Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O=[C:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]3[N:13]=[C:15]([CH3:22])[CH:16]=[C:17]([OH:18])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1cc(O)n2nc(-c3cccc(Cl)c3)cc2n1
Temperature: 157.5 °C
Yield: 88 %

Procedure:
A suspension of 3-(3-chlorophenyl)-1H-pyrazol-5-amine (10 g, 51.6 mmol) and ethyl 3-oxobutanoate (26.3 ml, 207 mmol) in o-xylene (200 mL) was heated at reflux (oil bath temp: 155-160° C.) for 20 h. Note: The reaction turned clear solution between 60-70° C. and solids started crashing out at 130° C. Then, cooled, diluted with hexanes (100 mL), filtered, washed with hexanes (100 mL) and dried to afford 2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (11.8 g, 45.4 mmol, 88% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 12.46 (s, 1H), 8.05 (s, 1H), 8.00-7.95 (m, 1H), 7.56-7.45 (m, 2H), 6.70 (s, 1H), 5.64 (s, 1H), 2.33 (s, 3H). LCMS (M+H) calcd for C13H11ClN6O: 260.06. found: 260.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:37][C:18]3=[N:19][CH:20]=[C:21]([Cl:36])[C:22]([C:23]4[S:27][C:26]([C:28]5([O:32]COC)[CH2:31][CH2:30][CH2:29]5)=[N:25][CH:24]=4)=[C:17]3[CH:16]=2)=[CH:11][CH:10]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:37][C:18]3=[N:19][CH:20]=[C:21]([Cl:36])[C:22]([C:23]4[S:27][C:26]([C:28]5([OH:32])[CH2:29][CH2:30][CH2:31]5)=[N:25][CH:24]=4)=[C:17]3[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(OCC6COCCO6)cc5)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: OC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(OCC6COCCO6)cc5)cc34)s2)CCC1

Procedure:
The title compound was prepared as described in Example 22E, substituting 5-(2-(4-((1,4-dioxan-2-yl)methoxy)phenyl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 71B) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.46 (s, 1H) 8.29 (s, 1H) 8.25 (s, 1H) 7.94 (d, 2H) 7.04 (d, 2H) 6.95 (d, 1H) 6.66 (s, 1H) 4.03 (m, 2H) 3.85 (m, 2H) 3.78 (m, 1H) 3.65 (m, 2H) 3.51 (m, 1H) 3.42 (m, 1H) 2.63 (m, 2H) 2.40 (m, 2H) 1.97 (m, 2H); MS ESI(+) m/z 498.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C@H:17]([CH2:22]OS(C)(=O)=O)[C:18]([O:20][CH3:21])=[O:19]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:16][C@@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COc1ccccc1S
Reactant: COC(=O)[C@H](C)COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)CSc1ccccc1OC
Reaction time: 24 h

Procedure:
In a round-bottom flask maintained under an inert atmosphere, 4.72 mL (38.8 mmoles) of 2-methoxythiophenol, 10.72 g (77.6 mmoles) of potassium carbonate, 5.13 g of diluted methyl (2R)-2-methyl-3-[(methylsulfonyl)oxy]propanoate (6a-1) and 100 mL of anhydrous THF then 329 mg (0.97 mmole) of tetrabutylammonium hydrogen sulfate are introduced. The reaction medium is brought to 60° C. for 24 h under vigorous stirring then concentrated under reduced pressure. The residue is taken up with water and is extracted with ethylic ether. The combined organic phases are washed with a 1 N soda solution, water, brine, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is taken up in methanol and concentrated then taken up again in methanol (10 mL/1 g of residue). The bis(methoxyphenyl) disulfide [13920-94-0] that slowly precipitates is eliminated by filtration. The filtrate is evaporated under reduced pressure to yield the title compound in the form of a pale yellow oil (6.4 g, 26.6 mmoles).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.Cl.C(OCC)(=O)C>CO.[OH-].[K+]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19](/[CH:18]=[CH:17]/[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[CH:20][CH:21]=1
Reactant: COC(=O)CCc1ccccc1OCCCC/C=C/c1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(/C=C/CCCCOc2ccccc2CCC(=O)O)cc1
Yield: 95.6 %

