Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=1)(=O)=O.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[C:29]([C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=2)[CH:38]=[CH:37][CH:36]=1)=[O:33]
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(C2=CCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
To a solution of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (300 mg, 0.95 mmol) in dioxane (4 mL) and H2O (1 mL) was added methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (298 mg, 1.13 mmol), Pd(dppf)Cl2 (66 mg, 0.09 mmol) and K2CO3 (392 mg, 2.84 mmol) at 27° C. The mixture was stirred at 100° C. for 16 h. The catalyst was filtered, the filtrate was concentrated and the residue was purified by column chromatography to give the title compound (213 mg, Yield 74.2%). 1H NMR (CDCl3, 400 MHz): δ 8.03 (d, J=19.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.55 (dd, J=15.7, 7.8 Hz, 1H), 7.38-7.45 (m, 1H), 6.22 (dt, J=16.4, 1.8 Hz, 1H), 4.43-4.58 (m, 2H), 4.24-4.38 (m, 2H), 3.88-3.96 (m, 3H), 1.51 (d, J=7.9 Hz, 9H).
Reaction SMILES: O.[OH-].[Li+].[O:4]=[S:5]1(=[O:25])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[CH2:7][CH2:6]1>O.C1COCC1.CO>[O:4]=[S:5]1(=[O:25])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2CCS(=O)(=O)c3ccccc32)cc1
Yield: 98 %

Procedure:
Lithium hydroxide hydrate (0.195 g, 4.65 mmol) dissolved in water (1 mL) was added to a solution of methyl 4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoate from reaction 33d (0.49 gm, 1.55 mmol) in THF (5 mL) and methanol (1 mL) under nitrogen atmosphere at room temperature. The reaction was stirred over night, concentrated then partitioned between 1 N HCl and ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give 4-(1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)benzoic acid (0.46 g, 98%) as an solid. MS found: (M−H)+=301.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:19]>C(O)C.N1CCCCC1>[CH2:36]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide as a yellow solid (74.4 mg, 61%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CS(C)=O.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>[F:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([F:17])[CH:23]=2)[N:7]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1cccc(CNc2cncc(Cl)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: COCCOC
Product: Fc1cccc(CNc2cncc(-c3ccnc(F)c3)n2)c1
Temperature: 110 °C
Yield: 41 %

Procedure:
To 6-chloro-N-(3-fluorobenzyl)pyrazin-2-amine (140 mg, 0.589 mmol) was added 2-fluoropyridin-4-ylboronic acid (125 mg, 0.884 mmol), PalladiumTetrakis (82 mg, 0.071 mmol), DME (3.3 ml), and 2M sodium carbonate (1.031 ml, 2.062 mmol). The resulting reaction mixture was stirred at 110° C. until completion as indicated by LCMS, about 3 hours. The reaction mixture was cooled to room temperature, diluted with 20 ml of ethyl acetate, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, filtered and purified by prep LC. After lyphilization, 72 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 299.1 (MH+), retention time=0.89 min.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1.O[C@@H]1CCN(C(OC(C)(C)C)=O)C1>>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OCc2cc(F)ccc2Br)C1
Agent: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cc(F)ccc2Br)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 216, starting from tert-butyl(R)-3-hydroxy-pyrrolidine-1-carboxylate.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=O.[NH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:2])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (64 mg, 0.14 mmol), glycine (3.42 g, 46 mmol) and NaOMe solution (69 mL, 35 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product obtained was further purified by silica gel chromatography (0-10% MeOH/EtOAc) to give 25 mg of the title compound. MS: (+) m/z 507.14 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][CH:5]=1.[Na+].[CH3:17][S:18]([O-:20])=[O:19]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCS(C)(=O)=O)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C starting from 4-(3-bromo-propoxy)-benzoic acid methyl ester and methanesulfinic acid sodium salt using DMF as solvent. MS (ES+) 273.1.
