Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9](=[NH:46])[C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[NH:33][C:34](=[O:45])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][P:41](=[O:44])([OH:43])[OH:42])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)=O)(C)(C)C.C[Si](I)(C)C>C(Cl)Cl>[C:9]([C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[NH:33][C:34](=[O:45])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][P:41](=[O:42])([OH:43])[OH:44])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)(=[NH:8])[NH2:46]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCCCCP(=O)(O)O)c1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCCCCP(=O)(O)O)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
[5-(3-{3′-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-pentyl]-phosphonic acid (0.058 g, 0.076 mmol), trimethylsilyl iodide (0.162 g, 0.756 mmol) and DCM [5 mL] were added to a flask and heated to 40° C. for 10 minutes. The reaction was removed from the heat bath and allowed to stir at room temperature for 1 hour. H2O [56 μL] was added to this solution and stirred for 1 hour. The reaction was concentrated in vacuo. MeOH [2 mL] and 20 wt. % HCl (aq.) [84 μL] were added to the concentrate and allowed to stir at room temperature for 18 hours. Reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01% TFA)] to yield the title compound. ESI-MS (m/z): Calcd. for C25H31N4O6PS3: 611.71 (M+H); found 611.0.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:45][C@@H:46]([C:48]2[CH:53]=[CH:52][C:51]([O:54]CC3C=CC=CC=3)=[C:50]([CH2:62][OH:63])[CH:49]=2)[OH:47])[CH2:26][C@H:27]([OH:44])[C:28]2[CH:33]=[CH:32][C:31]([O:34]CC3C=CC=CC=3)=[C:30]([CH2:42][OH:43])[CH:29]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:54][C:51]1[CH:52]=[CH:53][C:48]([C@@H:46]([OH:47])[CH2:45][N:25]([CH2:26][C@H:27]([OH:44])[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:42][OH:43])[CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:20][CH:19]=2)=[CH:49][C:50]=1[CH2:62][OH:63]
Reactant: O=C(NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)C[C@H](O)c2ccc(OCc3ccccc3)c(CO)c2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(O)c(CO)c2)C[C@H](O)c2ccc(O)c(CO)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.1 %

Procedure:
A suspension containing 65 (250 mg, 0.28 mmol) and palladium catalyst (10% Pd on carbon, 50% wet, 100 mg, 0.94 mmol) in ethanol (10 mL) was bubbled with nitrogen for 20 min. The reaction mixture was vacuumed, then charged with H2 gas (1 atm), and allowed to stir at room temperature for 24 h. The suspension was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of 0-20% (10% concentrated ammonium hydroxide in methanol and dichloromethane to afford the desired product 66 (45 mg, 28%) as an off white solid: m/z (ESI) 553 [C32H44N2O6+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.Cl.[CH:16]1([CH2:20][NH2:21])[CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.O>ClCCl>[CH:16]1([CH2:20][NH:21][C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:19][CH2:18][CH2:17]1
Reactant: NCC1CCC1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(NCC1CCC1)c1cnc(Cl)nc1C(F)(F)F
Temperature: -30 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine-5-carbonyl chloride (613 mg) (Maybridge) and C-cyclobutylmethylamine hydrochloride (304 mg) in dry dichloromethane (10 ml) was cooled to −30° C. and N,N-diisopropylethylamine (958 ul) was added dropwise. The mixture was stirred at room temp for 1 hour. Water (10 ml) was added, the layers separated and the organic layer was washed sequentially with 10 ml portions of water, dilute hydrochloric acid, water, dilute sodium bicarbonate solution and water, dried (MgSO4) and evaporated. Purification by chromatography on silica gel (dichloromethane/ether 25:1) gave the title compound (449 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[CH:12]2[CH2:17][CH2:18][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:14]([C@@H:13]3[CH:12]4[CH2:17][CH2:18][CH:9]([CH2:10][CH2:11]4)[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:34][C:35]=2[CH:39]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1C2CCC(CC2)[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC(CC2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 60 °C