Procedure:
A solution of 100 mg of 3-[2-[6-(4-methoxyphenyl)-(5E)5-hexenyloxy]-phenyl]-propionic acid methyl ester in 2 ml of methanol and 2 ml of in potassium hydroxide solution is stirred for 2 1/2 hours at room temperature. The reaction mixture is acidified to pH 1 with 2 n hydrochloric acid and shaken out with ethyl acetate, the organic phase is dried on sodium sulfate and concentrated by evaporation. 92 mg of the title compound is obtained as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:36](OC)(OC)(OC)[CH3:37]>CCO>[Br:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]2[N:1]=[C:36]([CH3:37])[O:10][C:3]=2[CH:4]=1
Reactant: Nc1cc(Cl)c(Br)cc1O
Reactant: COC(C)(OC)OC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: Cc1nc2cc(Cl)c(Br)cc2o1
Temperature: 90 °C
Yield: 80.2 %

Procedure:
A mixture of 2-amino-5-bromo-4-chlorophenol (29) (865 mg, 3.89 mmol), trifluoromethanesulfonic acid Ytterbium (III) salt (24 mg, 1% mol) and trimethyl orthoacetate (610 μl, 1.2 eq.) in 3 ml EtOH was heated at 90° C. for 1 h. After cooling down to r.t., off-white needles fell off, which were filtered, washed with MeOH, water and dried to give 791 mg title compound as off-white crystalline solid. Yield: 80.2%; purity>95%.
Reaction SMILES: [P:1]([O-:18])([O:10]CC1C=CC=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[CH3:20][N+:21]([CH3:24])([CH3:23])[CH3:22]>C(#N)C.O>[CH2:3]([O:2][P:1]([O-:18])[O-:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][N+:21]([CH3:24])([CH3:23])[CH3:22].[CH3:20][N+:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: [O-]P([O-])OCc1ccccc1

Procedure:
Dibenzyl phosphite (29.4 g, 112 mmol) is dissolved in a mixture of acetonitrile (140 mL) and water (30 mL) and the reaction mixture is treated with 2.8M aqueous tetramethylammonium hydroxide (40 mL, 112 mmol) at room temperature for 24 hours. After being washed with ether (3×20 mL), the aqueous layer is concentrated in vacuo. The residue is dried under high vacuum at 70° for 12 hours to yield tetramethylammonium benzyl phosphite as a semi-solid. The latter compound (2 g, 8 mmol) and α-(phenylacetoxy)isobutyl bromide (prepared from phenylacetyl bromide and isobutyraldehyde according to Helv. Chim. Acta 61, 2047, 1978) (1.26 mL, 8 mmol) are stirred in acetone (15 mL) for 18 hours at room temperature. The precipitate is filtered through Celite. The filtrate is concentrated under reduced pressure and purified by flash-chromatography on silica gel eluting with 37.5% of ethyl acetate in hexane. Evaporation of the pure fractions gives the unsymmetrical (α-phenylacetyloxyisobutyl) benzyl phosphite as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:12][C:13]([O:15]C)=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:3]([CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:12][C:13]([OH:15])=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC(CCCCCCCC)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCC(CCCCCCCC)CC(=O)O
Temperature: 80 °C
Yield: 89.1 %

Procedure:
[Synthesis Method]30 ml of an aqueous solution containing 1.7 g (43.5 mmol) of potassium hydroxide was added to 5.0 g (14.7 mmol) of methyl 3-octyl-tridecanoate under nitrogen atmosphere and heated at 80° C. for five hours. After acidifying the reaction solution with diluted hydrochloric acid, extraction was conducted using ether to obtain 4.2 g (13.1 mmol) of 3-octyl-tridecanoic acid as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([C:56]3[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=3)[CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:62]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([C:56]7[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=7)[CH2:54][CH2:55]6)=[O:49])=[CH:44][C:43]=5[CH3:62])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)N2CCN(c3cccnc3)CC2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5cccnc5)CC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and (4-bromo-3-methyl-phenyl)-(4-pyridin-3-yl-piperazin-1-yl)-methanone (70 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-(4-pyridin-3-yl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-311) as a yellow powder (41 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:5]2=[O:20].[CH3:21][N:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[CH:15][C:16]([O:19][C:23](=[O:24])[N:22]([CH3:21])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:17][CH:18]=1)[C:5]2=[O:20]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C1c2cc(Cl)c(Cl)cc2C(=O)N1c1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from 5,6-dichloro-2-(4-hydroxy-phenyl)-isoindole-1,3-dione and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (2%,). HPLC-MS: m/z=441.1 (M+1); Rt: 5.00 min.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].C(OCC)=O.Cl.[C:31](#[N:33])[CH3:32]>>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:32][C:31]#[N:33])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
In a 100 mL-volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed under argon atmosphere 1.94 g (6.66 mmol) of 2-cyclo-propyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 10 mL of acetonitrile and 0.422 g (10.6 mmol). of sodium hydride (purity: 60%). The content was stirred at room temperature for 2 hours. The resulting mixture was chilled to −10° C. To the chilled mixture was added 20 mL (248 mmol) of ethyl formate, and the mixture was stirred for 4 hours at the same temperature. Subsequently, to the mixture was slowly added 11 mL of hydrochloric acid (1 mol/L) which was previously chilled in an ice bath. In the mixture, an organic portion separated from an aqueous portion. The organic portion was taken out, washed with two 10 mL portions of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The organic portion was filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.71 g (yield: 85%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced. The organic portion was concentrated under reduced pressure to leave a yellow solid residue. The solid residue was recrystallized from toluene/hexane (1/8, vol. ratio) to obtain 1.79 g of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile as a yellow crystalline product (purity: 97%). The obtained 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile had the following characteristics:
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH2:12]Br>C(O)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH:12]=[O:3]
Reactant: Cc1cc(Cl)cc(CBr)c1
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: Cc1cc(Cl)cc(C=O)c1
Reaction time: 3 h
Yield: 42.2 %

