Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1.O>O1CCCC1>[Br:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:19])=[O:18])=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)c2c1CCCC2
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
tert-butyl amine [8.5 g, 12.32 ml, 116.0 mmol) was added dropwise to a stirred suspension of 4-bromo-5,6,7,8-tetrahydronaphthalene-1-sulfonyl chloride (59a, 12.0 g, 38.8 mmol) in 150 ml tetrahydrofuran at 0° C. The reaction mixture was then stirred at a temperature of about 25° C. for 2 hours. The progress of the reaction was monitored by TLC. Water (100 ml) was added to the reaction mixture, and the mixture so obtained was extracted with ethyl acetate (2×150 ml). The combined organic layer was then dried over sodium sulphate, and the dried organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate in hexanes as an eluent to obtain the title compound (2.34 g, 17.4%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45]([C:47]1[N:48]([CH3:53])[CH:49]=[C:50]([NH2:52])[CH:51]=1)=[O:46]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:52][C:50]3[CH:51]=[C:47]([C:45]([OH:46])=[O:44])[N:48]([CH3:53])[CH:49]=3)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(N)cn1C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)Nc3cc(C(=O)O)n(C)c3)cc2)cc1

Procedure:
The product from Example 233 and 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.89-12.33 (br.s, 1 H), 9.81 (s, 1 H), 8.94 (s, 1 H), 7.24 (m, 8 H), 6.98 (m, 7 H), 6.82 (d, 2 H), 6.65 (d, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.97 (t, 2 H), 3.79 (s, 3 H), 2.91 (s, 3 H), 2.38 (m, 5 H), 1.99 (m, 2 H); MS (ESI+) m/z 697 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:18][C:19]1[CH:20]=[C:21]([C:2]3[C:11]4[C:6](=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])[CH:22]=[CH:23][CH:24]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])#[N:17]
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: Nc1cccc(B(O)O)c1
Product: N#Cc1cnc2c(C(F)(F)F)cccc2c1Nc1cccc(-c2c(C#N)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 4-chloro-8-(trifluoromethyl)quinoline-3-carbonitrile and 3-aminophenylboronic acid according to the procedure of Example 1 as a side product. MS (ES) m/z 531.8.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH:14]=[CH:13][C:12]2=[O:17])=[CH:7][CH:6]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C1(C)C=CC=C(S(O)(=O)=O)C=1.Cl>C(O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:12](=[O:17])[CH:13]=[CH:14][C:15]2=[O:16])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(N2C(=O)C=CC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1cccc(S(=O)(=O)O)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: O=C1C=CC(=O)N1c1ccc(O)cc1

Procedure:
As indicated by the Reaction Scheme, maleic anhydride (I) was first reacted with para- (ortho- or meta-) aminophenol (II) in tetrahydrofuran to give N-4-hydroxyphenyl maleamic acid (III) which was, then, refluxed together with acetic anhydride at 120° C. in the presence of a catalyst, such as sodium acetate, to obtain N-4-acetoxy phenyl maleimide (IV). After being dissolved in ethanol, the compound IV was refluxed along with at least one selected from the group consisting of para-toluene sulfonic acid, ortho-toluene sulfonic acid, meta-toluene sulfonic acid and hydrochloric acid, to give N-4-hydroxyphenyl maleimide (V). Using a radical initiator, such as azo-iso-butyronitride (AIBN), dibenzoyl peroxide (BPO) or di-tert-butylperoxide, N-4-hydroxyphenyl maleimide (V) was polymerized into a polymaleic imide resin (VI). Following dissolution in a solvent, the polymer (VI) was reacted with chloromethylethyl ether (Cl--CH2 --OCH2CH3) in the presence of a base selected from the group consisting of triethyl amine, potassium-tert-butoxide, potassium hydroxide (KOH), potassium methoxide (KOCH3), potassium ethoxide (KOCH2CH3), sodium-tert-butoxide, sodium hydroxide (NaOH), sodium methoxide (NaOCH3), sodium ethoxide (NaOCH2CH3), sodium hydride (NaH), potassium carbonate (K2CO3), sodium ethoxide (NaOCH2C3), sodium hydride (NaH) and sodium carbonate (Na2CO3), to create poly (N-4-hydroxyphenyl maleimide-co-N-4-ethoxymethoxyphenyl maleimide) (VII), a photoresist resin for ArF.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[C:44]([F:52])=[C:45]([S:48](Cl)(=[O:50])=[O:49])[CH:46]=[CH:47][C:39]1=2)#[N:27].CO>C1COCC1.CO.O>[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[C:44]([F:52])=[C:45]([S:48]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])[CH:46]=[CH:47][C:39]1=2)#[N:27]
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c1ccc(S(=O)(=O)Cl)c2F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2c1ccc(S(=O)(=O)Nc1nccs1)c2F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.036 g, 0.162 mmol) was added THF (0.482 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.177 ml, 0.177 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.062 g, 0.147 mmol) in THF (0.5 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was allowed to warm to rt over 1 hr providing a turbid brown mixture with product as the primary species according to LC-MS (m/z=605). To the turbid brown solution was added MeOH and the mixture concentrated under reduced pressure. To the crude residue was added DCM (2 ml) and TFA (0.2 ml). After 2 hr, the mixture was concentrated under reduced pressure and purified with a 25 g SNAP column ramping EtOAc in heptane (0-75%, 10% DCM throughout) to yield product as a sticky white solid, which was lyophilized from MeOH/H2O affording product as a fluffy white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.04 g, 0.083 mmol, 56.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.83-3.95 (m, 2 H) 4.34-4.46 (m, 2 H) 6.56 (dd, J=8.90, 1.27 Hz, 1 H) 6.84 (d, J=4.60 Hz, 1 H) 7.17 (dd, J=8.85, 7.29 Hz, 1 H) 7.27 (d, J=4.60 Hz, 1 H) 7.76 (d, J=8.61 Hz, 1 H) 8.11 (dd, J=8.80, 2.05 Hz, 1 H) 8.42 (d, J=1.76 Hz, 1 H) 12.80 (br. s., 1 H). m/z (ESI) 485.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:4]([C:18]([OH:20])=O)[CH2:3]1.C(N(CC)CC)C.ClC(OCC)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[OH:1][CH:2]1[CH2:6][N:5]([C:7](=[O:17])[C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:4]([C:18]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:20])[CH2:3]1
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2)N1CCOCC1
Reaction time: 0.5 h