Reaction SMILES: NC1C=CC(C2CCC(C(OC)=O)C2)=CC=1.C(OC([NH:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36])=O)C1C=CC=CC=1.CCO>CCOC(C)=O>[NH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1cccc(OCCCNC(=O)OCc2ccccc2)c1
Agent: COC(=O)C1CCC(c2ccc(N)cc2)C1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cccc(OCCCN)c1

Procedure:
Following the procedure described for methyl 3-(4-aminophenyl)cyclopentanecarboxylate, replacing methyl 3-(4-nitrophenyl)cyclopentanecarboxylate (Intermediate 84 (i)) with methyl 3-(3-{[(benzyloxy)carbonyl]amino}propoxy)benzoate and using EtOAc as solvent instead of EtOH the title compound was obtained; 1H NMR δ 1.77-1.83 (2H, m), 2.70 (2H, t), 3.86 (3H, s), 4.09 (2H, t), 7.21-7.23 (1H, m), 7.43 (2H, t), 7.54 (1H, d); MS m/e MH+ 210.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7](C2SC(=S)N(C)C2=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].N.C=O.[S:27]1[CH:31]=C[CH:29]=[C:28]1[C:32]([NH2:34])=[O:33]>C(O)(=O)C.O.CO>[CH3:14][C:12]([C:9]1[CH:8]=[C:7]([CH2:29][CH:28]2[S:27][CH2:31][NH:34][C:32]2=[O:33])[CH:6]=[C:5]([C:2]([CH3:3])([CH3:4])[CH3:1])[C:10]=1[OH:11])([CH3:15])[CH3:13]
Reactant: CN1C(=O)C(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S
Reactant: NC(=O)c1cccs1
Agent: C=O
Agent: N
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(CC2SCNC2=O)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To 3.22 g (9.2 mmol) of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]}-methyl-2-thioxo-4-thiazolidinone, in a 25 mL pressure tube equipped with magnetic stir bar, 13 mL of methanol was added. The resulting reaction mixture was cooled to 0° C. and ammonia gas (1.6 g, 91 mmol) was slowly added. Formalin (0.76 mL, 0.8 g, 10 mmol) was then added. The pressure tube was sealed and heated to 80° C. for approximately 17 hours with stirring. Reaction was deemed complete when the amount of thiolamide was below 4%, as determined by HPLC. Deionized water (12 mL) was then added in a drop-wise manner, followed by acetic acid (6 mL). After 30 min, the reaction mixture was cooled to 0° C. for 1 hour. The reaction mixture was filtered and the resulting crystalline product was dissolved in ethyl acetate (5 vol). Dissolution was facilitated by heating to 66° C. The resulting solution was filtered and seeded with a small amount of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl-4-thiazolidinone as the solution was slowly cooled to ambient temperature. Crystallization ensued and the resultant slurry was stirred for approximately 4 hours. The slurry was concentrated under reduced pressure (1 vol ethyl acetate) and stirred for an additional 16 hours. The slurry was filtered and the wet cake was washed with water (2×10 mL) and 1/4 ethyl acetate/hexane (2×10 mL). The product was dried in an oven at 50° C. to obtain 2.07 g (70% yield) of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.[OH-].[K+].Br[CH2:20][CH3:21]>CS(C)=O>[CH2:20]([N:9]1[C:6]2=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[CH:11]=[C:10]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:21]
Reactant: CCBr
Reactant: CCOC(=O)c1cc2cc(OC)cnc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2cc(OC)cnc2n1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (150 mg, 0.68 mmol available, for example, from Shanghai Haoyuan Chemexpress Co., Ltd) in DMSO (4 ml) was added powdered potassium hydroxide (115 mg, 2.04 mmol) followed by bromoethane (0.071 ml, 0.95 mmol). The mixture was stirred at rt for 2 hr then further bromoethane (0.020 ml) was added and the mixture stirred for a further 18 hr. The reaction was quenched by the addition of water then partitioned between water and diethyl ether. The organic phase was washed with water then passed through a hydrophobic frit and finally concentrated under reduced pressure to give the product as an orange/brown oil. The crude material was purified with column chromatography (eluted with DCM and ethyl acetate from 0 to 10%) to give the title compound as clear oil (60 mg, 36%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)=[N:7]2.[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]4[S:13][CH:14]=[CH:15][N:16]=4)=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Clc1ccnc2nc(-c3nccs3)ccc12
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(-c2ccnc3nc(-c4nccs4)ccc23)ccc1F
Yield: 59 %

Procedure:
This was prepared in 59% yield from 5-chloro-2-(thiazol-2-yl)-[1,8]naphthyridine (from step a) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (from Example 2, step e) using a similar procedure to that described in Example 55, step a. δH (400 MHz, CDCl3) 7.45 (1H, t, J 9.0), 7.51 (1H, d, J 4.3), 7.54 (1H, td, J 7.4, 1.2), 7.58 (1H, d, J 3.1), 7.60-7.63 (3H, m), 7.71 (1H, td, J 7.4, 1.2), 7.84 (1H, dd, J 7.4, 1.2), 8.02 (1H, d, J 3.1), 8.48 (1H, d, J 8.6), 8.54 (1H, d, J 8.6), 9.46 (1H, d, J 4.7). m/z (ES+) 409 [MH]+.
