Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CC(NC(=O)C2CCCCC2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (328 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (529 mg, 84%).
Reaction SMILES: Cl.[O:2]=[C:3]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[N:21]=2)[CH2:14]1)[CH2:4][NH:5]C(=O)OC(C)(C)C>O1CCOCC1.CO>[NH2:5][CH2:4][C:3]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[N:21]=2)[CH2:14]1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of hydrochloric acid in dioxane (4M, 10 mL) was added to a solution of tert-butyl (2-oxo-2-{(3R)-3-[(6-pyrazolo[1,5-a]pyridin-3-ylpyrazin-2-yl)amino]piperidin-1-yl}ethyl)carbamate (Preparation 38, 88 mg, 0.23 mmol) in methanol (3 mL) and the resulting mixture was stirred at ambient temperature for one hour. The solvents were then evaporated to half of their volume and the yellow solid that precipitated was filtered, washed with diethyl ether and dried to give the title compound (76 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:20](OC)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=1.FC1C=C(F)C=CC=1C1C=[C:34](COS(C)(=O)=O)[C:35](=O)[N:36]([CH2:38][CH:39](C)C)N=1.C(NCC)C>>[CH2:35]([N:36]([CH2:20][C:11]1[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:10]=1)[CH2:38][CH3:39])[CH3:34]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2F)nn(CC(C)C)c1=O
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Solvent: CCNCC
Product: CCN(CC)Cc1cc(-c2ccc(F)cc2F)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9 (4), 6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a pale yellow oil (yield: quantitative).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CC(C)O
Solvent: CCCCO
Product: CCC(CC)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg (0.77 mmoles) of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.088 ml (0.96 mmoles) of aniline in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for two days at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C.
Reaction SMILES: O[CH2:2][C:3]1[NH:22][C:6]2=[CH:7][C:8]3[C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=3[CH:13]=[C:5]2[N:4]=1.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][CH2:2][C:3]1[NH:22][C:6]2=[CH:7][C:8]3[C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=3[CH:13]=[C:5]2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CO)nc3cc21
Solvent: ClC(Cl)Cl
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CCl)nc3cc21
Temperature: 60 °C
Reaction time: 15 h

Procedure:
E1 (330 mg) is dissolved in CHCl3 (5 ml), thionyl chloride (1.2 ml) is added and the mixture is stirred at 60° C. for 15 h. The reaction mixture is concentrated in vacuo to give the compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added butyryl chloride (19.6 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (46.2 mg, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](CC(C)C)(C)C)[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(O[Si](C)(C)CC(C)C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2cccc(O)c2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound H) 40.0 mg (0.076 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.00 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 7.90 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.4 Hz), 7.35 (2H, s), 7.15-7.07 (2H, m), 6.77-6.69 (3H, m), 5.92 (1H, t, J=4.7 Hz), 2.25 (2H, d, J=4.7 Hz), 1.23 (6H, s).
Reaction SMILES: ClCCCl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:9][CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[C:17]=2[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccccc2)cc1

Procedure:
To 300 ml. of 1,2-dichloroethane maintained at 0° C. were added 6.0 g. (0.022 mole) of 2-(4-methoxyphenyl)-6-methoxybenzothiophene and 3.10 g. (0.022 mole) of benzoyl chloride. The mixture was stirred vigorously, and 3.2 g. (0.024 mole) of aluminum chloride were added in small portions. The resulting red solution was stirred for one hour, and water then was added. The yellow organic layer was separated, washed with 200 ml. of 1N sodium hydroxide and then with 200 ml. of saturated sodium chloride solution. The mixture then was dried over potassium carbonate, and the solvent was evaporated to give a pale yellow solid which was purified by chromatography over silica gel using benzene and 5% ethyl acetate in benzene as eluant. The appropriate fractions gave product as yellow crystals. The product was recrystallized from methanol to obtain 3.5 g. (42 percent) of 2-(4-methoxyphenyl)-3-benozyl-6-methoxybenzothiophene, melting point 110.5°-111° C.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]#[C:15][Si](C)(C)C)=[CH:8][CH:7]=1>O.C1COCC1>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:5]([OH:20])=[O:4])=[CH:11][CH:10]=1)#[C:13][C:14]#[CH:15]
Reactant: COC(=O)c1ccc(C#CC#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC#Cc1ccc(C(=O)O)cc1
Reaction time: 16 h
Yield: 91.4 %