Procedure:
4.5 g (0.016 mol) of 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 6 are suspended in 110 ml of acetonitrile at 0° C. 1.1 equivalents of triethylamine are added and the reaction mixture is stirred for 30 minutes, then 1.1 equivalents of ethyl chloroformate are added while maintaining the temperature between 0° and 5° C. After stirring for 30 minutes, 1.1 equivalents of morpholine are added to the filtrate. One equivalent is stirred at room temperature for 2 hours. The precipitate is separated, the filtrate is evaporated under vacuum. The residue is recrystallized.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1.[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(#N)C>[C:15]1([CH3:27])[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])=[CH:13][CH:14]=2)=[O:26])(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCCCOC(=O)c1ccc(N)cc1
Solvent: CC#N
Product: CCCCOC(=O)c1ccc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
A three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser was charged with 15.4 g of n-butyl 4-aminobenzoate and then with 150 ml of acetonitrile. The mixture in the flask was agitated to dissolve the n-butyl 4-aminobenzoate in acetonitrile. To the solution, 17.3 g of p-toluenesulfonylisocyanate were added dropwise through the dropping funnel at room temperature, while the resultant mixture was agitated by a magnetic stirrer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].OCC1C=CC(OC[C@@H](NC(=O)OC(C)(C)C)C)=CC=1>C1COCC1.O.C(N(CC)CC)C.CS(C)=O.C1(C)C=CC=CC=1>[CH:16]([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])=[CH:21][CH:20]=1)=[O:17]
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: C[C@@H](COc1ccc(CO)cc1)NC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of methyl 4-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)benzoate (816 mg) in THF (10 mL) was added a toluene solution (1.0 M, 5.28 mL) of diisobutylaluminum hydride at −78° C., and the mixture was stirred at room temperature for 30 min under an argon atmosphere. Sodium sulfate decahydrate (22.7 g) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was filtered through celite, and the solvent of the filtrate was evaporated under reduced pressure to give a mixture of tert-butyl {(1S)-2-[4-(hydroxymethyl)phenoxy]-1-methylethyl}carbamate and methyl 4-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)benzoate as a pale-yellow oil (813 mg). A mixture of the aforementioned mixture (813 mg) of tert-butyl {(1S)-2-[4-(hydroxymethyl)phenoxy]-1-methylethyl}carbamate and methyl 4-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)benzoate, sulfur trioxide pyridine complex (657 mg), DMSO (7 mL) and triethylamine (3 mL) was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (504 mg).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCCC1.O>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:16])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 2-(4-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (2.0 g, 8.24 mmol) in tetrahydrofuran (16 mL) at room temperature is added water (4 mL) followed by lithium hydroxide monohydrate (0.69 g, 16.4 mmol). The reaction is stirred for 16 h at room temperature. After this time, the mixture is diluted with water and washed with DCM. The aqueous phase is separated, acidified to pH ˜2 with 1M aqueous HCl solution and then extracted with DCM (x2). The combined organic extracts are washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound as a white solid (1.45 g, 82%). 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.62 (6H, s), 6.89 (2H, d, J=9.0 Hz), 7.24 (2H, d, J=9.0 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.CO.[O:46]1[CH2:49][C:48](=O)[CH2:47]1>C(Cl)Cl>[CH:1]1([N:4]2[C:8]3[C:9]([O:28][C@@H:29]([C@@H:31]4[CH2:35][C:34](=[O:36])[NH:33][CH2:32]4)[CH3:30])=[N:10][C:11]([C:13]4[CH:18]=[C:17]5[NH:19][C:20](=[O:27])[C:21]6([CH2:22][CH2:23][N:24]([CH:48]7[CH2:49][O:46][CH2:47]7)[CH2:25][CH2:26]6)[C:16]5=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C1COC1
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCNCC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C32CCN(C3COC3)CC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reaction time: 0.75 h