Yield: 43.8 %

Procedure:
To a solution of (3S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.2]octane-3-carboxylic acid (0.511 g) and triethylamine (0.348 mL) in tetrahydrofuran (5 mL) was added isobutyl chloroformate (0.26 mL) while stirring under ice-cooling. After stirring at room temperature for 30 min, a solution of 3-amino-5-bromothiophene-2-carboxamide (0.221 g) produced in Example 1, step D, in tetrahydrofuran (1 mL) was added. The reaction system was stirred with heating at 60° C. for 4 days. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (3.0 mL) and 1,2-dimethoxyethane (6.0 mL) were added to the residue, and the mixture was stirred with heating in a microwave reactor at 150° C. for 1 hr. Insoluble material was removed by filtration, and the mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (193 mg) as a colorless solid. The optical purity was 70% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (800/200), flow rate: 1.0 mL/min, column temperature: 30° C., detection 220 nm).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([CH2:26]Br)[CH:23]=[CH:22][C:21]=1[F:28])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24]([CH2:26][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)[CH:23]=[CH:22][C:21]=1[F:28])[CH3:17]
Reactant: CCOC(=O)c1cc(CBr)ccc1F
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1F
Yield: 78.9 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.2 g (1 mmol) of 3-piperidin-4-yl-1H-indole and 0.33 g (1.3 mmol 5-bromomethyl-2-fluoro-benzoic acid ethyl ester. After ionic exchange purfication, 0.30 g (79% of yield) of 2-fluoro-5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid ethyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]2[NH:7][C:8](=[O:29])[CH:9]([NH:18]C(=O)OCC3C=CC=CC=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.Br.C(OCC)C>CC(O)=O>[NH2:18][CH:9]1[C:8](=[O:29])[NH:7][C:6]2[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:10]1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)OCc1ccccc1)C(=O)N2
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(c1ccccc1)=NC(N)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 7B (0.5 g, 1.2 mmol) was treated with 3.5 mL (7 volumes) of 33% HBr in AcOH and was stirred at room temperature for 2 hrs. Diethyl ether (25 mL) was added to the reaction mixture and the precipitated solid was collected by filtration. The solid was dissolved in water (3 mL), and 10% sodium bicarbonate solution was added until the solution was basic. The product was extracted with 2×25 mL of ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The solvents were removed under vacuum to afford Intermediate 7C as a white solid: yield 0.32 g (98%). HPLC: RT=1.228 (H2O/ACN with NH4OAc, PUROSPHER® Star RP-18 (4×55) mm, 3 μm, gradient=3 min, wavelength=220 nm); MS(ES):m/z=282 [M+H+]; 1H NMR (DMSO-d6: δ 10.46 (brs, 1H), 7.42-7.53 (m, 5H), 7.19-7.25 (m, 2H), 6.72 (d, J=2.4 Hz, 1H), 4.25 (s, 1H), 3.39 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=[O:7])[CH3:3].[NH2:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].CN(OC)[C:31](=[O:38])[C@H:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH2:33].[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)[O-].[K+]>O1CCCC1.O>[CH3:3][CH:2]([CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C:6]([OH:8])=[O:7])[CH3:1].[NH2:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].[NH2:33][C@H:32]([CH:31]=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CON(C)C(=O)[C@@H](N)CC(C)C
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](N)C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Z-L-leucine-L-leucine-L-leucine N,O-dimethylhydroxylamide (546 mg) was dissolved in 15 mL dry tetrahydrofuran (THF) and cooled to 0° C. Lithium aluminum hydride (1M solution in THF, 4.1 mL) was added and the mixture was stirred at 0° C. for 30 minutes. Potassium bisulfate (1.39 g) in 30 mL water was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with aqueous 5% HCl, saturated NaHCO3, and brine, then dried over anhydrous MgSO4, filtered, and evaporated to afford the product (446 mg) as a white solid. This was further purified by reverse phase HPLC (water/acetonitrile).