Procedure:
Potassium hydroxide (3.700 g, 65.9 mmol) was dissolved in H2O (10 mL) and added to a solution of 4-(4-trimethylsilanyl-buta-1,3-diynyl)-benzoic acid methyl ester 3 (3.420 g, 13.5 mmol) in THF (26 mL) in the absence of light. After stirring 16 h, the reaction was quenched with 1.0 M HCl (120 mL) and the resulting precipitate was filtered, washed with 1:1 hexanes/benzene (150 mL) and dried in vacuo to afford 2.100 g (91% yield, 98% pure) of 4-(buta-1,3-diynyl)-benzoic acid 4 as a brown solid, mp>230° C. Although diyne 4 was found to be unstable at room temperature it could be stored for several weeks at 0° C. with only small amounts of decomposition observed by TLC. Rf=0.2 (4:1 Hexanes/EtOAc); HPLC (300 nm, 28 min run) 16.0 min; LRMS (ES+) m/z 171.0 (C11H6O2+H requires 171.04).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C@H:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: C[C@@H]1NCCc2ccccc21
Product: C[C@H]1c2ccccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(S)-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:10]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: O=Cc1cccc(NC(=O)c2ccc(Cl)cc2)c1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-chloro-N-(3-formyl-phenyl)-benzamide (2.1 g, 8.09 mmol), ethyl isonipecotate (1.53 g, 9.55 mmol) in DCM (45 mL) is treated with sodium triacetoxy borohydride (2.5 g, 11.2 mmol) in 5 portions over 20 min. and the reaction mixture is stirred for 18 h at RT. Aq. sat. NaHCO3 (20 mL) is added and the mixture is stirred for 30 min. The phases are separated and the aqueous phase is extracted twice with DCM (50 ml). The combined organic phases are dried over MgSO4 and evaporated. The title compound is obtained as a colorless solid (3.24 g, 98%); LC-MS A: tR=0.72 min; [M+H]+=401.01.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])=[O:27])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCO
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Product: O=C(NCCCCO)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-benzyloxycarbamoyl-phenylamino)methyl]-2-fluoro-benzoic acid (Example 498) and 4-amino-butan-1-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:19]([O-])=[O:20].[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][N:9]([N:19]=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1(Cc2ccccc2)CCN(N=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of 4-ethoxycarbonyl-4-benzylpiperidine (495 mg) in water (5 mL) was added sodium nitrite (276 mg) and acetic acid (201 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) and dried in vacuo to give 4-ethoxycarbonyl-4-benzyl-1-nitrosopiperidine (565 mg, yield: 100%) as a colorless solid. To a solution of the product (565 mg) in methanol (3 mL) was added zinc powder (654 mg) and then added acetic acid (3 mL) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution and chloroform and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-amino-4-benzyl-4-ethoxycarbonylpiperidine (508 mg, yield: 97%) as a colorless viscidity.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][C:22]1([CH3:31])[CH2:27][CH2:26][C:25](B(O)O)=[CH:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][CH2:9][C:8]([C:6]1[CH:5]=[CH:4][C:3]([NH2:20])=[C:2]([C:25]2[CH2:26][CH2:27][C:22]([CH3:31])([CH3:21])[CH2:23][CH:24]=2)[CH:7]=1)([CH3:19])[CH3:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)c(Br)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: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)ccc2N)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a mixture of 2-bromo-4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-phenylamine (as prepared in the previous step, 1.50 g, 4.19 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (1.09 g, 4.61 mmol) and Pd(PPh3)4 (484 mg, 0.419 mmol) in 50 mL of 1,4-dioxane was added aqueous Na2CO3 (16.8 mL, 33.5 mmol, 2.0 M). The resulting mixture was stirred at 90° C. for 16 h under Ar. After cooling to RT, the mixture was treated with 150 mL of EtOAc and washed with H2O (3×30 mL) and brine (30 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5-10% EtOAc/hexane) to afford 1.46 g (90%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C24H41NOSi, 388.3 (M+H). found 388.3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:32])[CH2:22][N:23](C(OC(C)(C)C)=O)[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:32])[CH2:22][NH:23][CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.7 %

Procedure:
N-tert-Butoxycarbonyl-N-methyl-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27) (2.19 g; 4.99 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 2.5 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a white solid. CIMS: MH− 339
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccc(OC(F)F)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 111.5 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (348 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were suspended in dimethoxyethane (10 mL) and water (4 mL), and the mixture was stirred under a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 550 mg, quantitative yield).
Reaction SMILES: I[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34].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.[Cu]I.C(N(CC)CC)C>[CH3:13][S:12][C:4]1[N:3]=[C:2]([C:34]#[C:33][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CSc1ncc(C(F)(F)F)c(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1C#Cc1nc(SC)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
4-Iodo-2-(methylthio)-5-(trifluoromethyl)pyrimidine (I12) (2.00 g, 6.24 mmol), PdCl2(PPh3)2 (438 mg, 625 μmol), CuI (119 mg, 625 μmol) and triphenylphosphine (164 mg, 625 μmol) were placed into an oven dried microwave reaction vial under nitrogen. Methyl 2-(2-ethynylphenyl)acetate (I4) (1.31 g, 7.49 mmol), THF (20 mL) and triethylamine (10 mL) were added and the resulting mixture was stirred at 100° C. under microwave irradiation for 10 min. The volatiles were evaporated under reduced pressure then the residue was adsorbed onto silica from DCM. The pre-adsorbed material was chromatographed on silica gel (6-25% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I13) (1.571 g, 69%) as an orange solid; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=0.8 Hz, 1H), 7.68 (dd, J=7.7, 1.1 Hz, 1H), 7.50-7.29 (m, 3H), 3.93 (s, 2H), 3.71 (d, J=3.4 Hz, 3H), 2.62 (d, J=3.4 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([OH:32])[C@H:27]1[OH:33].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[I:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][C@@H:28]([OH:32])[C@H:27]5[OH:33])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Reactant: N[C@@H]1CCC[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1[C@H](O)CCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Temperature: 120 °C
Yield: 30.5 %

Procedure:
To a suspension of 6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (350 mg, 0.8 mmol) and (1R,2S,3R)-3-aminocyclohexane-1,2-diol hydrochloride (258 mg, 1.6 mmol), prepared as described in Gauthier Errasti, et al, Org. Lett. 2009, 13, 2912-2915, in anhydrous DMA (1.5 mL) was added DIEA (402 μL, 2.4 mmol). The mixture was heated in a sealed tube at 120° C. for 15 h. The mixture was cooled to rt and partitioned between EtOAc (150 mL) and 0.5 M aq K2CO3 (100 mL). The organic layer was separated and washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5% MeOH in DCM to afford (1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (127 mg, 32%) as a yellow solid. LCMS (ESI) m/z 521 (M+H)+.