Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>>[C:15](=[O:16])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([CH3:13])[C:8]=1[O:12][C:15](=[O:16])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(C(C)(C)C)cc(O)c1O
Product: Cc1cc(C(C)(C)C)cc(OC(=O)Oc2ccccc2)c1OC(=O)Oc1ccccc1
Yield: 75.2 %

Procedure:
Prepared from 5-tert-butyl-3-methylbenzene-1,2-diol and phenyl chloroformate; purified by recrystallization from ethanol to yield a while solid (75.2%); 1H NMR (500 MHz, CDCl3, ppm): δ 7.35-7.38 (m, 4H), 7.23-7.28 (m, 7H), 7.16-7.17 (m, 1H), 2.36 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1)OCc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2)cn1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of benzyl {4-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (5.99 g, 16.4 mmol) in ethanol (80 mL)/water (16 mL) were added reduced iron (5.8 g, 98.4 mmol) and calcium chloride (1.42 g, 11.5 mmol), and the mixture was heated under reflux for 16 hr. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethanol. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, a solid was precipitated with hexane/ethyl acetate (=2/1, 30 mL) and collected by filtration to give the title compound (4.43 g, 81%). The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (NH silica, hexane/ethyl acetate=3/1→1/3) to give the title compound (0.43 mg, 8%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.[Br:14]Br>C(OCC)C.C(Cl)Cl.C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1
Temperature: 25 °C