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH3:19][N:20]1[CH2:24][CH2:23][C:22]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:21]1=[O:30].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:18][C:3]1[C:2]([N:27]2[CH2:28][CH2:29][C:22]3([C:21](=[O:30])[N:20]([CH3:19])[CH2:24][CH2:23]3)[CH2:25][CH2:26]2)=[CH:7][C:6]([C:8]#[N:9])=[CH:5][C:4]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CN1CCC2(CCNCC2)C1=O
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCC2(CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2)C1=O
Temperature: 105 °C
Yield: 44.7 %

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (349 mg, 1.052 mmol), 2-methyl-2,8-diazaspiro[4.5]decan-1-one (177 mg, 1.052 mmol), Pd2dba3 (96 mg, 0.105 mmol), BINAP (197 mg, 0.316 mmol), and Cs2CO3 (1028 mg, 3.16 mmol) in Dioxane (15 mL) was evacuated and filled with nitrogen 3× and heated at 105° C. overnight. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 10% to 100% EtOAc in Hexane) to give tert-butyl (2-chloro-5-cyano-3-(2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)phenyl)carbamate (197 mg)
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][O:7][C@H:6]1[C@H:2]([O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:3][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
(+/−)-Trans-Benzyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (7.7 g, 30.6 mmol) and N,N-dimethylpyridin-4-amine (0.374 g, 3.06 mmol) were dissolved in DCM (75 mL). Cooled to 0 deg. Celsius and added 4-methylbenzene-1-sulfonyl chloride (8.76 g, 46 mmol) and triethylamine (6.41 ml, 46.0 mmol). The reaction was stirred to warm to RT overnight. The solvent was removed and the residue was passed thru a pad of silica to give the product, (+/−)-Trans-benzyl 3-methoxy-4-(tosyloxy)pyrrolidine-1-carboxylate (10.3 g, 25.4 mmol, 83% yield).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:13])=[CH:6][C:5]=1[NH:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Br:23][C:19]1[CH:18]=[C:17]([C:16]2[C:15](=[O:24])[NH:14][C:5]3[C:4]([C:3]=2[OH:25])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([Cl:13])[CH:6]=3)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(=O)Cc1cccc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(O)c1-c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of 2-[2-(3-bromophenyl)-acetylamino]-4-chloro-5-nitro-benzoic acid methyl ester (1.18 g in 15 mL dry tetrahydrofuran) at 0° C. was added dropwise a solution of sodium bis(trimethylsilyl)amide (6.9 mL of a 1.0M solution in tetrahydrofuran) and the mixture warmed to room temperature. After 2 hours, the reaction was quenched by the addition of 200 mL iced 6N hydrochloric acid. The slurry was stirred for 10 minutes then filtered and washed (2×) with ice water and then cold acetonitrile. The residue was dried overnight at 45° C. to give the title compound (887 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[O:21]=[S:18]1(=[O:22])[CH2:19][CH2:20][CH:16]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:17]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=S1(=O)CCC(Br)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(C3CCS(=O)(=O)C3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromotetrahydrothiophene 1,1-dioxide (56 mg, 0.28 mmole; ChemBridge, Cat. No. 4011807), cesium carbonate (0.25 g, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield 74 mg of the product. LCMS (M+H)+: m/z=313.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11](Cl)[O:12][CH:13]=1)=[O:8].[CH:24]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]([CH3:26])[CH3:25])[CH:28]=2)[O:12][CH:13]=1)=[O:8]
Reactant: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2coc(Cl)n2)cc1F
Reactant: CC(C)c1cccc(O)c1
Product: CC(C)c1cccc(Oc2nc(C(=O)NCc3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 72.3 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide (38 mg, 0.11 mmol) was reacted with 3-isopropyl phenol (18 mg, 0.12 mmol) to give the title compound (37 mg, 70%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]1.C1COCC1>[Pd].CO>[F:30][C:2]([F:1])([F:29])[CH2:3][CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([NH2:13])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:18]1[CH2:19][CH2:20][CH:21]([C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:23]1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1N
Reaction time: 2 h

Procedure:
A mixture of N-(3,3,3-trifluoro-propyl)-2-[4-trifluoromethyl-piperidinyl]-4-methylamino-5-nitro-benzoic acid amide (2.5 g, 5.7 mmol), Pd/C (200 mg), THF (10 mL) and MeOH (100 mL) is stirred for 2 h under 3 bar H2-atmosphere. The mixture is filtered, and the filtrate is concentrated. Yield: 2.3 g. HPLC Rt=1.25 min (method A). MS m/z: 413 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=[O:28])[C:22](=[O:27])[C:23]=4OCC)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=[O:28])[C:22](=[O:27])[C:23]=4[N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Reactant: C1COCCN1
Solvent: CCO
Product: O=c1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(N2CCOCC2)c1=O
Temperature: 25 °C

Procedure:
A mixture of 0.8 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione, 4 mL of morpholine, and 20 mL of ethanol was refluxed for 2 hr. The mixture was cooled to room temperature and the solid was collected and washed with ethanol and ether giving 0.69 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-morpholin-4-yl-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 480.1, 482.1.
