Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([CH3:12])[C:3]=1[Cl:13].[OH-].[Na+]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:12])[C:3]=1[Cl:13]
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N)ccc(Br)c1Cl

Procedure:
A solution of N-(4-bromo-3-chloro-2-methyl-phenyl)-acetamide (3.37 g, 12.80 mmol) in H2SO4: H2O (1:1) was refluxed for 3 hours. The reaction mixture was cooled to room temperature and neutralized with NaOH and extracted with Et2O (3×150 mL). The combined organic phases were washed with H2O (3×100 mL) and brine (1×100 mL), then dried over MgSO4 and concentrated. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded the title aniline. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 2.31 (s, 3H), 3.93 (br s, 2H), 6.47 (d, J=8.79 Hz, 1H), 7.24 (d, J=7.91 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:27]3[S:31][CH:30]=[N:29][CH:28]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:37][CH3:38].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:27]3[S:31][CH:30]=[N:29][CH:28]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCCCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCCC#Cc1cncs1)C(C)(C)C)CC2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
A solution of 300 mg of 17g in 3 ml of dioxane was mixed with 130 mg of KOH in 1 ml of water. The mixture was stirred at 50° C. for 1.5 hr, cooled, diluted with 20 ml of water, acidified to pH3 (0.2N HCl) and extracted with ethyl acetate. The extract was washed twice with water, dried and concentrated, to give 240 mg of acid 17h as a colorless foam.
Reaction SMILES: C(OC(=O)COC1C=CC(Cl)=CC=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])(C)(C)C.Br[C:24]1[CH:29]=[C:28]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=1[CH3:36]>>[CH3:19][Si:18]([CH3:21])([CH3:20])[C:17]#[C:16][C:24]1[CH:29]=[C:28]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=1[CH3:36]
Reactant: CCCS(=O)(=O)c1ccc(C)c(Br)c1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Product: CCCS(=O)(=O)c1ccc(C)c(C#C[Si](C)(C)C)c1
Yield: 75 %

Procedure:
Following the general method as outlined in Intermediate 2, starting from 2-bromo-1-methyl-4-(propylsulfonyl)benzene (Intermediate 37) and trimethylsilylacetilene, the title compound was obtained as a brown liquid in 75% yield.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:38]=[CH:37][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]2)=[CH:16][CH:15]=1.[S:39]1[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C1(C)C=CC=CC=1>[S:39]1[CH:43]=[CH:42][C:41]([CH2:44][O:13][C:14]2[CH:38]=[CH:37][C:17]([CH2:18][N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:20]3)=[CH:16][CH:15]=2)=[CH:40]1
Reactant: OCc1ccsc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccsc3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A toluene solution (1.74 g) of 40% diethyl azodicarboxylate was added dropwise slowly to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), 3-thiophenemethanol (0.236 ml), triphenyl phosphine (984 mg), and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred overnight at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(3-thienylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (629 mg, yield: 56%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:10][C:11]([CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].Br[CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([C:4]1([NH:10][C:11](=[O:12])[CH:13]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:5][CH2:6][N:7]([CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:8][CH2:9]1)#[N:3]
Reactant: O=C(O)CCCBr
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(CCCC(=O)O)CC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethyl]-amide hydrochloride and 4-bromo-butyric acid in the presence of a hindered tertiary amine base such as Hunig's base in a solvent such as methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:37])[CH2:18][NH:19]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C>[NH2:19][CH2:18][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:14]=1)=[O:37]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of #B118 (7.0 g, 14.0 mmol, 1.0 eq) in DMF (70 mL) was added piperidine (4.7 mL, 47.5 mmol, 3.4 eq.) at room temperature. The mixture was stirred at room temperature for 30 min, evaporated in vacuo. The residue was washed with petroleum ether (100 mL×2) and re-crystallized from EtOAc (50 mL) and petroleum ether (200 mL) to gave #B119 (3.3 g, 84.6%) as a white solid. 1H NMR (400 Hz, CDCl3): δ 9.37 (s, 1H), 7.57 (d, 2H), 7.25 (d, 2H), 4.80 (br, 1H), 4.27 (d, 2H), 3.47 (s, 2H), 1.45 (s, 9H)
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:15]#[N:16])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:37]>C1COCC1>[Br:37][CH2:2][C:3]1[CH:4]=[C:5]([C:15]#[N:16])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: N#Cc1cc(CO)ccc1-c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cc(CBr)ccc1-c1ccccc1
Reaction time: 16 h

