Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([C:18](=[O:20])[CH3:19])=[CH:5][S:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[OH:2][C:3]1[C:4]([C:18](=[O:20])[CH3:19])=[CH:5][S:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=1
Reactant: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCCC2
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: CC(=O)c1csc(-c2ccc3c(c2)CCCC3)c1O
Temperature: 0 °C
Yield: 46 %

Procedure:
To 2.4 g of 1-[4-methoxy-5-(5,6,7,8-tetrahydronaphthalen-2-yl)thiophen-3-yl]ethanone in chloroform (25 ml) cooled with ice, 9.4 ml of boron tribromide (1.0 M dichloromethane solution) was added dropwise, and then the reaction mixture was allowed to react for 1.5 hours. The reaction mixture was poured into 300 ml of ice-cold water and extracted with 250 ml of chloroform. The aqueous layer was extracted with 100 ml of chloroform once, and the extract was combined with the previously chloroform extract, washed with 150 ml of saturated aqueous sodium chloride twice, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue (dark brown oil) was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20), and the resulting solid was washed with hexane to obtain 1.05 g of the desired product (yield 45%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[S:27][C:28]([CH2:32]O)=[C:29]([CH3:31])[N:30]=1.ClC1C=CC=CC=1C(N)=S.ClC(C(C)=O)C(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][C:28]2[S:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:30][C:29]=2[CH3:31])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccccc2Cl)sc1CO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NC(=S)c1ccccc1Cl
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccccc3Cl)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with (2-(2-chloro-phenyl)-4-methyl-thiazol-5-yl]-methanol (prepared from 2-chloro-thiobenzamide and ethyl 2-chloro-acetoacetate in analogy to the procedures described in examples 33 a] and 33 b]) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-3-{4-[2-(2-chloro-phenyl)-4-methyl-thiazol-5-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][O:29][S:31]([CH3:30])(=[O:33])=[O:32])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCO)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCOS(C)(=O)=O)CC1
Yield: 104 %

Procedure:
Suspend 4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (5.07 g; 11.96 mmol) and TEA (35.88 mmol; 5.0 mL) in DCM (50 mL) and cool in ice bath. Add methanesulfonyl chloride (14.35 mmol; 1.1 mL) dropwise over 9 min and stir for 30 additional min. Quench with saturated sodium bicarbonate, dry over MgSO4, filter and evaporate to provide the title compound (6.246 g; 104%) as a foam. MS (ES): m/z=502 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:27])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=2)[S:10][C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:41][C:42]1[CH:43]=[C:44]([C:51](=[O:53])[CH3:52])[CH:45]=[CH:46][C:47]=1[NH:48][CH2:49][CH3:50]>CN(C=O)C>[C:51]([C:44]1[CH:45]=[CH:46][C:47]([NH:48][CH2:49][CH3:50])=[C:42]([N:41]=[C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:27])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=3)[S:10]2)[CH:43]=1)(=[O:53])[CH3:52]
Reactant: COCCOc1ccc(N(C)C=C2SC(=S)N(Cc3ccccc3)C2=O)cc1
Reactant: CCNc1ccc(C(C)=O)cc1N
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=CN(C)c2ccc(OCCOC)cc2)C(=O)N1Cc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
A mixture of 3-benzyl-5-({N-[4-(2-methoxy-ethoxy)-phenyl]-methylamino}-methylene)-2-thioxothiazolidin-4-one (60 mg, 0.14 mmol) and methyl p-toluenesulfonate (54 mg, 0.29 mmol) in DMF (1.0 mL, anhyd) was heated at 130° C. After 2 h the reaction mixture was allowed to cool to ambient temperature, charged with 3′-amino-4′-ethylamino-acetophenone (50 mg, 0.28 mmol) and TEA (70 μL, 0.72 mmol), and then heated at 65° C. After 20 h the reaction mixture was cooled and chromatographed (HPLC-MS conditions) to yield the title product (7 mg) as a yellow solid. 1H-NMR (CDCl3): δ 7.82 (1H, s), 7.61 (1H, dd), 7.48 (1H, d), 7.27-7.40 (5H, m), 7.08 (2H, m), 6.90 (2H, m), 6.44 (1H, d), 5.09 (2H, s), 4.20 (1H, br s), 4.07 (2H, m), 3.73 (2H, m), 3.46 (3H, s), 3.44 (3H, s), 3.00 (2H, m), 2.43 (3H, s), 1.00 (3H, t); MS (ESI): 559 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][S:7][C:8]2[N:13]=[N:12][C:11]([O:14]CC3C=CC(OC)=CC=3)=[C:10]([O:24]CC3C=CC(OC)=CC=3)[CH:9]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C:8]2[CH:9]=[C:10]([OH:24])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(COc2cc(SCc3ccc(Cl)cc3)nnc2OCc2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1[nH]nc(SCc2ccc(Cl)cc2)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 5471.2 %