Reaction SMILES: C(OC([N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22]3[O:23][C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][C:26](=[O:28])[CH:27]=3)[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:29]1([C:24]2[O:23][C:22]([C:17]3[C:16]4[S:15][C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:21]=4[CH:20]=[CH:19][CH:18]=3)=[CH:27][C:26](=[O:28])[CH:25]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2Sc2c(-c3cc(=O)cc(N4CCOCC4)o3)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(-c2cccc3c2Sc2ccccc2N3)oc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-phenothiazine-10-carboxylic acid tert-butyl ester (3.65 g, 7.63 mmol), in CH2Cl2 (30 ml) was added trifluoroacetic acid in a single portion. The mixture was stirred at room temperature for 20 hours whereupon the reaction was concentrated in vacuo to give a thick syrup that was basified in a dropwise fashion with saturated NaHCO3 (40 ml). The dark green mixture was then stirred at room temperature for 18 hours. The mixture was filtered and the filtrant retained, washed with water and dried to give the title compound as a dark green solid (2.89 g, 83.74% over 3 steps) m/z (LC-MS, ESP): 479 [M+H]+, RT=4.05 mins.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1cccc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Potassium hydroxide (0.42 g) was added to 4-hydroxyindole (1.00 g) in DMF (25 ml), and the solution was stirred at room temperature for 15 minutes. Benzyl bromide (1.00 ml) was added to the solution, and the solution was stirred at room temperature for 1.5 hours. Since the reaction was not completed, benzyl bromide (0.20 ml) was further added and the solution was stirred for 5 hours. After removing the solvent under reduced pressure, water (50 ml) was added to the residue and the resultant was extracted with ether (3×50 ml). The organic layers were washed with saturated brine, and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained crude product was purified by silica gel column chromatography to obtain the desired product (1.43 g, yield: 85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.N1C=CC=CC=1C1C=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:9]2[CH2:11][CH2:10]2)[C:4](=[O:8])[CH:3]=1
Reactant: OB(O)C1CC1
Reactant: O=c1cc(Br)cc[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Product: O=c1cc(Br)ccn1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask charged with a stir bar, 4-bromo-1H-pyridin-2-one (1.80 g), cyclopropylboronic acid (2.00 g), Cu(OAc)2 (2.00 g), 2,2′-bipyridine (1.70 g), Na2CO3 (2.47 g), and 1,2-dichloroethane (75 mL) was heated to 70° C. and the mixture was stirred at this temperature in air overnight. Then, another portion of cyclopropylboronic acid (0.50 g) and Na2CO3 (0.55 g) were added and the mixture was further stirred at reflux temperature for another 4 h. After cooling to ambient temperature, aqueous NH4Cl solution was added and the resultant mixture was extracted with dichloromethane. The combined organic extracts were dried (MgSO4) and the solvent was evaporated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 50:50->35:65) to afford the title compound as an oil that crystallized on standing. Yield: 0.82 g (37% of theory); Mass spectrum (ESI+): m/z=214/216 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:29]([CH3:31])[CH3:30])[C:9]2[C:14]3[N:15]([CH3:28])[C:16](=[O:27])[N:17](CC4C=CC(OC)=CC=4)[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:29]([CH3:31])[CH3:30])[C:9]2[C:14]3[N:15]([CH3:28])[C:16](=[O:27])[NH:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c3c(N(c4ccc(Cl)cc4)C(C)C)cccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(c1ccc(Cl)cc1)c1cccc2[nH]c(=O)n(C)c12
Temperature: 65 °C
Reaction time: 19 h
Yield: 47.1 %

