Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@H:11]1[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)(=[O:24])=[O:23])=[CH:18][CH:17]=3)[C:12]1=[O:31])[CH2:6][CH2:5]2>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@H:11]1[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)(=[O:23])=[O:24])=[CH:18][CH:17]=3)[C:12]1=[O:31])[CH:6]=[CH:5]2
Reactant: O=C1[C@@H](N2CCc3cc(Cl)ccc32)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C1[C@@H](n2ccc3cc(Cl)ccc32)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 50 °C

Procedure:
A suspension of (S)-4-(3-(5-chloroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (11 mg, 0.023 mmol) and activated MnO2 (20 mg, 0.23 mmol) in CH2Cl2 (1.0 mL) was heated to 50° C. for 20 h. After cooling to RT, the reaction mixture was filtered through a syringe filter, concentrated and dissolved in DMSO/MeOH (1:1, 0.8 mL). Purification via reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave (S)-4-(3-(5-chloro-1H-indol-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide. 1H NMR (400 MHz, MeOD-d4) δ 7.83 (d, J=3.8 Hz, 2H), 7.81 (d, J=2.5 Hz, 2H), 7.46 (d, J=2.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.04-6.99 (m, 2H), 6.62 (d, J=4.7 Hz, 1H), 6.43 (d, J=3.2 Hz, 1H), 5.51 (dd, J=8.9, 11.0 Hz, 1H), 3.99 (dd, J=6.1, 9.7 Hz, 2H), 2.75-2.67 (m, 1H), 2.48-2.38 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=473.2; tR=3.21 min.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:9][CH:8]=1
Reactant: OCCOc1ccc(Cl)cc1
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OCCOc1ccc(Cl)cc1
Yield: 48 %

Procedure:
The title compound was prepared by procedures of Example 4 from sulfamoyl chloride and 2-(4-chlorophenoxy)ethanol in 48% yield. A white solid, mp 117°-119° C., was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:20]([OH:21])=[C:19]2[C:14]([CH:15]=[C:16]([C:23]([OH:25])=O)[C:17](=[O:22])[O:18]2)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C=O)C>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:16]3[C:17](=[O:22])[O:18][C:19]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[C:11]([OH:10])[C:20]=4[OH:21])=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: O=C(O)c1cc2ccc(O)c(O)c2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2ccc(O)c(O)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (43.1 μL, 0.25 mmol) was added to 7,8-dihydroxy-3-carboxy-coumarin (50 mg, 0.23 mmol) and HATU (94.1 mg, 0.25 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (47.1 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo for final product: LCMS (ESI) m/z 414 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][O:6][C@H:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[OH:21].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CO.O>[CH:8]([C@@H:5]1[CH2:4][C@@H:3]([OH:21])[C@H:2]([NH:1][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:7][O:6]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: O
Product: Oc1ccc(CN[C@@H]2CO[C@H](C(c3ccccc3)c3ccccc3)C[C@H]2O)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (2S, 4R, 5R)-5-amino-2-benzhydryl-tetrahydro-pyran-4-ol 31a (0.02 g, 0.09 mmol), 4-hydroxybenzaldehyde (0.01 g, 0.09 mmol) and glacial acetic acid (0.005 g, 0.09 mmol) in 1,2-dichloroethane (5 ml) was added portionwise NaCNBH3 (0.007 g, 0.11 mmol) in methanol (1 ml). The reaction was continued for 4 hr. Water was added to quench the reaction and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was stirred with saturated aqueous NaHCO3 and the product was extracted with methylene chloride (3×10 ml). The combined organic phases were washed with brine, water and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography (Hexane/Ethyl Acetate/Triethylamine 3:2:0.2) to give (2S, 4R, 5R)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydropyran-4-ol, (−)-32a, 0.03 g (80%, [α]D=(−)72.6, c=1, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]1([S:19]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Fe].C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([S:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2cccs2)c1
Reactant: ClSc1ccccc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccc(Sc3ccccc3)s2)c1
Reaction time: 96 h
Yield: 21.5 %