Reaction SMILES: [Cl-].[Li+].Br[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]([I:17])=[CH:6][C:5]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C1C2C(=CC=CC=2)C=CC=1.C([Mg]Cl)(C)C.BrC1SC(Br)=CC=1CCCCCC.Cl>C1COCC1>[CH2:19]([O:18][C:5]1[CH:6]=[C:7]([I:17])[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:4]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCOc1cc(I)c(OCCCCCC)cc1Br
Agent: CC(C)[Mg]Cl
Agent: CCCCCCc1cc(Br)sc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: CCCCCCOc1ccc(OCCCCCC)c(I)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.042 g (0.99 mmol) of anhydrous lithium chloride was put in a flask, and vacuum dried with heating the flask using a heat gun, followed by carrying out argon substitution and returning the temperature to room temperature. Thereto were added 0.483 g (1.00 mmol) of 1-bromo-2,5-dihexyloxy-4-iodobenzene and 0.0448 g (0.350 mmol) of naphthalene as an internal standard material, and the flask was again subjected to argon substitution. 5 mL of dried THF was added thereto, and 0.5 mL (1.0 mmol) of a solution of isopropylmagnesium chloride in THF (2.0 mol/l) was added, followed by stirring for 1 hour at 0° C. to Grignardize the 1-bromo-2,5-dihexyloxy-4-iodobenzene. Thereafter, 0.0105 g (0.0199 mmol, 2.0 mol %) of Ni(dppe)Cl2 suspended in 5 mL of THF was added, followed by stirring at room temperature for 30 minutes. In another egg-plant type flask were put 0.373 g (1.00 mmol) of 2,5-dibromo-3-hexylthiophene, 0.0329 g (0.257 mmol) of naphthalene, 5 mL of dried THF and 0.5 mL (1.0 mmol) of a solution of isopropylmagnesium chloride in THF (2.0 mol/l), and they were stirred at 0° C. for 1 hour to Grignardize 2,5-dibromo-3-hexylthiophene. A THF solution thereof was added to the reaction mixture, followed by stirring at room temperature for 10 minutes. After completion of the reaction, 5M HCl was added, followed by extraction with chloroform, and the organic layer was washed with water and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a block copolymer (Mn=16200, Mw/Mn=1.27) represented by the following formula. A block copolymer having a narrow molecular weight distribution was obtained by first polymerizing the Grignardized 2,5-dihexyloxy-4-iodobenzene greater in parameter of aromatic ring charge (−0.104), and then copolymerizing 2,5-dibromo-3-hexylthiophene (−0.116).
Reaction SMILES: [N-]=[N+:2]=[N-:3].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:16]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>O.C(O)C>[C:21]([O:20][C:18](=[O:19])[C:17](=[N+:2]=[N-:3])[C:16]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH3:23])([CH3:24])[CH3:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.9 %

Procedure:
A mixture of sodium azide (1.37 grams, 21.0 mmol), p-toluenesulfonyl chloride (4.0 grams, 21.0 mmol), and 70% aqueous ethanol (60 mL) was stirred at room temperature for 1 hour. Di-t-butyl malonate (4.48 mL, 20.0 mmol) and triethylamine (2.92 grams, 21.0 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and then poured into deionized water (200 mL). The mixture was extracted with petroleum ether (2×200 mL). The extracts were combined and then washed with a saturated aqueous sodium chloride solution. The organic solution was dried using anhydrous magnesium sulfate, filtered, and concentrated to give 6.10 grams of di-t-butyl-2-diazomalonate as a yellow oil. IR(film): 2110 cm-1. Decomposition temperature: 178° C. (by DSC).