Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[O:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:17][C:16]=4[C:12]=3[CH:11]=[C:10]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[B:38]([O:43]C)([O:41]C)OC.Cl>CCCCCC.C(Cl)(Cl)Cl.O1CCCC1>[C:27]1([C:10]2[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([B:38]([OH:41])[OH:43])[CH:7]=[CH:6][CH:5]=3)[C:13]3[O:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:17][C:16]=4[C:12]=3[CH:11]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1cccc(-c2cc(-c3ccccc3)cc3c2oc2ccc(-c4ccccc4)cc23)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OB(O)c1cccc(-c2cc(-c3ccccc3)cc3c2oc2ccc(-c4ccccc4)cc23)c1
Temperature: -80 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
In a 50 mL three-neck flask was put 1.2 g (2.5 mmol) of 4-(3-bromophenyl)-2,8-diphenyldibenzofuran. The air in the flask was replaced with nitrogen. To this mixture was added 15 mL of tetrahydrofuran (THF), and this solution was cooled to −80° C. Then, 1.9 mL (3.0 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, this solution was stirred at the same temperature for 1 hour. Then, 0.56 L (5.0 mmol) of trimethyl borate was added to this solution, and the mixture was stirred for 18 hours while its temperature was returned to room temperature. After that, about 10 mL of diluted hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. Then, the aqueous layer of this mixture was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give a solid, and a mixed solvent of chloroform and hexane was added to the solid. The mixture was irradiated with ultrasonic waves, whereby a solid was precipitated. This solid was collected by suction filtration to give 0.62 g of a light-brown powder in 58% yield, which was the substance to be produced.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:14](=[O:16])[CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:22]Br>C(O)(=O)C>[Br:22][C:15]1[C:14](=[O:16])[C:13]2([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[O:12][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(C2=CC(=O)C3(CCCCC3)O2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCCC3)O2)cc1

Procedure:
50 mg of 2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,5]dec-2-en-4-one was reacted with bromine (0.5 ml) in the presence of 0.1 ml acetic acid to yield 68 mg of 3-bromo-2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,5]dec-2-en-4-one by following a procedure similar to the procedure in Step 5 of Example 53. mp: 163-164° C. NMR: δ1.79 (m, 10H), 3.11 (s, 3H), 8.10 (d, J=8.1 Hz, 2H), 8.40 (d, J=8.1 Hz, 2H). IR (cm−1): 2936, 1709, 1583, 1316, 1149, 912, 744.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([C:32]#[C:33][CH2:34][OH:35])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]>CO.O=[Pt]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:36])=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][OH:35])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C#CCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=[Pt]=O
Solvent: CO
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(CCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 36 h
Yield: 77.3 %

Procedure:
A solution of 3-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenyl)prop-2-yn-1-ol (714 mg, 1.28 mmol) in MeOH (75 mL) was sparged with argon, charged with PtO2 (30 wt %, 214 mg) and then pressurized to 65 psi under hydrogen atmosphere in a Parr shaker for 36 h. The reaction was monitored by LCMS and upon completion the mixture was filtered through Celite™ to remove the catalyst. The filtrate was concentrated and purified by flash chromatography (80% EtOAc/Hex) to yield the title compound (560 mg, 0.99 mmol). MS (EI) m/z 561 (MH+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21].[OH-].[Na+]>>[N+:20]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:3][CH:4]=1)([O-:22])=[O:21]
Reactant: c1ccc(CC2CCCCCN2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(CC2CCCCCN2)cc1
Temperature: 25 °C