Procedure:
To a solution of sodium metal (52 mg, 2.3 mmol) in ethanol was added 2-nitropropane (0.23 g, 2.4 mmole) followed by the addition of 3-chloro-5-methybenzylbromide (0.5 g, 2.3 mmol). The reaction was allowed to stir for 3 hours and the precipitate formed was filtered off. The filtrate was concentrated under reduced pressure, redissolved in diethylether and washed with 1N sodium hydroxide (twice), water, and dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography using 10% dichloromethane and 90% petroleum ether, to give 0.15 g of 3-chloro-5-methylbenzaldehyde. 1H-NMR (CDCl3): 2.46 (s, 3H) 7.43 (s, 1H) 7.56 (s, 1H) 7.68 (s, 1H), 9.92 (s, 1H).
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[OH:15][C:16]([C@H:19]1[CH2:23][CH2:22][NH:21][C@H:20]1[CH3:24])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:15][C:16]([C@H:19]1[CH2:23][CH2:22][N:21]([C:2]2[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=2)[C@H:20]1[CH3:24])([CH3:18])[CH3:17]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: Cc1cc(C#N)c(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1cc(C#N)c(C(F)(F)F)cc1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using 4-fluoro-5-methyl-2-(trifluoromethyl)benzonitrile (89 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (100 mg) and lithium carbonate (78 mg), the title compound was obtained as a colorless solid (yield: 17 mg) by an operation similar to that in Example 3.
Reaction SMILES: Br[C:2]1[C:3]2[S:9][CH:8]=[C:7](Br)[C:4]=2[S:5][CH:6]=1.[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]>>[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[C:3]4[S:9][CH:8]=[C:7]([C:34]5[CH:35]=[CH:36][C:31]([C:28]6[NH:27][C:26]([C@@H:22]7[CH2:23][CH2:24][CH2:25][N:21]7[C:19](=[O:20])[C@@H:15]([NH:14][C:13]([O:12][CH3:11])=[O:46])[CH:16]([CH3:17])[CH3:18])=[N:30][CH:29]=6)=[CH:32][CH:33]=5)[C:4]=4[S:5][CH:6]=3)=[CH:35][CH:36]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: Brc1csc2c(Br)csc12
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3csc4c(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5)csc34)cc2)[nH]1)C(C)C
Yield: 28 %