Procedure:
A mixture of 89 g (0.46 mole) of 2-(m-chlorophenyl)thiophene, 400 ml of reagent carbon tetrachloride, 54 ml (67 g, 0.46 mole) of benzenesulfenyl chloride and 0.05 g of iron powder was allowed to stand for four days at room temperature. A further 12 ml (15 g, 0.10 mole) of benzenesulfenyl chloride and 0.05 g of iron powder were added. After four days the carbon tetrachloride was removed by distillation. The residue was distilled at reduced pressure to give 30 g (22%) of 2-(m-chlorophenyl)-5-(phenylthio)thiophene, b.p. 200°-205° C. (0.15 mm).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.C(N(CC)CC)C.II.Cl>C(OCC)(=O)C.O1CCCC1.O>[N:4]([CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][CH2:11]1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: II
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](CN=C=S)CC1
Temperature: 25 °C
Reaction time: 44 h

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising trans-4-(aminomethyl)cyclohexanecarboxylic acid (0.24 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 44 hours. The obtained reaction mixture was dropwise added to a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (1.5 mL) was added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the obtained residue, a solvent mixture of hexane (3 mL) and ethyl acetate (3 mL) was added and thoroughly mixed, and the insoluble matter was filtered off. Then, the filtrate was concentrated under reduced pressure to dryness to obtain trans-4-(isothiocyanatomethyl)cyclohexanecarboxylic acid as a ocher solid (0.30 g, yield: 101%, and 1H-NMR spectrum showed no distinct by-product). LC-MS ES-198(retention time: 20.3 min, condition 3).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[NH:16][C:17]([CH3:28])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24](O)=[O:25])[NH:20][C:19]2=[O:27].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.N>CN(C)C=O>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:15]1[NH:16][C:17]([CH3:28])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24]([NH2:35])=[O:25])[NH:20][C:19]2=[O:27]
Reactant: Cc1[nH]c(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c(=O)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(C(N)=O)[nH]c(=O)c12
Yield: 0 %

Procedure:
A mixture of Example 40 (0.05 g, 0.105 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.048 g, 0.126 mmol), N-ethyl-N-isopropylpropan-2-amine (0.092 mL, 0.527 mmol) and 0.5 M ammonia (1.054 mL, 0.527 mmol) in dimethylformamide (1 mL) was stirred at ambient temperature for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. Purification by reverse phase chromatography (C18, CH3CN/10 mM ammonium acetate in water, 10-100% gradient) afforded the title compound (0.011 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ 8.96-9.08 (m, 1H), 8.00 (d, J=2.37 Hz, 1H), 7.96-7.99 (m, 1H), 7.82 (dd, J=8.48, 2.37 Hz, 1H), 7.44-7.63 (m, 3H), 7.28 (s, 1H), 7.18-7.27 (m, 1H), 6.99 (d, J=7.46 Hz, 1H), 3.26 (s, 3H), 2.67 (s, 3H). MS (ESI+) m/z 474 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=[O:2].O.O.O.C([O-])(=O)C.[Na+].CO.C1COCC1>O.C(=O)(O)[O-].[Na+].CCCCCC>[OH:2][NH:1][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccccc1NO
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a stirring solution of ethyl 2-nitrobenzoate (1.0 g, 5.12 mmol), sodium acetate trihydrate (4.18 g, 30.7 mmol) in solvent mixture of MeOH (7 ml) and THF (7 ml) was added stannous chloride dihydrate (3.47 g, 15.37 mmol) slowly at 10-20° C. Reaction mixture was stirred at 25-30° C. for 16 h. Reaction mixture was diluted with water and basified with aq. sodium bicarbonate solution. Product was extracted with ethyl acetate. The organic layer was separated and distilled out to get crude product which was stirred with hexane to get white solid in 80% yield.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH:8]=[CH:9][CH:10]([CH3:13])[CH2:11][CH3:12])[CH:3](O)[CH:4]=[CH2:5].C[O:15][C:16](=O)[CH:17](C=O)[CH3:18]>>[CH3:18][CH:17]([CH2:5][CH:4]=[CH:3][CH:2]([CH3:1])[CH2:7][CH:8]=[CH:9][CH:10]([CH3:13])[CH2:11][CH3:12])[CH:16]=[O:15]
Reactant: COC(=O)C(C)C=O
Reactant: C=CC(O)C(C)CC=CC(C)CC
Product: CCC(C)C=CCC(C)C=CCC(C)C=O
Yield: 76.5 %