Procedure:
Add (drop by drop while stirring at -10° ) 10 g of 2-benzylperhydroazepine to 43 ml of concentrated sulfuric acid. Then, at the same temperature, add 33 ml of concentrated nitric acid to the thus-prepared reaction mixture and allow it to heat slowly to room temperature. Stir it for a further hour. Pour the resulting admixture into 500 g of ice, alkalize it with 6 N caustic soda solution and then extract it with diethyl ether. Dry the organic phase over sodium sulfate and distil off the solvent from the dried organic phase to obtain 12.0 g (97% of theory) of the title compound as a red oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:26])([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[S:35]([N:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:26])([C:14]([F:16])([F:17])[F:15])[C:18]#[C:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:9][CH:8]=1)(=[O:37])=[O:36]
Reactant: OC(C#Cc1ccccc1)(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(c1cc(Cl)ccc1Cl)N(c1ccc(C(O)(C#Cc2ccccc2)C(F)(F)F)cc1)C1CCCC1
Temperature: 70 °C

Procedure:
A mixture of 53 mg of 2-(4-cyclopentylamino-phenyl)-1,1,1-trifluoro-4-phenyl-but-3-yn-2-ol (0.15 mmol) and 44 mg of 2,5-dichlorobenzenesulfonyl chloride (0.18 mmol) in 0.2 ml of pyridine was heated to 70° C. for 14 hours. After this time the reaction mixture was allowed to cool to room temperature, quenched by the addition of a saturated aqueous solution of ammonium chloride, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 1.36–1.58 (m, 6H), 1.97–2.07 (m, 2H), 4.73–4.78 (m, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.37–7.55 (m, 7H), 7.76 (d, J=8.4 Hz, 2H), 7.84 (d, J=2.4 Hz, 1H). Mass Spectrum (CI+) m/e=590.0 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[C:12]([OH:16])[CH:11]=[CH:10][C:9]=2[F:17].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:41])[C@@H:38](Cl)[CH3:39]>O>[CH3:35][O:36][C:37](=[O:41])[C@H:38]([O:16][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]2[C:13]=1[C:14]([CH3:15])=[C:5]([CH2:4][C:3]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=1[Cl:1])[C:6](=[O:18])[NH:7]2)[CH3:39]
Reactant: COC(=O)[C@H](C)Cl
Reactant: Cc1c(Cc2ccc(Cl)cc2Cl)c(=O)[nH]c2c(F)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)Oc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.30 g), N,N-dimethylformamide (4.0 mL), potassium carbonate (0.13 g) and (S)-2-chloropropionic acid methyl ester (0.11 g) was stirred at 45° C. for 3 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 6:4 by volume) to afford title compound as a pale peach solid, 0.17 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1>C(O)C>[ClH:1].[F:30][C:31]1([F:35])[CH2:34][N:33]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[C:12](=[O:13])[C:11]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[CH:10][NH:9]3)[CH:3]=2)[CH2:32]1
Reactant: O=c1c(-c2cccnc2)c[nH]n1-c1cc(Cl)ncn1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(N2CC(F)(F)C2)ncn1
Reaction time: 0.5 h

Procedure:
100 mg (0.4 mmol) of the compound from Example 23, 94 mg (0.7 mmol) of N,N-diisopropylethylamine and 95 mg (0.731 mmol) of 3,3-difluoroazetidine hydrochloride are suspended in 3 ml of ethanol and reacted at 120° C. in a single-mode microwave oven (CEM Explorer) for 40 min. The solvent is then removed, and the residue is taken up in 6 ml of DMSO. Undissolved components are removed by filtration, and the solution obtained is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined and concentrated on a rotary evaporator, and the residue is dried under high vacuum. The residue is then stirred in 5 ml of a 4 N solution of hydrogen chloride in dioxane for 30 min. The solid is filtered off, washed with tert-butyl methyl ether and dried under high vacuum.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]>O1CCCC1.O.Cl>[CH3:1][S:2]([O:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(OCCc2ccc(OCc3ccccc3C(=O)O)cc2)cc1
Yield: 7.7 %