Procedure:
5-Hydroxymethyl-biphenyl-2-carbonitrile from step 3 (1.3 g, 6.2 mmol) was dissolved in THF (31 ml) and treated with Ph3P (2.4 g, 9.3 mmol) followed by CBr4 (3 g, 9.3 mmol). The reaction was mixture stirred at room temp. for 16 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C(Cl)(Cl)Cl.[Br:14]Br.S(=O)(O)[O-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([Br:14])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1F
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(Br)cc1F
Temperature: 10 °C
Yield: 93.9 %

Procedure:
Into a flask of 5 l were charged 384 g (3.04 mol) of 2-fluoroanisole and 2.5 l of chloroform, to which was added dropwise 504 g (3.16 mol) of bromine over about 3 hours while cooling on an ice water bath at 10° C. The resulting mixture was stirred at room temperature over a night and heated under reflux for 8 hours. After the air cooling, the product was added with 1 l of water and 50 g of sodium bisulfite and sufficiently shaken to separate into two layers. The resulting organic layer was washed with an aqueous solution of 5% sodium hydrogen carbonate and further with 1 l of water and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and distilled under a reduced pressure (4 mmHg, bp: 93-°96° C.) to obtain 585 g (yield: 94%) of 3-fluoro-4-methoxybromobenzene.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:10]([I:11])[C:4]=2[N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:29][OH:30])[CH:20]=[N:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:16][C:17]1[CH:18]=[C:19]([CH2:29][OH:30])[CH:20]=[N:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([C:2]2[NH:3][C:4]3[C:10]([I:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24]1
Reactant: OCc1cnc(N2CCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1cc(I)c2nc(Cl)[nH]c2c1
Product: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(I)c4[nH]3)CC2)c(Cl)c1

Procedure:
The benzoimidazole from step (c) above (69 mg, 0.2 mmol) reacted with (5-chloro-6-piperazin-1-yl-pyridin-3-yl)methanol (68 mg, 0.3 mmol, Example 60c) under the conditions of Example 3c to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 538 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1.Cl.[C:36](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([F:34])=[CH:8][C:9]([C:13]3[O:14][C:15]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:27])[CH3:36])[CH3:24])[N:18]=[CH:17][C:16]=4[N:33]=3)=[CH:10][C:11]=2[F:12])[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1cc2oc(-c3cc(F)c(OCC4CC4)c(F)c3)nc2cn1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4)c(F)c3)nc2cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (1.42 g) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (701 mg).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9][CH:10]2OCC[O:11]2)[CH:6]=[CH:5][N:4]=[CH:3]1>O1CCCC1>[Cl:22][C:17]1[CH:16]=[C:15]([CH:8]([CH2:7][N:2]2[CH:6]=[CH:5][N:4]=[CH:3]2)[CH2:9][CH:10]=[O:11])[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: Clc1ccc(C(CC2OCCO2)Cn2ccnc2)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=CCC(Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.2 %

Procedure:
5N Aqueous hydrochloric acid solution (100 ml) was added to an ice-cooled solution of 1-(imidazol-1-yl)-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane (11 g) (see Preparation 17) in tetrahydrofuran (100 ml). The mixture was allowed to warm slowly to room temperature and then left to stand for 24 hours. The tetrahydrofuran was removed under reduced pressure and the acidic phase extracted with dichloromethane (2×100 ml). The organic phases were combined, washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to give the crude product which was chromatographed on silica gel eluting with a solvent gradient of 97.5:2.5 changing to 95:5, by volume, dichloromethane:methanol, to give 3-(3,4-dichlorophenyl)-4-(imidazol-1-yl)butan-1-al (4.4 g) as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][C@H:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[CH3:19]>>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][C:20]([C@@H:18]([NH:17][C:13]([C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH3:19])=[CH:21][CH:22]=1)=[O:25]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 93.2 %

Procedure:
The title compound (D7) (815 mg) was prepared according to the general procedure for amides preparation starting from (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #433818), and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (501 mg). Reaction time: 18 hrs
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[Br:13]Br>ClCCl>[Br:13][C:3]1[C:2]([F:1])=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: BrBr
Reactant: O=C1COc2ccc(F)cc2N1
Solvent: ClCCl
Product: O=C1COc2cc(Br)c(F)cc2N1
Temperature: 30 °C
Reaction time: 15 h
Yield: 99.9 %