Procedure:
The appropriate acetophenone (Intermediate A) was dissolved in diethyl ether, methylene chloride, or chloroform, and cooled to 0° C. Bromine (1.1 equiv) was dissolved in either methylenechloride or diethyl ether and added to the solution of acetophenone via a dropping funnel. After the addition of bromine was complete 2 drops of acetic acid were added and the solution was warmed to room temperature. Solvent was removed under reduced pressure to provide crude 2-bromoacetophenone (Intermediate B) which was generally used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH3:2].N1CCC[C@@H]1C(OCC1C=CC=CC=1)=O>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH3:2]
Reactant: CCN1CCC[C@H]1C(=O)OCc1ccccc1
Agent: O=C(OCc1ccccc1)[C@H]1CCCN1
Product: CCN1CCC[C@@H]1C(=O)OCc1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 107, starting from benzyl (R)-pyrrolidine-2-carboxylate as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.Br[CH2:19][CH2:20][CH3:21].CC(C)([O-])C.[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:17][CH2:19][CH2:20][CH3:21])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2
Reactant: CCCBr
Reactant: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(=O)OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A mixture of (S)-methyl 6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.110 g, 0.366 mmol), 1-bromopropane (0.166 mL, 1.832 mmol), and potassium tert-butoxide (0.103 g, 0.916 mmol) in DMF (3.0 mL) was heated in a sealed tube at 100° C. After 24 h, additional 1-bromopropane (0.166 mL, 1.832 mmol) and potassium tert-butoxide (0.103 g, 0.916 mmol) were added and the mixture was heated in a sealed tube at 100° C. for 24 h. The reaction mixture was cooled to rt and water was added. The mixture was extracted with dichloromethane and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-methyl 6-bromo-2-methyl-5-propoxy-3,4-dihydroquinoline-1 (2H)-carboxylate (0.120 g, 96%) as a colorless oil. MS (ESI, pos. ion) m/z 342, 344 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>N1C=CC=CC=1>[C:20]([C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]([CH2:24][CH3:25])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH2:26][CH3:27])=[O:30])=[CH:6][CH:7]=1)#[N:21]
Reactant: CCN=C=O
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Solvent: c1ccncc1
Product: CCNC(=O)NCCOc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, is combined with ethyl isocyanate (18 μL, 0.21 mmol) and pyridine (300 μL). This mixture is stirred at room temperature for 90 minutes, and is then partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (EtOAc) yields 1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}-3-ethyl-urea (34 mg, 93%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:26]I>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH3:26])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CCCNS(=O)(=O)c1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CI
Product: COC(=O)CCCN(C)S(=O)(=O)c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
(prepared from 4-cyano-4'-[(3-methoxycarbonylpropyl)-aminosulphonyl]biphenyl by methylation with methyl iodide)
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C:3]1=[O:12].CN1CCOCC1.[Cl-].[CH3:21][SiH:22]([CH3:24])[CH3:23].C1(C)C=CC=CC=1>O1CCCC1.O>[CH3:21][Si:22]([CH3:24])([CH3:23])[O:1][C@@H:2]1[C@@H:7]([O:8][Si:22]([CH3:24])([CH3:23])[CH3:21])[C@H:6]([O:9][Si:22]([CH3:24])([CH3:23])[CH3:21])[C@@H:5]([CH2:10][O:11][Si:22]([CH3:24])([CH3:23])[CH3:21])[O:4][C:3]1=[O:12]
Reactant: C[SiH](C)C
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Temperature: 35 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one (85 g, 0.47 mol) was suspended in THF (tetrahydrofuran) (932 mL). To the resulting mixture was added N-methylmorpholine (405 mL, 4.78 mol). Then the resulting mixture was cooled to −5° C. under a nitrogen protection, and TMSCI (trimethylsilane chloride) (360 mL, 4.78 mol) was added dropwise thereto. After the completion of dropwise addition, the resulting mixture was stirred at room temperature for 1 h and at 35° C. for 5 hr. Then the mixture was stirred overnight while the temperature was maintained at 25° C. TLC indicated the completion of reaction. To the reaction mixture was added toluene (200 mL) and added dropwise water (1 L) in an ice-water bath. The organic phase was collected, washed with sodium dihydrogen phosphate for one time, with water for one time, and with a saturated sodium chloride solution for one time, dried and concentrated to produce 218 g of a product in a yield of 100%.
Reaction SMILES: C([S:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])(=O)C1C=CC=CC=1>COCCN>[SH:9][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCC(CSC(=O)c1ccccc1)C(=O)O
Agent: COCCN
Product: O=C(O)CCC(CS)C(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
S-Benzoyl-2-mercaptomethylglutaric acid (2 g, 7.08 mmol) was added with stirring to 2-methoxyethylamine (20 mL) kept at 0°-5° C. The resulting solution was stirred for 2 hours at 0° C. and at 30° C. for 1 hour. The thick viscous liquid was evaporated at 60° C. under vacuum to a transparent gel. The residue was dissolved in oxygen-free water (40 mL) and extracted with three portions of EtOAc. The aqueous fraction was acidified with 18% HCl and reextracted with EtOAc. The EtOAc layer was dried over Na2SO4 and evaporated to a thick gel. The residue was dissolved in a mixture of EtOAc/hexane and cooled to -18° C. overnight. The white precipitate formed was collected by filtration, washed and dried under vacuum at room temperature to yield, 1.16 g (91.8%) of the captioned product (mp 75° C.)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C@H:14]2[CH2:19][N:18]([C:20](=[O:24])[CH:21]([F:23])[F:22])[CH2:17][CH2:16][O:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.Cl.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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:22][CH:21]([F:23])[C:20]([N:18]1[CH2:17][CH2:16][O:15][C@@H:14]([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[N:5][CH:6]=[CH:7][N:8]=3)[CH:3]=[C:2]([C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]4)=[CH:38][CH:39]=3)[N:11]=2)[CH2:19]1)=[O:24]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)cc2)OC1(C)C
Reactant: O=C(C(F)F)N1CCO[C@@H](CNc2nc(Cl)cc3nccnc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(C(F)F)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCNCC4)cc3)cc3nccnc23)C1
Yield: 108.9 %

