Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[O:9][C:8]([CH3:18])([CH3:17])[CH2:7]C2=O.P(Cl)(Cl)(Cl)(Cl)[Cl:21].[C:26]([Cl:30])(Cl)(Cl)Cl>>[Cl:21][C:7]1[C:8]([CH3:18])([CH3:17])[O:9][C:10]2[C:5]([C:26]=1[Cl:30])=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH:14]([CH3:16])[CH3:15])[CH:11]=2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1OC(C)C)OC(C)(C)CC2=O
Product: COc1cc2c(cc1OC(C)C)OC(C)(C)C(Cl)=C2Cl
Temperature: 30 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A suspension of 2.64 g (10 millimoles) of 6-methoxy-7-isopropoxy-2,2-dimethyl-4-chromanone, 4.2 g (20 millimoles) of phosphorous pentachloride and 30 ml of carbon tetrachloride is stirred at 30° C. for 8 hours. The reaction mixture is evaporated and the residue is purified by crystallization from ethanol. Thus 3.8 g of the desired compound are obtained. Yield 60%. Mp.: 80°-85° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:18]2[CH:23]=[C:22]([CH2:24][CH3:25])[C:21]([OH:26])=[C:20]([Br:27])[CH:19]=2)[C:15]([O-:17])=[O:16])=[CH:9][CH:8]=1)#[N:6].[C:28]([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:18]2[CH:23]=[C:22]([CH2:24][CH3:25])[C:21]([O:26][CH2:1][CH:2]=[CH2:3])=[C:20]([Br:27])[CH:19]=2)[C:15]([O:17][CH3:28])=[O:16])=[CH:9][CH:8]=1)#[N:6]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(C(Nc2ccc(C#N)cc2)C(=O)[O-])cc(Br)c1O
Reactant: C=CCBr
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOc1c(Br)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)cc1CC
Reaction time: 4 h
Yield: 81.1 %

Procedure:
Allyl bromide (0.92 mL, 10.7 mmol) was added drop wise over 5 min to vigorously stirred mixture of 2-(4-cyanophenylamino)-2-(3-bromo-5-ethyl-4-hydroxyphenyl)acetate 3 (3.8 g, 9.76 mmol), Cs2CO3 (3.5 g, 10.74 mmol) and DMF (40 mL). The mixture was stirred vigorously for 4 h, then poured into ½-saturated NH4Cl (400 mL). The mixture was extracted with Et2O (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine (1×100 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (SiO2, gradient elution 10–15–20% ethyl acetate/hexanes) to yield 3.4 g (81%) of methyl 2-(4-cyanophenylamino)-2-(4-(allyloxy)-3-bromo-5-ethylphenyl)acetate 4 as a colorless solid.
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1Cl)=[S:6])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CS(C)=O>[C:1]([C:5]1[S:6][C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:13][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)C(=S)Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1

Procedure:
A solution of 171 g of N-tert-butylthiocarbonyl-2,5-dichloro-4-nitroaniline (described in European patent application No. 85810418.5 published under No. 0175650) and 605 ml of N-methylpiperazine in 1700 ml of dimethylsulphoxide is heated at 140° for 8 hours, cooled and poured into water. The solid is filtered, washed with water and cold isopropanol to yield 2-tert-butyl-5-(4-methylpiperazin-1-yl)-6-nitrobenzothiazole, melting at 132°-135°.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:31])([F:30])[CH2:4][N:5]=[C:6]([NH2:29])[NH:7][C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:12]=1.[OH-].[Na+].Cl>O.C(O)C>[ClH:1].[ClH:1].[F:31][C:3]([F:2])([F:30])[CH2:4][N:5]=[C:6]([NH2:29])[NH:7][C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:12]=1
Reactant: Cc1sc(NC(N)=NCC(F)(F)F)nc1CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1sc(NC(N)=NCC(F)(F)F)nc1CCCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.6 %