Procedure:
To a solution of 6-[(4-chlorobenzyl)sulfanyl]-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (Intermediate 8; 527 mg, 1.04 mmol) in methanol (5177 μl) was added a solution of hydrogen chloride in dioxane (4.0 M, 5177 μl, 20.71 mmol) and the reaction was allowed to stir at room temperature for 72 hours. The resulting mixture was concentrated in vacuo to afford a yellow solid which was recrystallised from ethanol to afford 6-[(4-chlorobenzyl)sulfanyl]-4-hydroxypyridazin-3(2H)-one as white crystals (153 mg, 56.9 mmol, 55%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][CH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23].Cl>CN(C)C=O>[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[O:17][CH2:18][C:19]1[CH:20]=[C:21]([C:22]2[NH:23][N:3]=[N:2][N:1]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(COc2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1cc(COc2ccc3ccccc3c2)cc(-c2nnn[nH]2)c1
Temperature: 125 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a mixture of sodium azide (1.46 g, 22.5 mmol) and ammonium chloride (1.28 g, 24.0 mmol) in dry dimethylformamide (20 mL) under an atmosphere of nitrogen, 3-(naphthalen-2-yloxymethyl)-benzonitrile (3.9 g, 15 mmol) was added and the reaction mixture was stirred at 125° C. for 4 hours. The cooled reaction mixture was poured on to ice water (300 mL) and acidified to pH=1 with 1 N hydrochloric acid. The precipitate was filtered off and washed with water, dried at 100° C. for 4 hours affording 4.2 g (93%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.[CH2:20]([Mg]Br)[CH3:21]>O1CCCC1.CCOCC>[CH2:20]([C:2]1([OH:1])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:4][CH2:3]1)[CH3:21]
Reactant: O=C1CCC(CNC(=O)OCc2ccccc2)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC1(O)CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a vigorous stirring solution of benzyl (4-oxocyclohexyl)methylcarbamate (1 g) in tetrahydrofuran (20 mL) at −78° C. was slowly added 1 M ethylmagnesium bromide (11.48 mL) in ether. After completion of the addition, the mixture was stirred at −78° C. for 2 hours and then was warmed to 0° C., and stirred in an ice bath for 30 minutes. The reaction was quenched with a cold NH4Cl aqueous solution. The precipitates were filtered off and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane, loaded onto an Analogix purification system, and eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:19])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[C:5]([O:7]CC)=[O:6].[OH-].[Li+].[OH-].[Na+].CCOCC>CO.O.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:19])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[C:5]([OH:7])=[O:6]
Reactant: C#CCCCOc1c(C)cc(C(=O)OCC)cc1C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: C#CCCCOc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.2 %

Procedure:
The ethyl ester of part (a) (7.4 g) was hydrolyzed, first with 0.9 g lithium hydroxide in 25 ml methanol and 10 ml water, stirred at room temperature for 3 days, and then with 50 ml 10% sodium hydroxide in 100 ml ethanol, heated at reflux for 2 hrs. The product was isolated by acidification, extraction with ether and concentration to give 4.7 g 3,5-dimethyl-4-(3-ethynylpropoxy)benzoic acid, m.p. 129°-130° C.
Reaction SMILES: C(OC([C:8]#[C:9][CH2:10][CH:11]([OH:23])[CH:12]([OH:22])[CH:13]([NH2:21])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=O)(C)(C)C.FC(F)(F)C(O)=O.CCOC(C)=O>C(Cl)Cl.CCCCCC>[NH2:21][C@@H:13]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C@@H:12]([OH:22])[C@@H:11]([OH:23])[CH2:10][C:9]#[CH:8]
Reactant: CC(C)(C)OC(=O)C#CCC(O)C(O)C(N)CC1CCCCC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#CC[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1
Yield: 100 %

Procedure:
To a solution of the diol heptyne of Step 6 isomer (2.85 mmol) in CH2Cl2 (5.5 mL) was added trifluoroacetic acid (71.3 mmol). The reaction was monitored by TLC (50% EtOAc in hexane). After 30 minutes the solution was concentrated and an aqueous 1.0N NaOH solution (7 mL) was added. The solution was extracted with EtOAc (4×10 mL). The organic layer was dried with MgSO4. The filtrate was concentrated to give the title amine as a white sticky solid (0.67 g, 100% yield). The 1H, 13C and APT NMR spectral data were consistent with the prepared structure.
Reaction SMILES: C(=O)=O.C[O:5][C:6]([C:8]1[C:9]([CH2:25][CH2:26][O:27][CH3:28])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[N:12][C:13]=1[CH3:14])=O.CC(C[AlH]CC(C)C)C>O1CCCC1>[CH3:28][O:27][CH2:26][CH2:25][C:9]1[C:8]([CH2:6][OH:5])=[C:13]([CH3:14])[N:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:10]=1
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1C(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: C1CCOC1
Product: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CO
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 103.5 %