Procedure:
To a solution of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one: 3.78 (TFA salt) (28 mg) in DCM (2 mL) and MeOH (1 mL) was added oxetan-3-one (4.98 mg, 0.069 mmol) and TEA (1 mL) (to neutralize TFA). The mixture was stirred for 45 minutes then followed by addition of Na(CN)BH3 (5.1 mg, 0.081 mmol). Reaction mixture was stirred for 30 minutes. Reaction was done based on LCMS. The solvent was removed and the residue was purified by prep HPLC (MeCN:water gradient, TFA modified) to provide 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one: (3.79) as a TFA salt.
Reaction SMILES: [CH3:1][C:2]1([C:21]([NH:23][C@H:24]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)[CH3:25])=[O:22])[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1.O[Li].O>>[CH3:1][C:2]1([C:21]([NH:23][C@H:24]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=2)[CH3:25])=[O:22])[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2Cc2ccc(C(F)(F)F)cc2)CC3)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)C1(C)CC2(CCN1Cc1ccc(C(F)(F)F)cc1)CC2)c1ccc(C(=O)O)cc1
Yield: 24.4 %

Procedure:
The title compound (E11) (4.5 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from methyl 4-((1S)-1-(5-methyl-6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)ethyl)benzoate (D130) (19 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10]1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([NH:34][O:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10]1
Reactant: Cc1cccc(CN2CC[C@@H](Nc3ncc(/C=C/C(=O)O)cc3Cl)C2)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(CN2CC[C@@H](Nc3ncc(/C=C/C(=O)NOC4CCCCO4)cc3Cl)C2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
A mixture of A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (410 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (142 mg), HOBt (156 mg) and EDCI (180 mg) in DMF (15 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-(5-chloro-6-([(3R)-1-(3-methylbenzyl)-3-pyrrolidinyl]amino)-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (400 mg).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][CH:22]=1.Cl[CH2:32][CH2:33][CH2:34]/[C:35](=[CH:40]\[C:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]2)=[C:43]([O:53][CH3:54])[CH:42]=1)/[C:36]([NH:38][NH2:39])=[O:37].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(Cl)CCl>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]([NH:39][N:38]2[CH2:32][CH2:33][CH2:34]/[C:35](=[CH:40]\[C:41]3[CH:46]=[CH:45][C:44]([N:47]4[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]4)=[C:43]([O:53][CH3:54])[CH:42]=3)/[C:36]2=[O:37])=[O:30])=[CH:25][CH:26]=1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NN)ccc1-n1cnc(C)c1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C2\CCCN(NC(=O)Cc3ccc(Br)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 45.9 %

Procedure:
EDC (109 mg), HOBT (76.9 mg) and IPEA (408 μL) were added to a mixture of 4-bromophenylacetic acid (102 mg), 5-chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene]-pentanoic acid hydrazide (200 mg) and DMF (4 mL), and the reaction solution was stirred at room temperature for 14 hours. The reaction solution was heated to 80° C. and stirred for two hours. The reaction solution was brought to room temperature. A saturated sodium bicarbonate solution was added, followed by separatory extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=8:1) to obtain the title compound (111 mg). The property value of the compound is as follows.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12]C(C)(C)C)=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2sc(C(=O)O)cc2/C1=C/c1ccc[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
tert-Butyl (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylate (150 mg, 0.47 mmol) was dissolved in dichloromethane (8 ml), cooled to 0° C., treated with trifluoroacetic acid (0.75 ml) and stirred for 2 hours warming to room temperature. The reaction mixture was evaporated to dryness and triturated with diethyl ether to give 70 mg of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylic acid as a red solid. MS(ES): m/e 260 [M+H].
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[C:18]([OH:24])(=[O:23])[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>O.N1C=CC=CC=1>[C:20]([C:19]([C:18]([OH:24])=[O:23])=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)([OH:22])=[O:21]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C(O)C(=Cc1ccc(-c2ccc(-c3cccs3)s2)s1)C(=O)O
Yield: 83.9 %

Procedure:
1.30 g of 5-formyl-2,2':5',2"-terthiophene, 1.04 g of malonic acid, 20 ml of pyridine and 0.1 ml of piperidine were heated at 50°-60° C. for 2 hours. 100 ml of water was added after reaction was completed. The mixture was acidified by diluted HCl and the precipitate collected was recrystallized from ethanol to give reddish crystal (1.43 g). The melting point thereof was 202°-203° C. The yield was 84%.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[OH:34])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.Cl[C:45]1[N:50]=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][C:45]1[N:50]=[CH:49][CH:48]=[CH:47][N:46]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Oc2ncccn2)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) is dissolved in N,N-dimethylformamide (3 ml), and thereto are added 2-chloropyrimidine (45 mg) and potassium carbonate (55 mg), and the mixture is stirred at 85° C. overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=41:9→13:7) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(pyrimidin-2-yloxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (120 mg). MS (m/z): 704 [M+H]+