Procedure:
To a mixture of 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-(4-phthalimidobutyl)-5-methylthiazole hydrochloride (0.60 g.) in water (2 ml.) and ethanol (2 ml.) was added sodium hydroxide pellets (0.2 g.). The resulting yellow solution was heated on a steam bath for 10 minutes and then allowed to cool to ambient temperature. The reaction mixture was adjusted to pH3 by addition of 2 N hydrochloric acid and then reheated on a steam bath for 1 hour. After cooling to ambient temperature the mixture was extracted three times with equal volumes of ethyl acetate. The aqueous layer was evaporated to dryness, azeotroped twice with toluene, the residue dissolved in methanol (10 ml.) and the solution filtered. The filtrate was evaporated to dryness to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-5-methylthiazole dihydrochloride (0.31 g.) as an oil which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)c1cc(CCC(=O)O)ccc1O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CCC(=O)Oc2ccccc2)ccc1O
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A mixture of 55 g of 3-(3-tert-butyl-4-hydroxyphenyl)-propionic acid, 35 g of phenol, 7 g of dimethylformamide, 19.1 g of phosphorus oxychloride and 250 ml of toluene was stirred at 70° C. for 6 hours. The mixture was cooled to room temperature, and 800 ml of toluene was added thereto. The mixture was washed with water and an aqueous solution of sodium hydroxide, followed by washing with water. The mixture was concentrated, and the residue was purified by silica gel column chromatography to give 66.5 g of phenyl 3-(3-tert-butyl-4-hydroxyphenyl)propionate as a white crystal, m.p. 106°-109° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[Na+].[CH:24]1([C:30]([Cl:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>CC(C)=O>[ClH:32].[CH:24]1([C:30]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:19])[CH3:20])=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)NCC(O)COc1ccc(O)c2c1CCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)NCC(O)COc1ccc(OC(=O)C2CCCCC2)c2c1CCC(=O)N2
Yield: 45.5 %

Procedure:
0.66 g of 8-hydroxy-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril was suspended in 10 ml of acetone, and 3.0 ml of 1 N sodium hydroxide was added thereto to form a homogeneous solution. 0.35 g of cyclohexylcarbonyl chloride dissolved in a small amount of acetone was added dropwise to the solution while ice-cooling and stirring. After the reaction mixture was allowed to stand under ice-cooling for 30 minutes, 1 N hydrochloric acid was added thereto to adjust to a pH of 3. The solvent was evaporated under reduced pressure, and the residue was dissolved in water and extracted with chloroform. The aqueous layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography using chloroform-methanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.45 g of 8-cyclohexylcarbonyloxy-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 227°-228° C.
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][C@@H:4]([NH2:18])[CH2:3][C@@H:2]([F:1])[CH2:8]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)C[C@@H](F)C1

Procedure:
Following the procedure for Example 101, starting with Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 126 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.80 (s, 1H), 7.37-7.28 (m, 2H), 7.08-6.98 (m, 3H), 6.13 (s, 2H), 4.83-4.78 and 4.72-4.68 (2 m, 1H), 3.79-3.72 (m, 3H), 3.54-3.30 (m, 3H), 3.24-3.12 (m, 2H), 2.31-2.22 (m, 1H), 2.18-2.07 (m, 1H), 1.93-1.76 (m, 2H). LCMS (ES+) m/z 466 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.C([Li:16])(CC)C.CCCCCC.[F:23][C:24]1[C:29]([B:30]([C:42]2[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:43]=2[F:52])[C:31]2[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=2[F:41])=[C:28]([F:53])[C:27]([F:54])=[C:26]([F:55])[C:25]=1[F:56].C1(C)C=CC=CC=1>C(OCC)C>[F:1][C:2]1[C:7]([B-:30]([C:31]2[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=2[F:41])([C:42]2[C:47]([F:48])=[C:46]([F:49])[C:45]([F:50])=[C:44]([F:51])[C:43]=2[F:52])[C:29]2[C:28]([F:53])=[C:27]([F:54])[C:26]([F:55])=[C:25]([F:56])[C:24]=2[F:23])=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[C:3]=1[F:11].[Li+:16]
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: Fc1cc(F)c(F)c(F)c1F
Reactant: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1c(F)c(F)c([B-](c2c(F)c(F)c(F)c(F)c2F)(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Product: [Li+]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of pentafluorobenzene (4.40 g, 26.2 mmol) and diethyl ether (50 ml) was added dropwise a 20 wt. % sec-butyllithium/hexane solution (7.98 g, 25.0 mmol) while keeping the temperature of the reaction mixture at -55° to -65° C., and, after the completion of dropwise addition, the mixture was stirred for about 0.5 hours while keeping the temperature at -25°-50° C. Thereafter, a 20.0 wt. % tris(pentafluorophenyl)borane/toluene solution (63.8 g, 25.0 mmol was mixed while keeping the temperature of the reaction mixture at -25° to -40° C., which was stirred for 30 minutes at the same temperature and then the temperature was raised to room temperature. From the solution of lithium tetrakis(pentafluorophenyl)borate thus obtained, diethyl ether was removed by distillation and the organic layer was washed thrice with 20 mL of water. After combining the aqueous layers, 1.1 equivalent to the boron source of an aqueous solution of N,N-dimethylanilinium chloride was reacted with the aqueous layer to deposit white crystals. The crystals obtained were filtered, washed with water and then dried under vacuum to obtain N,N-dimethuylanilinium tetrakis(pentafluorophenyl)borate in 96.1% yield. When determining the purity by means of 1H and 19F NMR using pentafluorotoluene as an internal standard material, it showed 98% or higher.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[CH2:12][CH2:13][C@@H:14]2[CH2:16][C:15]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>O1CCCC1>[C:23]1([C:15]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:16][C@H:14]2[CH2:13][CH2:12][C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:10])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(CC[C@@H]1CC1(c1ccccc1)c1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: O=C(CC[C@@H]1CC1(c1ccccc1)c1ccccc1)NCCCCc1cccnc1
Yield: 87.1 %