Procedure:
Methyl 2-{[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (0.18 g, 0.38 mmol) was dissolved in a mixture of tetrahydrofuran and water 7:1 (5 ml). The reaction was performed in a single node microwave oven (150° C. in 7 minutes). The mixture was diluted with HCl (2 ml, 1 M) and the organic phase was isolated. The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 13 mg of 2-{[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]-methyl}benzoic acid (yield 7.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:39])[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:5](=[O:6])[C:4]3[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[CH:3]=3)=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:36][CH2:37][CH3:38])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccc(F)c(F)c3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Difluoro-benzoyl chloride (45 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H31F2N3O3+H: 520, observed: 520.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:40][C:41](=[O:50])[CH2:42][N:43]1[CH2:49][CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH3:39]>>[CH2:38]([O:40][C:41](=[O:50])[CH2:42][N:43]1[CH2:49][CH2:48][CH2:47][N:46]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:45][CH2:44]1)[CH3:39]
Reactant: CCOC(=O)CN1CCCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOC(=O)CN1CCCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with homopiperazine-acetic acid ethyl ester to give 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-1-yl}-acetic acid ethyl ester. The ester was hydrolyzed, then the corresponding acid was treated with amonium chloride to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2927.
Reaction SMILES: FC(F)(F)C1C=C[C:6]([C:7](O)=[O:8])=[CH:5]C=1.[O:14]([C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:20]=2[CH2:5][CH2:6][C:7]3=[O:8])=[N:26][CH:25]=1
Reactant: Nc1ccc(Oc2ccccc2)nc1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-(trifluoromethyl)benzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-phenoxy-3-pyridinylamine obtained in Reference Example 32 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain. the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].Cl>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-phenoxybenzoate (0.220 g, 0.487 mmol) was dissolved in a mixed solution of an aqueous 1N NaOH solution (3 ml) and 1,4-dioxane (5 ml) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was diluted with water, rendered acidic with concentrated hydrochloric acid and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the titled compound (0.210 g, 0.479 mmol, 98%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:38][C:39]1[N:40]=[C:41]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[C:42]2[S:47][CH:46]=[CH:45][C:43]=2[N:44]=1.C(C1CCN(C(OC(C)(C)C)=O)CC1)=O>ClCCl>[Cl:38][C:39]1[N:40]=[C:41]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[C:42]2[S:47][C:46]([CH:2]([OH:1])[CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)=[CH:45][C:43]=2[N:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reaction time: 2 h
Yield: 21 %

Procedure:
Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1 g) in 20 mL of dichloromethane was combined with 2 g of Dess-Martin periodinane and stirred for 2 h, filtered through celite, extracted with saturated sodium bicarbonate, and evaporated. The crude product was placed on a column and 325 mg of the aldehyde, tert-butyl 4-formylpiperidine-1-carboxylate, was isolated. 260 mg 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 was reacted with 325 mg of tert-butyl 4-formylpiperidine-1-carboxylate following General Procedure D to give 100 mg of tert-butyl 4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(hydroxy)methyl)piperidine-1-carboxylate. The Boc group was removed from 100 mg of the alcohol using 0.125 mL of a 4.0 M HCl solution in dioxane in 10 mL of DCM with 0.5 mL of methanol. After several hours the DCM, methanol, and HCl was evaporated. The crude amine, (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)(piperidin-4-yl)methanol, was mesylated in 3 mL of DCM and 0.04 mL of triethylamine with 0.03 mL of methanesulfonyl chloride. The 4-N-methylsulfonylpiperidinyl compound was then coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 following General Procedure A to give 70 mg of 353 after reversed phase HPLC purification. MS (Q1) 530 (M)+
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11]#[N:12])=[CH:6][CH:5]=1)[CH3:3].[F:17][C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[CH:24][N:23]([CH2:26][C:27](O)=[O:28])[C:22]=2[C:30]=1[F:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CC#N.O>[C:11]([C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:2]([NH:1][C:27](=[O:28])[CH2:26][N:23]2[C:22]3[C:30]([F:31])=[C:18]([F:17])[CH:19]=[CH:20][C:21]=3[N:25]=[CH:24]2)[CH3:3])=[CH:5][CH:6]=1)([CH2:13][CH3:14])[CH2:15][CH3:16])#[N:12]
Reactant: CCC(C#N)(CC)c1ccc(C(C)N)cc1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCC(C#N)(CC)c1ccc(C(C)NC(=O)Cn2cnc3ccc(F)c(F)c32)cc1
Reaction time: 2 h