Procedure:
55 g (0.3 mole) of 4,8-dimethyl-deca-1,6-dien-3-ol and 46 g (0.4 mole) of α-formyl-propionic acid methyl ester are heated at from 140° to 200° C, whilst stirring, the methanol thereby eliminated is distilled off through a column, and the carbon dioxide eliminated is recorded by a gas flow meter. When the reaction has ceased, the contents of the flask are fractionated. 51 g of 2,6,10-trimethyl-dodeca-4,8-dien-1-al (yield, 77% of theory) are obtained. B.p. = 72° - 75° C at 0.01 mm Hg; nD25 = 1.4566. Odor: sweet, fruity, orange scent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:21])([F:20])[C:15](OCC)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:20])([F:21])[CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
Ethyl (4′-bromobiphenyl-4-yl)(difluoro)acetate (2.8 g, 7.8 mmol) was dissolved in methanol (20 mL), and sodium borohydride (0.59 g, 16 mmol) was added at 0° C., followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and hydrochloric acid (1 M) was added to the residue, which was subsequently extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (2.4 g, 7.7 mmol) as a white solid (yield 99%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]1(C)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([N:2]2[CH2:1][C:3](=[O:4])[N:2]([CH3:1])[C:3]2=[O:4])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN=C=O
Reactant: Cc1ccccc1
Product: CN1C(=O)CN(c2ccccc2)C1=O
Reaction time: 7 h
Yield: 35 %

Procedure:
A mixture of n-phenyl glycine (22.3 grams, 0.15 moles), methylisocyanate (14.2 grams, 0.25 moles) and 30 ml of toluene was stirred at 40°-45° C. for 7 hours and allowed to stand overnight at room temperature (21° C.). The product was collected and washed with toluene, crystallized from toluene and yielded 10.5 grams (35% yield) of the above-identified product having a melting point of about 168°-170° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([CH2:27][N:28]([CH:45]([CH3:47])[CH3:46])[C:29](=[O:44])[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[C@H:24]([CH2:48][N:49]([C:53](=[O:62])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([NH2:61])[CH:56]=2)[CH:50]2[CH2:52][CH2:51]2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>CN(C1C=CN=CC=1)C.C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([CH2:27][N:28]([CH:45]([CH3:47])[CH3:46])[C:29](=[O:44])[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:31]=2)[C@H:24]([CH2:48][N:49]([C:53](=[O:62])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([NH:61][C:8](=[O:10])[CH3:9])[CH:56]=2)[CH:50]2[CH2:51][CH2:52]2)[CH2:23]1)=[O:21])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2cccc(N)c2)C2CC2)C(C)C)ccc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)Cc2cccc(NC(C)=O)c2)C2CC2)C(C)C)ccc1OC

Procedure:
Triethylamine (67 μL, 0.48 mmol), DMAP (0.4 mg, 0.003 mmol) and acetic anhydride (46 μL, 0.48 mmol) are added to a solution of (3R*,4R*)-3-({[2-(3-amino-phenyl)-acetyl]-cyclopropyl-amino}-methyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (215 mg, 0.32 mmol) in THF (20 mL). The reaction mixture is stirred at RT for 16 h before water is added for workup. Extraction with ethyl acetate, drying of the combined extracts (Na2SO4), filtration and evaporation of the solvent affords the crude product which is purified by flash chromatography on silica gel (eluent: CH2Cl2 to CH2Cl2/MeOH 9:1) to give the title compound. MS (LC-MS): 709.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.04 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[OH:42][CH2:43][Sn](CCCC)(CCCC)CCCC.[F-].[NH4+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:42][CH2:43][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39]
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1c(-c2ccc(CO)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 90 °C
Reaction time: 2.7 h
Yield: 23.4 %