Procedure:
As in Example 141, (R)-2,2-diphenylcyclopropanepropanoic acid 4-nitrophenyl ester (4.8 g) was treated with 3-pyridinebutanamine (1.88 g) in tetrahydrofuran (110 mL) at 25° C. for 2 hours. The crude product, isolated in the normal manner, was purified by HPLC (ethyl acetate-hexane; 9:1) and lyophilized from benzene to give 4.3 g of (R)-2,2-diphenyl-N-[4-(3-pyridinyl)butyl]cyclopropanepropanamide as an oil, [α]D25 +86.4° (c, 1.0, MeOH).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.CN([CH:35]=[O:36])C.Cl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:35]=[O:36])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C=O)n2C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 2-chloro-9-methyl-6-((S)-3-methylmorpholin-4-yl)-9H-purine (500 mg, 1.67 mmol) and TMEDA (419 μL, 2.80 mmol) in THF (10 mL) at −78° C. was added n-BuLi (1.12 mL, 2.80 mmol, 2.5M solution in hexanes). The resulting mixture was allowed to warm to −40° C. and stir for 30 min then cooled back to −78° C. before the addition of DMF (435 μL, 5.61 mmol). The reaction mixture was allowed to stir at −78° C. for 30 min then poured onto 1M HCl. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-50%) affording the title compound as a white solid (450 mg, 81%). LCMS (method H): RT 3.28 min [M+H]+ 296.3
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[O:6][C:5]([C:7]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:40])([F:38])[F:39])[CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)oc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (134 mg, 0.59 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (228 mg, 0.59 mmol)[prepared according to Preparation 6] and N,N-diisopropylethylamine (0.52 ml, 2.96 mmol) in Dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (304 mg, 0.65 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (202 mg, 0.33 mmol, 55.8% yield) as a yellow oil: LCMS (ES) m/e 557, 559 (M, M+2)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[N:10]=1.[C:20](Cl)(=[O:22])[CH3:21].C(N(CC)CC)C>CN(C)C=O>[C:20]([NH:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[N:10]=1)(=[O:22])[CH3:21]
Reactant: NCCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCCc1nc(-c2csc(N=C(N)N)n2)cs1
Yield: 36.3 %