Procedure:
To a dry-ice cooled solution of 4.9 g (13.83 mmol) 4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester in 50 ml tetrahydrofurane was dropped 34.57 ml (41.48 mmol) of DIBALH-solution (1.2 M in Toluene). The reaction mixture was stirred for 15 min at −70° C. and then the dry-ice bath was removed, the reaction temperature was allowed to come to RT and the reaction mixture was stirred for 2 h at RT. To the reaction mixture was then dropped carefully, under ice-cooling, 10 ml of 6N HCl. After 4 min was the whole taken up in ether and washed with water. The ether-phase was concentrated under reduced pressure providing 4.67 g pure crystalline [4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O>[N:1]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of pyrrolidine (17 mL, 237 mmol) in 20 mL of H2O at room temperature was added p-flourobenzenesulfonyl chloride (15 g, 79 mmol) in portions over a 5 minute period. After 1 hour, the solution was diluted with 100 mL of H2O and extracted with ethyl acetate (3×50 mL). The organic was dried (Na2SO4) and concentrated in vacuo to give 12.3 g (72%) of 4-(pyrrolidinosulfonyl)-flourobenzene as a colorless oil that solidified on standing. This material was used in the following reaction without further purification. MS.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH2:25]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: OC(C1=NN(c2cccc(N3CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, cyclopropanesulfonyl chloride (9.3 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:41]=[CH:42][CH:43]=4)[O:24][CH2:25][C:26]([NH:28][C@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N[C@H]1CCNC1

Procedure:
To (3S)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (3 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((S)-pyrrolidin-3-yl)acetamide. (33 mg, 0.069 mmol)
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([CH3:32])[C:29]([CH3:33])=[CH:28][C:27]=5[O:34][C@H:35]([CH2:37]C=C)[CH3:36])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44][CH3:45])=[O:43])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:47]([O:46][C@@H:41]([C:12]1[C:13]([CH3:40])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:51])([O:4][CH2:1][CH:2]=[CH:3][CH2:36][C@H:35]([CH3:37])[O:34][C:27]2[CH:28]=[C:29]([CH3:33])[C:30]([CH3:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:42]([O:44][CH3:45])=[O:43])([CH3:48])([CH3:50])[CH3:49]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)c(C)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(C)c(C)cc1-c1cccc-3c1
Yield: 80 %