Procedure:
2-[4-(1-Aminoethyl)phenyl]-2-ethylbutanenitrile (520 mg, 2.41 mmol) prepared according to scheme 24, (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (510 mg, 2.41 mmol) prepared according to scheme 2 and Et3N (731 mg, 7.22 mmol, 1.00 mL) are mixed in MeCN (15.0 mL). HATU (915 mg, 2.41 mmol) is added and the mixture is stirred for 2 hours. 1N NaOH (40.0 mL) is added, and the aqueous phase is extracted with EtOAc (4 times 40.0 mL). The combined organic phases are dried with MgSO4, filtered and concentrated on the rotovaporator. The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (50 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (804 mg, 1.96 mmol, 81%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.77 (t, J=7.32 Hz, 6H) 1.40 (d, J=7.03 Hz, 3H) 1.83-2.13 (m, 4H) 4.96 (ddd, J=14.65, 7.23, 7.03 Hz, 1H) 5.08 (s, 2H) 7.21 (ddd, J=11.57, 8.93, 7.62 Hz, 1H) 7.35-7.41 (m, 4H) 7.45 (ddd, J=8.84, 3.86, 0.78 Hz, 1H) 8.19-8.22 (m, 1 H) 8.83 (d, J=8.01 Hz, 1H); MS [M+H], calcd: 411.0. found: 411.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:18]([OH:20])=O.Cl.[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@@H:37]([NH2:44])[C:38]3[O:42][N:41]=[C:40]([CH3:43])[N:39]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@@H:37]([NH:44][C:18]([C:4]3[CH:5]=[C:6]([C:9]4[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=4)[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:20])[C:38]3[O:42][N:41]=[C:40]([CH3:43])[N:39]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C(=O)O
Agent: Cl
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 69.7 %

Procedure:
4-Methoxy-4′-nitro-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.045 g) was prepared from 4-Methoxy-4′-nitro-biphenyl-3-carboxylic acid (0.03 g, 0.11 mmol) and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride salt (0.04 g, 0.11 mmol) following general procedure A
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[CH3:36][O:37][C:38](=[O:44])[C@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1>>[CH3:36][O:37][C:38]([C@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])=[O:44]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1CCCN1
Product: COC(=O)[C@H]1CCCN1C(=O)SCCN
Yield: 103.8 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (675 mg) and D-proline methylester (0.18 g) were subjected to similar reactions to those described in References 2 and 4 to give 2-[(R)-2-methoxycarbonylpyrrolidino]carbonylthioethylamine (crude formate: 336 mg). The product was dissolved in anhydrous methanol (6 ml). To the solution were added triethylamine (1.01 ml) and mitomycin A (338 mg: 0.8 molar equivalent). The solution was then treated in a similar manner to that described in Example 1 to obtain Compound 32 (286 mg) in the form of grayish blue powders with a yield of 43%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:18]1[N:23]=[C:22]([C:24]([OH:28])([CH3:27])[CH2:25][OH:26])[CH:21]=[CH:20][CH:19]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[S:3][C:2]([NH:1][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:24]([OH:28])([CH3:27])[CH2:25][OH:26])[N:23]=3)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=2)=[CH:11][CH:12]=1
Reactant: CC(O)(CO)c1cccc(Br)n1
Reactant: NC(=O)c1cc(-c2ccc(Cl)cc2)sc1N
Product: CC(O)(CO)c1cccc(Nc2sc(-c3ccc(Cl)cc3)cc2C(N)=O)n1

Procedure:
The title compound was prepared by using the procedure described in Example 1 with 2-amino-5-(4-chlorophenyl)thiophene-3-carboxamide (240 mg, 0.95 mmol) and 2-(6-bromopyridin-2-yl)propane-1,2-diol (200 mg, 0.86 mmol) as the starting materials.