Procedure:
Compound A26 was synthesized from 3,6-dibromothieno[3,2,b]thiophene (0.335 mmol) and compound 8 (0.738 mmol), following the procedure as described for compound A155. The residue was purified by semi-preparative HPLC to give compound A86 as a yellow solid in 28% yield. 1H NMR (CD3OD, 400 MHz) δ (ppm) 0.92 (d, J=6.69 Hz, 6H), 0.97 (d, J=6.69 Hz, 6H), 1.01 (d, J=6.69 Hz, 2H), 2.01-2.13 (m, 4H), 2.20-2.40 (m, 6H), 3.67 (s, 6H), 3.87-3.93 (m, 2H), 3.99-4.04 (m, 2H), 4.25 (d, J=7.42 Hz, 2H), 5.18-5.21 (m, 2H), 7.37 (s, 2H), 7.79-7.86 (m, 10H); MS (ESI, EI+) m/z=877.5 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:15]([O:14][C:12]([CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])=[O:13])[CH3:16]
Reactant: O=Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-hydroxybenzaldehyde (5.17 g, 42.34 mmol), K2 CO3 (5.85 g) and acetone (50 ml) was added ethyl bromoacetate (5.2 ml). The reaction mixture was stirred at room temperature overnight, additional K2CO3 (1 equivalent) was added, the mixture was stirred for one hour, then additional ethyl bromoacetate (0.5 equivalents) was added and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was filtered, water was added to the filtrate and the solvent was removed. The residue was dissolved in ether, extracted with 1M NaOH (2×100 ml), and the ether layer was dried over MgSO4 and stripped to afford, as a liquid, 7.89 g of 3-(ethoxycarbonylmethoxy) benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:20](=[O:22])=[O:21]>C1COCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[C:14]2[CH:13]([C:20]([OH:22])=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1Cc1ccccc1-2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A solution of 1-methylfluorene (3.8 g, 21.1 mmol) in 100 mL of THF at -78° C. was charged with n-butyl lithium (3.5M solution in hexane, 6.29 ml, 22.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5 g, 113.6 mmol) was introduced via cannula over a period of 15 min. The reaction mixture was warmed up to room temperature and stirring was continued until no color was apparent (approximately 2 hr). The slurry was diluted with water (100 mL) and ethyl acetate (50 mL). The layers were separated, the water layer was washed with ethyl acetate (3×50 mL), then acidified with conc. HCl. The precipitate was collected, washed with water and dried to give 1-methyl-9-fluorenecarboxylic acid (4.02 g, 84.8%).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18](=O)[CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH:22]([CH2:27][O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH2:21]2)=[N:14][CH:15]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH:22]([CH2:27][O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH2:21]3)=[N:17][N:16]=2)[CH:15]=1
Reactant: CC(C)[Si](OCC1CN(CC(=O)NNc2ccc(F)cn2)CCN1C)(C(C)C)C(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[Si](OCC1CN(Cc2nnc3ccc(F)cn23)CCN1C)(C(C)C)C(C)C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
Hexachloroethane (426 mg, 1.80 mmol) was added portion-wise to a stirred mixture of Intermediate 56c (410 mg, 0.90 mmol), Ph3P (472 mg, 1.80 mmol) and Et3N (500 μL, 3.60 mmol) in THF (15 mL) at RT. The reaction mixture was stirred for 18 h, then filtered and concentrated in vacuo. The resulting residue was purified by FCC, using 0-25% MeOH in EtOAc, to give the title compound (237 mg, 60%). LCMS (Method 3): Rt 2.95 min, m/z 436 [MH+].
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH:13]([CH3:15])[CH3:14])[N:10]([CH2:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[O:18])[C:9]2=[O:30])=[CH:4][CH:3]=1.[CH2:31]([Mg]Br)[CH2:32][CH3:33].[Cl-].[NH4+]>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C\C(C)=O.C/C(/[O-])=C\C(C)=O.C/C(/[O-])=C\C(C)=O.[Fe+3]>[O:30]=[C:9]1[N:8]([C:5]2[CH:6]=[N:7][C:2]([CH2:31][CH2:32][CH3:33])=[CH:3][CH:4]=2)[CH2:12][C@H:11]([CH:13]([CH3:15])[CH3:14])[N:10]1[CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:18]
Reactant: CC(C)[C@H]1CN(c2ccc(Br)nc2)C(=O)N1CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CCC[Mg]Br
Agent: [Fe+3]
Agent: CC(=O)/C=C(\C)[O-]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCc1ccc(N2C[C@H](C(C)C)N(CC(=O)Nc3cccc(C(F)(F)F)c3)C2=O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-[(5S)-3-(6-bromopyridin-3-yl)-2-oxo-5-(propan-2-yl)imidazolidin-1-yl]-N-[3-(trifluoromethyl)phenyl]acetamide (50 mg) and tris(2,4-pentanedionato)iron(III) (55 mg) in THF (1 mL) and NMP (0.1 mL) was added n-propylmagnesium bromide (2M solution in THF, 0.31 mL), and the mixture was stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added thereto, the resulting mixture was extracted with acetic acid, and the organic layer was washed with water and brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane/ethyl acetate) to afford the title compound (24 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[C:23](S(C)(=O)=O)[N:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[NH2:33][CH2:34][CH2:35][OH:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[C:23]([NH:33][CH2:34][CH2:35][OH:36])[N:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: NCCO
Reactant: CS(=O)(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ncn1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2cc(NCCO)ncn2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 110 °C
Yield: 53.4 %

Procedure:
A solution of 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[4-(6-methanesulfonyl-pyrimidin-4-yloxy)-phenyl]-urea (100 mg, 0.2 mmol) in dichloromethane (1 ml) and 2-aminoethanol (124 μl, 2.0 mmol) is sealed in a reaction tube and heated in the microwave at 110° C. for 15 minutes. The reaction mixture is evaporated and purified by preparative HPLC to yield 50 mg (52%) of a white powder.