Procedure:
To a mixture of 7-[(4-chlorophenyl)(isopropyl)amino]-3-(4-methoxybenzyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (80 mg, 0.18 mmol) and trifluoroacetic acid (3 ml) was stirred at 65° C. for 19 h. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (30 ml). The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was flash chromatographed eluting with a 33% ethyl acetate/hexanes to give 26.8 mg (34%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)(=[O:13])=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH4+].[Cl-]>CO.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[CH:15]=2)(=[O:12])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(S(=O)(=O)c2ccc([N+](=O)[O-])c(C)c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(S(=O)(=O)c2ccc(N)c(C)c2)c1
Yield: 93.1 %

Procedure:
0.29 g (0.00086 mol) of 1-(3,5-dimethoxyphenylsulphonyl)-3-methyl-4-nitrobenzene was suspended in a mixture of 10 ml of methanol and 10 ml of water, treated with 0.30 g of iron powder and 0.30 g of NH4Cl and heated at reflux for 1.5 hrs. After cooling the mixture was diluted with 50 ml of methanol, treated in an ultrasound bath for a short time and suction filtered. The filter material was washed with a large amount of methanol and the filtrate was concentrated. The residue was suspended in water and treated in an ultrasound bath. The precipitate which thereby resulted was filtered off under suction and chromatographed on silica gel with ethyl acetate/hexane 1:1. There was obtained 0.246 g (92.5%) of 4-(3,5-dimethoxybenzenesulphonyl)-2-methyl-phenylamine as yellow coloured crystals; m.p.: 121-123° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[O:6]=[C:2]([CH3:1])[CH2:3][C:4]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][CH:18]=1)=[O:5]
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(=O)CC(=O)Nc1ccc(Nc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Diketene (160.13 g, 1.904 mol) and a solution of N-phenyl-p-phenylenediamine (344.00 g, 1.867 mol) in 40% strength acetic acid (1300.00 g) were simultaneously added dropwise at 60° C. in the course of about 4.5 h to 40% strength acetic acid (300.00 g). After addition of the starting materials had taken place, the reaction mixture was stirred at 65° C. for 30 min and then cooled to 15° C. The resulting precipitate was filtered off on a suction filter, washed with 40% strength acetic acid (2×200 g) and with water (2×200 g) and dried at 50° C. in vacuo (20 mbar). 415.31 g (95.3% content, 79% yield) of 3-oxo-N-[4-(phenylamino)phenyl]butyramide were obtained as a light grey solid. Mp: 89.5° C.;
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:27]([C:38]([O:40][CH2:41][CH:42]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[C@H:28]([C:35](O)=[O:36])[CH2:29][O:30]C(C)(C)C.C[N:56]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(#N)C.O.C(N(CC)CC)C>[NH2:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)/[C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:38]([NH:27][C@H:28]([C:35]([NH2:56])=[O:36])[CH2:29][OH:30])([O:40][CH2:41][CH:42]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: NC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile hydrochloride (1,007 mg, 2.65 mmols), 1,105 mg of Fmoc-L-Ser(OtBu)OH, 1,370 mg of a BOP reagent and 618 mg of HOBt.H2O were dissolved in 50 ml of acetonitrile, and 0.8 ml of triethylamine were added thereto. The mixture was reacted at 60° C. for 42 hours. One-hundred milliliters of water and a small amount of sodium hydrogencarbonate were added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified using a silica-gel column (eluent, mixture of ethyl acetate and hexane at a ratio of 2:3), and then concentrated to produce 1,486 mg (2.14 mmols) of the final product in a yield of 81%.