Procedure:
30.0 g of 6-fluoro-4H-benz[1,4]oxazin-3-one are initially charged in 300 ml of dichloromethane, and 37.4 g of bromine are then slowly added dropwise at room temperature. The mixture is heated at 30° C. with stirring for 15 h. The reaction solution is cooled to room temperature and poured onto ice. The aqueous phase is extracted repeatedly with dichloromethane. The combined organic phases are washed with saturated sodium thiosulphate solution, dried over magnesium sulphate and concentrated. This give 44.1 g (yield 99.5% of theory) of 7-bromo-6-fluoro-4H-benz[1,4]oxazin-3-one of melting point 244° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)(=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl[Sn](Cl)(Cl)Cl.Cl>C1C=CC=CC=1>[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1ccsc1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)c1cccs1
Yield: 75.6 %

Procedure:
In a 5 liter-five-necked flask, 112.5 g (1.34 mol) of thiophene, 300 g (1.37 mol) of n-dodecanoyl chloride and 2.25 liter of dry benzene were placed and cooled below 0° C. To the mixture under stirring, 148.5 (5.70×10-1 mole) of SnCl4 was added dropwise in 1 hour below 0° C. The mixture was stirred for 30 min. below 0° C., followed by stirring for 4 hours while being gradually restored to room temperature. After the reaction, 2 liter of 10% HCl was added to the reaction mixture, followed by stirring for 10 min. The separated organic layer was successively washed three times with 500 ml each of 10% HCl, water, 5% Na2CO3 and water, followed by drying with CaCl2 and distilling-off of the solvent to obtain 315 g of a crude product. The crude product was subjected to reduced-pressure distillation under an atmosphere of nitrogen to obtain 270 g of a pure product (yield: 75.7%). b.p.: 146° C./0.65 mmHg
Reaction SMILES: [CH2:1]([C:4]1([CH2:10][CH2:11][OH:12])[O:9][CH2:8][CH2:7][CH2:6][O:5]1)CC.[C:13](OCC)(=O)[CH2:14]C(C)=O>>[CH3:1][C:4]1([CH2:10][CH2:11][OH:12])[O:5][CH2:6][C:7]2([CH2:14][CH2:13]2)[CH2:8][O:9]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCC1(CCO)OCCCO1
Product: CC1(CCO)OCC2(CC2)CO1
Yield: 36 %