Procedure:
A solution of (S)-1-(2-((7-chloropyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholino)-2,2-difluoroethanone (70 mg, 0.19 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine hydrochloride (96 mg, 0.29 mmol), Pd(PPh3)4 (45 mg, 0.04 mmol) and Cs2CO3 (191 mg, 0.59 mmol) in 8 mL of dioxane and 0.1 mL of water, under N2, was stirred at 110° C. overnight. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:10˜8:1) to give 100 mg of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([Br:22])[C:18]([F:21])([F:19])[F:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(NN=CC(F)(F)F)cc1SCC(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(NN=C(Br)C(F)(F)F)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
3.6 g (10.3 mmol) of trifluoroacetaldehyde {2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}hydrazone was dissolved in 30 ml of N,N-dimethylformamide, and 2.0 g of N-bromosuccinimide was added at room temperature, followed by stirring at room temperature for 2 hours. The resulting reaction mixture was poured into water and extracted with toluene, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.1 g of N-{2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}trifluoroacetohydrazonoyl bromide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([F:23])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCCCC>O1CCOCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:23][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 70 °C
Yield: 85.9 %

Procedure:
To an ambient temperature solution of 4-(trifluoromethyl)phenylboronic acid (5.05 g, 26.59 mmol) in dioxane/water (15/15 mL) is added 4-bromo-2-fluoro-benzaldehyde (4.91 g, 24.17 mmol), tetrabutylammonium bromide (7.79 g, 24.17 mmol, potassium carbonate (9.18 g, 66.48 mmol) and is degassed for 10 min. Palladium(II) acetate (895 mg, 1.33 mmol) is added and the reaction mixture is heated to 70° C. After 2 h TLC (20% EtOAc/hexane) indicates complete consumption of starting material. The reaction is cooled to room temperature diluted with water and extracted with EtOAc (3×200 mL). The combined organic extracts are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (330 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (5.57 g, 86%). 1NMR (400 MHz, CDCl3) δ ppm: 10.41 (s, 1H), 7.98 (t, 1H, J=7.5 Hz), 7.74 (q, 4H, J=7.8 Hz), 7.52 (d, 1H, J=7.9 Hz), 7.41 (dd, 1H, J=11.2, 1.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.BrBr.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][N:21]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:17][C:16]=1[OH:31].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1COCC1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][N:21]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:17][C:16]=1[O:31][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([CH3:10])=[O:11]
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4-Fluorophenylacetone (388 μl, 2.9 mmol) in DCM (12 ml) was cooled to 0° C. and bromine (672 mg, 2.9 mmol) was slowly added. The mixture was stirred for 30 min and then concentrated in vacuo. The crude intermediate was added to a mixture of 6-chloro-1-(4-fluorophenyl)-1H-indazol-5-ol, (99c) (762 mg, 2.9 mmol) and potassium carbonate (804 mg, 5.8 mmol) in THF (12 ml). The mixture was stirred for 4 h, filtrated and concentrated. The crude product was purified by flash chromatography (EtOAc/heptane, product eluted at 40% EtOAc) to give the title compound (1.06 g, 88%).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([O:21]C)[CH:19]=[CH:20][C:14]=2[C:13]=1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=1)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([C:23]2[C:13]3[C:14]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:15]=4[S:16][C:12]=3[CH:5]=[C:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=[CH:11]3)=[CH:30][CH:29]=1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2c3ccccc3cc3sc4cc(O)ccc4c23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.6 %

Procedure:
Boron tribromide (5 mL, 52.9 mmol) was added slowly to a stirrred solution of (2-benzyl-6-methoxy-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (2.30 g, 5.92 mmol) in dichloromethane (30 mL) at -78° C. under a dry nitrogen atomosphere. The solution was allowed to warm to ambient temperature and was stirred for 4 h. The reaction mixture was quenched with water and partitioned between water and ether. Silica gel was added to the ether phase and the solvent was removed, The adsorbate was flash chromatographed (eluent 7:3 pet. ether:ethyl acetate) to provide the title compound as a white solid (2.08 g, 96%): mp: 197-199° C.; NMR (CDCl3); δ 8.28 (s, 1H), 7.92 (d, J=8 Hz, 1H), 7.59 (dm, J=8 Hz, 1H), 7.50 (ddd, J=8, 7, 1 Hz, 1H), 7.39-7.25 (m, 5H), 7.21 (d, J=2 Hz, 1H), 7.11 (d, J=9 Hz, 2H), 6.69 (d, J=9 Hz, 1H), 6.57 (dd, J=9, 2 Hz, 1H), 5.03 (s, 1H), 4.94 (s, 1H); MS (FAB+): 343 (15%, M+H); Anal. Calc. for C22H14O2S: C, 77.17, H, 4.12, N, 0:00. Found: C, 76.74, H, 4.04, N, 0.02.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:26]>CO.O>[NH2:26][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: N
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C)n2)cc1
Solvent: O
Solvent: CO
Product: Cc1nc(C(O)CNC(C)Cc2ccc(OCC(N)=O)cc2)cs1

