was obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:35](OC(C)C)([O:40]C(C)C)[O:36]C(C)C.Cl>C1(C)C=CC=CC=1.C1COCC1>[C:18]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:35]([OH:40])[OH:36])=[CH:3][CH:4]=2)[CH:17]=[CH:16]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc(-c2ccc3cc(-c4ccccc4)ccc3c2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(-c2ccc3cc(-c4ccccc4)ccc3c2)cc1
Temperature: -60 °C
Yield: 63 %

Procedure:
Under an argon gas atmosphere, a mixture of 15.3 g (42.6 mmol) of 2-(4-bromophenyl)-6-phenylnaphthalene and 200 mL of dehydrated THF was cooled down to −60 degrees C., and added with 32.8 mL (51.1 mmol) of hexane solution of 1.56M n-butyllithium in drops while being stirred. Then, the reaction mixture was stirred for two hours at −60 degrees C. 24.0 g (128 mol) of triisopropyl borate was dropped into the reaction solution at −60 degrees C. Subsequently, the reaction mixture was warmed up to room temperature, and stirred for 17 hours. The reaction mixture was cooled down to 0 degree C. to be further added with solution of hydrochloric acid, and then stirred for one hour at room temperature. After the reaction, the reaction mixture was further added with toluene, so that aqueous phase thereof was eliminated. After organic phase thereof was dried with magnesium sulfate, the solvent was distilled away under reduced pressure. By recrystallizing residue by toluene and hexane, 8.7 g of 4-(6-phenylnaphthalene-2-yl) phenylboronic acid was obtained at an yield of 63%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])=[C:10]([F:13])[CH:11]=2)[CH:6]=[C:5]1[C:31]([CH3:34])([CH3:33])[CH3:32].CCN(CC)CC.[C:42](Cl)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:18][CH2:19]3)=[O:16])=[C:10]([F:13])[CH:11]=2)[CH:6]=[C:5]1[C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:44])[CH3:43]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1CCN
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (47 mg, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) in DMF (1 mL) was added acetyl chloride (7.1 μL, 0.10 mmol). The mixture was stirred at room temperature for 1 h before being filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to yield N-(1-(2-acetamidoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.15 (t, J=5.9 Hz, 1H), 7.53 (s, 1H), 7.43-7.31 (m, 4H), 6.17 (s, 1H), 4.22 (m, 2H), 3.30 (m, 2H), 1.85 (s, 3H), 1.47 (m, 2H), 1.41 (s, 9H), 1.13 (m, 2H). HPLC ret. time 2.06 min, 10-99% CH3CN, 3 min run; ESI-MS 516.4 m/z (M+H+).
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].[CH2:7]=[C:8]([CH3:10])[CH3:9]>C(O)C>[C:8]([NH:2][C:1](=[O:6])[O:3][CH2:4][CH3:5])([CH3:10])([CH3:9])[CH3:7]
Reactant: CCOC(N)=O
Reactant: C=C(C)C
Solvent: CCO
Product: CCOC(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
A stirred mixture of 89 g of ethyl carbamate, 5 g of ethanol, 10 g of ®LEWASORB AC-10 and 70 g of isobutene was heated to 70° C. in a stirred autoclave, and stirring was continued at this temperature for 4 hours. After the reaction was complete, the catalyst was separated off and the mixture was worked up by distillation. 136 g (93% of theory) of ethyl N-tert.-butylcarbamate of boiling point 70°-71° C./20 mbar were obtained. Gas chromatography showed that the crude product contained 0.2 percent by weight of diisobutene, but not diethyl carbonate was detected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:18][NH2:19])=[O:17])[N:13]=2)=[N:6][CH:7]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[O:17][C:32]([OH:33])=[N:19][N:18]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Solvent: C1CCOC1
Product: Oc1nnc(CCc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)o1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanehydrazide (0.150 g, 0.345 mmol) in THF (5 mL) was added TEA (0.04814 mL, 0.3454 mmol) and cooled in an ice bath. To this mixture was added CDI (0.0672 g, 0.414 mmol) in one portion. The mixture was allowed to warm to ambient temperature and was then heated at 50° C. overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2 and washed with water, dried over Na2SO4, concentrated, to a residue that was purified by preparative HPLC to give the title compound (0.045 g, 28.31% yield) was white solids. 1H NMR (d6 DMSO) δ 2.91 (s, 4H), 6.75 (s, 1H), 7.10 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 2H), 8.22 (d, J=2.1 Hz, 1H), 11.03 (br s, 1H), 12.04 (br s, 1H).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[CH3:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:14]=O>C(Cl)(Cl)Cl>[CH3:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:14]=[C:1]1[C:2](=[O:3])[CH2:4][O:5][C:6]1=[O:7]
Reactant: Cc1ccsc1C=O
Reactant: O=C1COC(=O)C1
Solvent: ClC(Cl)Cl
Product: Cc1ccsc1C=C1C(=O)COC1=O
Reaction time: 0.67 h
Yield: 42 %

Procedure:
1.00 gm of tetronic acid (FW=100, 10mmole) was added to a stirring solution of 3.78 gm of 3-methyl-2-thiophenecarboxaldehyde (FW=126, 30 mmole) together with 1 mL conc. Hc1. The mixture was stirred for 40 minutes after which all had solidified. The residue was dissolved in CHCl3 and washed with water, dried with HgSO4, filtered and put through a silica plug with CHCl3. The yellow crystals had a melting point of 164°-166° C. (lit. 164-165). The yield was 42%. All other spectral data corresponded with the published ones. C10H8O3S: %C 57.69; %H 3.87; found %C 57.81; %H 3.82. NMR results: 1HNMR (d6DMSO(H2 0)/TMS) δ 2.56 (3H, s); 4.71 (2H, d, 7 Hz); 7.28 (1H, m); 8.01 (1H, m); 8.27 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH2:16])[S:14][CH:15]=3)=[C:9]([CH3:17])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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>[CH3:17][C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:22]4[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]4)=[CH:31][CH:30]=3)[CH:3]=[C:4]2[C:10]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1
Reactant: Cc1[nH]c2ncc(Br)cc2c1-c1csc(N)n1
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1[nH]c2ncc(-c3ccc(CN4CCN(C)CC4)cc3)cc2c1-c1csc(N)n1
Temperature: 175 °C

Procedure:
In a personal chemistry microwave reaction vial 4-(5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (0.2 g, 0.64 mmol) and 1-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (0.23 g, 0.71 mmol), bis(triphenylphosphine)-palladium(II) dichloride (0.004 g, 0.006 mmol) in acetonitrile (2 mL), and 1 M Na2CO3 (2 mL) were added. The resulting mixture was de-gassed with N2 for 10 min, after which it was heated at 175° C. for 30 min in a Personal Chemistry Optimizer. The mixture was diluted with DMF (3 mL), and concentrated in vacuo and purified on silica gel column using dichloromethane and methanol to afford 4-{2-Methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-thiazol-2-ylamine.