Procedure:
Prepared in 80% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-dimethyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=7.8 Hz, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.55-7.47 (m, 1H), 7.35-7.29 (m, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 6.26-6.14 (m, 1H), 6.06 (br. s., 1H), 5.89-5.74 (m, 1H), 4.57-4.44 (m, 1H), 4.10-4.05 (m, 1H), 4.03-3.93 (m, 2H), 3.84-3.73 (m, 1H), 3.69 (s, 3H), 3.07 (d, J=8.3 Hz, 1H), 2.68 (d, J=7.5 Hz, 1H), 2.51 (br. s., 1H), 2.46 (s, 3H), 2.43-2.34 (m, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 1.97 (t, J=12.5 Hz, 2H), 1.75 (td, J=12.9, 4.5 Hz, 2H), 1.32 (s, 3H), 1.25 (s, 9H), 1.10 (d, J=6.3 Hz, 3H); LCMS (ESI, M+1): 666.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:7]1[CH:12]=[CH:11][N:10]2[C:13](Br)=[CH:14][N:15]=[C:9]2[N:8]=1)([CH3:6])[CH3:5].[F:18][C:19]1[C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:23]([F:31])[CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:1][O:2][C:3](=[O:17])[C:4]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:20]3[CH:21]=[CH:22][C:23]([F:31])=[C:24]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[C:19]=3[F:18])=[CH:14][N:15]=[C:9]2[N:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Product: COC(=O)C(C)(C)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionic acid methyl ester and 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid were coupled in the same way as described in Example 65 to give 2-[3-(2,4-difluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl)-2-methylpropionic acid methyl ester as a white solid: δH (360 MHz, CDCl3) 1.69 (6H, s), 3.70 (3H, s), 6.91 (1H, d, J 7), 7.20-7.25 (1H, m), 7.43-7.47 (1H, m), 7.50-7.57 (1H, m), 7.84-7.87 (1H, m), 7.89 (1H, s), 8.21 (1H, dd, J 7 and 3), 8.69 (1H, dd, J 5 and 2), 8.78 (1H, d, J 1); m/z (ES+) 409 (M++H).
Reaction SMILES: C([CH:4]1[O:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[CH2:6][O:5]1)=CC.C1(CO)C([CH2:21][OH:22])=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>COCCOC>[CH3:21][O:22][CH:4]1[O:5][CH2:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][O:10]1
Reactant: CC=CC1OCc2ccccc2CO1
Reactant: OCc1ccccc1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: COCCOC
Product: COC1OCc2ccccc2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A method for synthesizing 3-(1-propenyl)-1,5-dihydro-3H-2,4-benzodioxepine is illustrated in Scheme 3. 1,2-Benzenedimethanol (500 mg, 3.62 mmol) and p-toluenesulfonic acid (172 mg, 0.9 mmol) were dissolved in 2 mL of dry DME and triethylortoformate (0.396 mL, 3.62 mmol) was added. The solution was stirred at rt. and under argon for 1 h. Ether (20 mL) was added and the organic layer washed with a saturated solution of NaHCO3 and water, then dried (Na2SO4). The solvent was evaporated giving crude 3-methoxy-1,5-dihydro-3H-2,4 benzodioxepine as a colorless oil (526 mg, 89%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:12][CH2:13]O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:39]I>C(Cl)Cl>[I:39][CH2:13][CH2:12][N:10]1[CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:9]1
Reactant: OCCn1cnc(-c2ccccc2)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICCn1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 2-(4-phenyl-1H-imidazol-1-yl)ethanol (500 mg, 2.66 mmol, 1 eq) in DCM (10 mL) was added PPh3 (778 mg, 2.96 mmol, 1.1 eq), imidazole (203 mg, 2.98 mmol, 1.1 eq) and iodine (753 mg, 2.97 mmol, 1.1 eq). The reaction mixture was allowed to stir at RT overnight. The organic layer was extracted with 1N HCl. The combined acid extracts were then adjusted to pH˜8 with solid sodium carbonate. The aqueous layer was extracted 2× with Et2O. The combined ether extracts were dried over sodium sulfate, filtered and concentrated to dryness to give 1-(2-iodoethyl)-4-phenyl-1H-imidazole (623 mg, 78% yield) which was used without further purification. LC-MS M+H+298.9.
Reaction SMILES: [Br-].[CH:2]1([CH2:8][NH:9]CC2CCCCC2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C([Sn](CCCC)(CCCC)C1[N:23]=CSC=1)CCC>CN(C=O)C>[NH:23]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: C1CCC(CNCC2CCCCC2)CC1
Agent: [Br-]
Solvent: CN(C)C=O
Product: c1ccc2[nH]ncc2c1
Temperature: 135 °C
Reaction time: 19 h
Yield: 75.6 %

Procedure:
A mixture of bromide (IXb-75) (120 mg, 0.24 mmol), N,N-dicyclohexylmethylamine (52 mg, 0.27 mmol), 4-(tributylstannyl)thiazole (138 mg, 0.37 mmol), dihydrogen dichlorobis(di-tert-butylphosphinito-kP)palladate(2-) (7 mg, 0.01 mmol) in DMF (3 mL) was stirred at 135° C. for 19 h. The mixture was then cooled to RT and partitioned between EtOAc (20 mL) and saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic solutions were dried (MgSO4), filtered and concentrated. The orange residue was purified by LCMS (column LUNA 10μ C18(2) 00G-4253-V0 250×50 mm) using water-acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford azaindole (I-116) (24.1 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 1.51-1.67 (m, 4H), 2.03-2.16 (m, 6H), 2.57-2.64 (m, 1H), 3.04-3.12 (m, 5H), 3.82 (t, J=6.0 Hz, 2H), 3.84-3.87 (m, 2H), 6.44 (d, J=3.4 Hz, 1H), 7.31 (d, J=3.4 Hz, 1H), 7.80 (d, J=1.9 Hz, 1H), 8.01 (s, 1H), 8.05 (d, J=1.9 Hz, 1H), 10.29 (br s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:19])[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:17]C)=[CH:12][CH:13]=2)[CH2:8]1.[BrH:20]>>[BrH:20].[BrH:20].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:19])[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([OH:17])=[CH:12][CH:13]=2)[CH2:8]1
Reactant: COc1ccc2c(c1)CC(N(C)CCCCN)CC2
Agent: Br
Product: CN(CCCCN)C1CCc2ccc(O)cc2C1
Yield: 100 %

Procedure:
A mixture of N-(4-aminobutyl)-7-methoxy-2-(R,S)-methylamino-1,2,3,4-tetrahydronaphthalene (0.79 g, 3.0 mmol) and aqueous HBr (48%; 20 ml) was heated at reflux for 5 h, then evaporated in vacuo to give the title compound (1.2 g, 100%).