Procedure:
1 g (0.0027 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine is dissolved in 5 ml of methanol and stirred with 5 of concentrated ammonia at room temperature for 3 hours. The mixture is then diluted with water and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol =9:1 as eluant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([NH:25][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:24])=[CH:20][N:19]=1)=[O:23])([CH3:30])[CH3:29]
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NC(C)(C)CO)cn1
Yield: 94 %

Procedure:
As described for example 80c, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol), was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (95 mg, 94%) which was obtained as a light yellow gum. MS: m/e=401.3 [M+H]+.
Reaction SMILES: N[C:2]1([NH:35][CH:36]([CH3:38])[CH3:37])[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]1[NH:16][C:17]([C:19]1[C:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C.[Cl:46][CH2:47][C:48](Cl)=[O:49].O>C(Cl)(Cl)Cl>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:16][C:17]([C:19]2[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:2]([N:35]([C:48](=[O:49])[CH2:47][Cl:46])[CH:36]([CH3:38])[CH3:37])[CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)NC1(N)C=C(OCc2ccccc2)C=CC1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)N(C(=O)CCl)c1cc(OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-4-benzyloxy-2-isopropylaminophenyl)amide (140 mg) and triethylamine (42 mg) in chloroform was added chloroacetyl chloride (48 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After addition of water to the reaction solution, it is extracted with chloroform. The extract was dried over sodium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 4′-trifluoromethylbiphenyl-2-carboxylic acid {4-benzyloxy-2-[(2-chloroacetyl)isopropylamino]phenyl}amide (140 mg).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]2[CH2:7][CH2:8][O:9][C:10]3[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[N:13]=1)=[N+:2]=[N-:3].[CH3:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22]>>[Br:18][C:16]1[CH:15]=[CH:14][C:11]2[C:12]3[N:13]=[C:4]([N:1]4[C:21]([C:20]([CH3:24])([CH3:23])[CH3:19])=[CH:22][N:3]=[N:2]4)[S:5][C:6]=3[CH2:7][CH2:8][O:9][C:10]=2[CH:17]=1
Reactant: [N-]=[N+]=Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: C#CC(C)(C)C
Product: CC(C)(C)c1cnnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 414, Step 3, 2-azido-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3,3-dimethyl-1-butyne to afford the title compound as a pale yellow solid. LCMS (Method A): RT=4.95 min, [M+H]+=405 and 407. 1H NMR (CDCl3): 8.16 (1H, dd, J=8.1, 0.9 Hz), 7.55 (1H, s), 7.28 (2H, m), 4.42 (2H, t, J=5.1 Hz), 3.37 (2H, t, J=5.1 Hz), 1.54 (9H, s).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([NH:13][C:14](=[O:25])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[CH3:16])[CH3:12].CC(N)CC.O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([NH:13][C:14](=[O:25])[CH:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:21][CH:22]=1)[CH3:16])[CH3:12]
Reactant: C#Cc1ccc(C(C)C(=O)NCC)cc1
Reactant: CC(C)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)C(C)c1ccc(C#Cc2ccc(C(C)C)cc2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To 0.025 g (0.10 mmol) 4-iodoisopropylbenzene are added 20 g (0.10 mmol) N-ethyl-2-(4-ethynyl-phenyl)-propionamide (XVII.1) in 1 mL THF, followed by the addition of 0.5 mL 2-butylamine and 0.75 mL water. Subsequently 3 mg (0.05 mmol) bis-(triphenylphosphine)-palladium dichloride are added and the mixture is stirred at 80° C. for 5 h. After that time, the solvent is removed. The residue is taken up in DMF and the desired product was purified using RP-HPLC (water/MeOH+0.1% TFA).