Procedure:
4-Trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in 1,4-dioxane (2.4 mL), and the solution was added with hydroxymethyltributyltin (87 mg, 0.27 mmol) synthesized in a similar manner to the method described in Synthetic Communications, 1994, vol. 24, p. 1117, and tetrakis(triphenylphosphine)palladium (12.5 mg, 0.0108 mmol), followed by stirring at 90° C. for 2.7 hours under argon atmosphere. The mixture was further added with tetrakis(triphenylphosphine)palladium (6.3 mg, 0.054 mmol) and stirred for 2.3 hours. Further, the mixture was added with hydroxymethyltributyltin (44 mg, 0.14 mmol), tetrakis(triphenylphosphine)palladium (6.3 mg, 0.0054 mmol) and 1,4-dioxane (1.2 mL), followed by stirring for 4 hours. The reaction mixture was added with 10% aqueous ammonium fluoride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 4-hydroxymethyl-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (15.0 mg, yield 23%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCN2C(=O)c3ccccc3C2=O)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Sodium hydride (60% in oil, 1.78 g, 44.5 mmol) was added in a small portions to a stirred solution of 4-tert-butoxycarbonyl-2-oxopiperazine (8.00 g, 40.0 mmol) in N,N-dimethylformamide (100 ml) at room temperature and the mixture was stirred at room temperature for 1 hour. Then, N-(3-bromopropyl)phthalimide (12.5 g, 46.6 mmol) was added to the mixture. After stirring at room temperature for 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was successively washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (150 g) with hexane-ehtyl acetate (1:1) to give 4-tert-butoxycarbonyl-1-(3-phthalimidopropan-1-yl)-2-oxopiperazine as a colorless oil (9.02 g, 55%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:21]1([NH2:28])[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[C:21]1([NH:28][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[NH:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:10][C:11]=3[CH:17]=2)=[O:19])[CH:26]=[CH:25][C:24]([NH:27][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[NH:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:10][C:11]=3[CH:17]=2)=[O:19])=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Reactant: Nc1ccc(N)cc1
Product: N#Cc1ccc(-c2nc3cc(C(=O)Nc4ccc(NC(=O)c5ccc6[nH]c(-c7ccc(C#N)cc7)nc6c5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 281 was prepared according to the procedure similar to that described in Scheme V from 2-(4-cyanophenyl)benzimidazole-5-carboxylic acid and 1,4-phenylenediamine. [M+H]+ calcd for C36H22N8O2: 599.19; found: 598.97.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:21](=[O:22])[C:20]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:19]=2[F:18])/[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)c1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1c[nH]/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
A mixture of 5-tert-butylthiazol-2-amine (1.93 g, 12.3 mmol) and triethylamine (3.44 mL, 2.46 mmol) in dichloromethane (50 mL) was treated with 2-fluoro-5-(trifluoromethyl)benzoyl chloride (Alfa, 1.87 mL, 12.3 mmol) and stirred at room temperature for 6 hours. The reaction mixture was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to give the title compound (3 g, 71% yield). MS (DCI/NH3) m/z 347 (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.[CH3:29][NH2:30].O>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[NH:30][CH3:29])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Solvent: CCO
Solvent: O
Product: CNc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)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, 15 mL of 33 % methylamine, 5 mL of water, and 5 mL of ethanol was refluxed for 5 hr. The mixture was cooled to room temperature and the solid was collected and washed with ethanol and ether giving 0.45 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-methylamino-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 426.0.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH3:7])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH:8]([C:9]#[N:10])[C:11]#[N:12])[CH3:7])=[CH:13][CH:14]=1
Reactant: CC(=C(C#N)C#N)c1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccc(Cl)cc1)C(C#N)C#N
Temperature: 25 °C
Yield: 56.1 %

Procedure:
First, 3.00 g of (4-chloro-α-methylbenzylidene)malononitrile was dissolved in 20 ml of ethanol, and while stirring at room temperature, a suspension of 0.15 g of sodium borohydride in 5 ml of ethanol was added dropwise, followed by stirring at room temperature for 30 minutes. Then, 10% hydrochloride acid was added to the reaction mixture, which was extracted with diethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.70 g of (1-(4-chlorophenyl)ethyl)malononitrile (the intermediate (6)).