Procedure:
The same procedure as in the steps (8a) and (8b) of Example 8, was repeated using ethyl acetoacetate and 1,1-bis(hydroxymethylcyclopropane) to obtain the title compound (2.9 g, total yield: 36%) as a light yellow oil.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:13]([O:14]C)=[C:12]([F:16])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]>C(Cl)Cl.C1COCC1.O>[F:5][C:6]1[C:13]([OH:14])=[C:12]([F:16])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1c(F)ccc(C=O)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(F)c(O)c1F
Temperature: -10 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
1M BBr3 in DCM (2.179 ml) was added dropwise in about 30 min. to a stirred solution of 2,4-difluoro-3-methoxybenzaldehyde (0.25 g, 1.452 mmol) in DCM, cooled at −10° C. and under nitrogen atmosphere The solution was stirred for 4 hrs at RT and then diluted with a mixture of THF/H2O (9/1) and heated for 30 min. at 80° C. The solvent was removed and the residue was partitioned between 10N NaOH and Et2O. The aqueous layer was acidified with 10 N HCl and extracted with Et2O/EtOAc (2/1). Organic layers were dried over sodium sulphate and evaporated to give 2,4-difluoro-3-hydroxybenzaldehyde (225 mg) as pale brown powder.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]4[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1.[CH3:37][S:38]([CH2:41][CH2:42][NH2:43])(=[O:40])=[O:39]>>[CH3:37][S:38]([CH2:41][CH2:42][NH:43][CH2:28][C:26]1[O:27][C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:32]=[CH:33][CH:34]=[C:3]([C:2]([F:36])([F:1])[F:35])[CH:4]=3)=[CH:31][CH:30]=2)=[CH:24][CH:25]=1)(=[O:40])=[O:39]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(C(F)(F)F)c5)cc4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(C(F)(F)F)c5)cc4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{4-(3-trifluoromethylbenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 300 MHz (DMSO-d6) 11.63 (bs, 1H); 9.88 (bs, 1H); 9.59 (bs, 1H); 8.88 (s, 1H); 8.43 (d, 1H); 7.97 (d, 1H); 7.90–7.67 (m, 6H); 7.34 (d, 1H); 7.19 (d, 2H); 6.89 (d, 1H); 5.30 (s, 2H); 4.45 (s, 2H); 3.78 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.19 (s, 3H); MS m/z 597 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]4[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=4[O:20][C:21]=3[C:22]#[N:23])=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:40]=[N+:41]=[N-:42])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]4[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=4[O:20][C:21]=3[C:22]3[NH:42][N:41]=[N:40][N:23]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2c(C#N)oc3ccccc23)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2c(-c3nnn[nH]3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A solution of methyl 2-butyl-1-[[4-(2-cyanobenzo[b]furan-3-yl)phenyl]methyl]benzimidazole-7-carboxylate (1.3 g) and trimethyltin azide (2.9 g) in toluene (125 ml) was heated under reflux for 2 days. After concentration to dryness, the residue was dissolved in a mixture of methanol (150 ml) and 1N hydrochloric acid (25 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and the residue was dissolved in methylene chloride. The resulting solution was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give pale yellow powders (1.3 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[C:41]1([NH2:48])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:48][C:8](=[O:10])[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:13]([OH:14])=[C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:11]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2N)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of 3,5-di-t-butyl-4-hydroxybenzoic acid (5.0 g) in methylene chloride (20 ml) was added dicyclohexylcarbodiimide (2.17 g) and the mixture was stirred overnight at room temperature. Subsequently, triethylamine (2.1 ml), 4-dimethylaminopyridine (0.37 g) and o-phenylenediamine (1.08 g) were added and the mixture was stirred overnight at room temperature. The insolubles was filtered off and the filtrate was concentrated to dryness. The residue was purified by a silica gel column chromatography (chloroform:ethyl acetate=20:1) and crystallized from diisopropyl ether to give N-(2-aminophenyl)-3,5-di-t-butyl-4-hydroxybenzamide (1.10 g, 32%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C@@H:21]([CH2:55][CH2:56]O)[C:22]([NH:24][CH2:25][C@H:26]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]3[CH:48]=[N:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[C:42]([CH3:54])[CH:41]=1)=[N:32][CH:33]=[N:34]2)[CH3:27])=[O:23].C(Br)(Br)(Br)[Br:59]>C(Cl)Cl>[Br:59][CH2:56][CH2:55][C@H:21]([OH:20])[C:22]([NH:24][CH2:25][C@H:26]([O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]3[CH:48]=[N:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[C:42]([CH3:54])[CH:41]=1)=[N:32][CH:33]=[N:34]2)[CH3:27])=[O:23]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CNC(=O)[C@@H](O)CCO)c34)cc2C)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CNC(=O)[C@@H](O)CCBr)c34)cc2C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
Triphenylphosphine (650 mg, 2.5 mmol) was added portion wise over 30 minutes to a solution of (2S)-2,4-dihydroxy-N-((2R)-2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}propyl)butanamide (856 mg, 1.65 mmol, obtained as described in Example 112) and carbon tetrabromide (658 mg, 2 mmol) in DCM (10 ml). The mixture was stirred overnight at room temperature. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2% to 5% 7N ammonia-methanol in DCM) to give the title compound (712 mg, 74%) as a solid; NMR Spectrum: (CDCl3) 1.53 (d, 3H), 2.07 (m, 1H), 2.28 (s, 3H), 2.38 (m, 1H), 2.52 (s, 3H), 3.51 (t, 2H), 3.80-3.65 (m, 2H), 4.34 (dd, 1H), 4.95 (m, 1H), 6.90 (m, 2H), 7.09 (d, 1H), 7.14 (dd, 1H), 7.28 (m, 1H), 7.50 (m, 3H), 7.63 (s, 1H), 8.23 (s, 1H), 8.44 (s, 1H); Mass spectrum: MH+ 580, 582.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.Cl>O1CCCC1>[CH2:11]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: OCc1ccc(F)c(Br)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(COCc2ccccc2)cc1Br
Temperature: 40 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
20.5 g (0.1 mol) of 3-bromo-4-fluoro-benzyl alcohol were added to a solution of 12.3 g (0.11 mol) of potassium tert.-butylate in 200 ml of tetrahydrofuran at 20° C. During this addition, the temperature increased to about 40° C. The mixture was subsequently stirred at 20° C. for about 1 hour and 12.6 g (0.1 mol) of benzyl chloride were then added dropwise to the reaction mixture. Thereafter, the mixture was heated under reflux for one hour. It was then cooled. About 200 ml of water and 50 ml of concentrated hydrochloric acid were added to the reaction mixture and the mixture was extracted twice with 200 ml of diethyl ether each time. The combined extracts were concentrated, dried over sodium sulphate and then subjected to fractional distillation. 14.2 g (48.2% of theory) of 3-bromo-4-fluoro-benzyl benzyl ether were obtained in the form of a light yellow oil of boiling point 165° C./7 mbars.