Procedure:
A suspension of 4-[2-(2-aminoethyl)thiazol-4-yl]-2-(diaminomethyleneamino)thiazole dihydrochloride (1.0 g), acetyl chloride (230 mg) and triethylamine (1.0 g) in N,N-dimethylformamide (30 ml) was stirred with cooling on an ice-water bath for 1 hour. The solvent was removed under reduced pressure. The residue was suspended in water (30 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution and then was extracted with ethyl acetate. The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with chloroform:methanol=10:1. Recrystallization from a mixture of methanol, ethyl acetate and diisopropyl ether afforded 4-[2-(2-acetylaminoethyl)thiazol-4-yl]-2-(diaminomethyleneamino)thiazole (0.33 g).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:13].Cl.[N:15]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:13].[C:1]([N:18]1[CH2:17][CH2:16][N:15]([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19]1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCOC(=O)CN1CCNCC1
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCN(CC(=O)O)CC1
Product: CCCCCCC/C=C/C(=O)N1CCN(CC(=O)OCC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl 2-(1-piperazinyl)acetate dihydrochloride as starting raw materials, to produce ethyl [4-[(E)-2-decenoyl)piperazin-1-yl)acetate (ethyl ester of a free form of Compound 39).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1>C(O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])=[C:22]([F:27])[CH:21]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cc1F
Solvent: CCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1[N+](=O)[O-]
Reaction time: 3.5 h

Procedure:
A mixture of 5.017 g (19.0 mmol) 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and .2.55 ml 22.8 mmol) 4-chloro-2-fluoroaniline was heated to reflux under N2. At 3.5 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, and washed with water. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent, and dried in vacuo, giving 6.54 g of yellow solid: mass spectrum (electrospray m/e): M+H=372.8, 374.8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1[CH:34]=[O:35].[F:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:38]=1[CH:39]=[C:40](B1OC(C)(C)C(C)(C)O1)[NH:41]2>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:36][C:37]1[C:38]2[CH:39]=[C:40]3[C:2]4[N:7]=[C:6]([C:8]5[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]6[O:15][C:14]([C:16]7[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=7)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=6[CH:27]=5)[CH:5]=[CH:4][C:3]=4[CH:34]([OH:35])[N:41]3[C:42]=2[CH:43]=[CH:44][CH:45]=1
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C=O)c(Cl)n3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C4O)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
To a degassed solution of 5-(6-chloro-5-formylpyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.29 mmol) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (94 mg, 0.35 mmol) in 1,4-dioxane (3 mL) and water (200 μL) was added CS2CO3 (189 mg, 0.58 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (30 mg, 0.05 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred for 3 hours. The reaction was cooled, filtered through a pad of celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with (30% ethyl acetate/DCM) to provide 5-(10-fluoro-5-hydroxy-5H-pyrido[2′,3′:3,4]pyrrolo[1,2-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, yield: 22%) MS (M+H)+: 615.
Reaction SMILES: Cl[Si:2]1(Cl)[CH2:5][CH:4]([CH3:6])[CH2:3]1.C[Si]([CH2:12][C:13]([O-:15])=[O:14])(C)C>>[C:13]([O:15][Si:2]1([O:15][C:13](=[O:14])[CH3:12])[CH2:5][CH:4]([CH3:6])[CH2:3]1)(=[O:14])[CH3:12]
Reactant: CC1C[Si](Cl)(Cl)C1
Reactant: C[Si](C)(C)CC(=O)[O-]
Product: CC(=O)O[Si]1(OC(C)=O)CC(C)C1

Procedure:
In accordance with the general procedure of Example 1, when 1,1-dichloro-3methylsilacyclobutane and trimethylsilylacetate are reacted it is predicted that the title compound is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:12][C:13]([F:20])([F:19])[C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:16]2[CH:17]=[CH:18][C:14]([C:13]([F:20])([F:19])[F:12])=[N:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccn(-c2ncccc2C(F)(F)F)n1
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A mixture of 2-chloro-3-trifluoromethylpyridine (3.62 g., 21 mmol), 3-trifluoromethylpyrazole (2.7 g., 20 mmol ), and potassium carbonate (6.0 g., 43 mmol) were heated at 100° C. for 18 h. The cooled reaction mixture was added to ice/water (100 mL). The mixture was extracted twice with ether (100 mL) and the combined ether extracts were washed twice with water (100 mL). The organic layer was dried with magnesium sulfate and concentrated to an oil. Chromatography on silica gel with hexanes:ethyl acetate 8:1 to 4:1 as eluent gave the title compound (3.5 g) as an oil. 1H NMR (CDCl3) δ 6.75 (m,1H), 7.5 (m,1H), 8.2 (m,2H), 8.7 (m,1H).