Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8]OS(C)(=O)=O)[CH:6]=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.CN(C=O)C>CC(=O)OCC>[N:27]1([CH2:8][CH2:7][N:5]2[CH:6]=[C:2]([Br:1])[N:3]=[C:4]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOS(C)(=O)=O)CC1
Reactant: C1CNC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCN2CCC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A reaction mixture of tert-butyl 4-(4-bromo-1-(2-((methylsulfonyl)oxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (28.0 g) and azetidine (11 ml) in to DMF (200 ml) was stirred at 50° C. overnight. The reaction was diluted with EA, washed with water followed by saturated aqueous sodium chloride, dried and concentrated. The residue was purified by column chromatography to give tert-butyl 4-(1-(2-(azetidin-1-yl)ethyl)-4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate as off-white solid. (17.2 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](B(O)O)=[CH:9]2)=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[CH3:28])[N:19]=[N:20][CH:21]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:16]3[CH:17]=[C:18]([CH2:22][N:23]4[CH:27]=[CH:26][N:25]=[C:24]4[CH3:28])[N:19]=[N:20][CH:21]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc2ccc(F)cc2c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc3ccc(F)cc3c2)cnn1

Procedure:
The title compound, MS: m/e=319 (M+H+), was prepared from 7-fluoro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](B(O)O)[CH:27]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:31])=[C:24]([C:2]2[CH:3]=[N:4][C:5]([N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[N:6][CH:7]=2)[CH:23]=1
Reactant: CCS(=O)(=O)N(Cc1ccccc1)c1ncc(Br)cn1
Reactant: OB(O)c1cc(Cl)ccc1O
Product: CCS(=O)(=O)N(Cc1ccccc1)c1ncc(-c2cc(Cl)ccc2O)cn1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.25 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][N:6]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:10])=[O:9])[CH:5]([CH2:20][C:21]([NH:23][C@H:24]2[C:33]3[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]2)=[O:22])[C:4](=[O:36])[NH:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:52]([NH2:56])([CH3:55])([CH3:54])[CH3:53]>CCOC(C)=O>[C:52]([NH:56][CH2:34][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[CH:24]([NH:23][C:21](=[O:22])[CH2:20][CH:5]1[C:4](=[O:36])[NH:3][C:2]([CH3:37])([CH3:1])[CH2:7][N:6]1[S:8]([C:11]1[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])(=[O:10])=[O:9])[CH2:25][CH2:26][CH2:27]2)([CH3:55])([CH3:54])[CH3:53]
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)N[C@@H]2CCCc3cc(C=O)ccc32)c(C)c1
Reactant: CC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)NC2CCCc3cc(CNC(C)(C)C)ccc32)c(C)c1
Temperature: 85 °C

Procedure:
2-[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)-yl]-N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-acetamide (Step b, 550 mg, 1.0 mmol) was dissolved in 1,2-dicholoethane (10 mL) and tert-butylamine (1.5 mL). NaBH(OAc)3 (1.5 g, 6.0 mmol) was added to the reaction, and heated to 85° C. in a sealed tube for 18 h. The mixture was cooled to RT, diluted with EtOAc (25 mL), washed with sat. NaHCO3 solution (2×), and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide a residue which was purified by column chromatography (SiO2, 10% MeOH in CH2Cl2+1% NH3) to provide the title compound. ESMS 583.4 (M+H), 581.5 (M−H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH2:18](I)[CH3:19]>>[CH2:18]([O:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:19]
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Reactant: CCI
Product: CCOCC1(CO)c2ccccc2-c2ccccc21
Yield: 51 %

Procedure:
The target product as white crystal was prepared from 9,9-bis(hydroxymethyl)fluorene and ethyl iodide through the same procedure as described above. Yield: 51%.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[S:4]([C:7]1[S:11][C:10]([NH:12]C(=O)C)=[N:9][C:8]=1[CH3:16])(=[O:6])=[O:5])[CH3:2].C[O-].[Na+]>CO.O>[CH2:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[S:11][C:10]([NH2:12])=[N:9][C:8]=1[CH3:16])(=[O:6])=[O:5])[CH3:18]
Reactant: CCN(CC)S(=O)(=O)c1sc(NC(C)=O)nc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CC)S(=O)(=O)c1sc(N)nc1C
Temperature: 5 °C
Yield: 22.4 %

Procedure:
The product from Step 1 (2.5 g) was dissolved in methanol (25 cm3) and cooled to 5° C. with stirring under an atmosphere of nitrogen. Sodium methoxide in methanol (2 cm3 of 25% wt./vol. solution) was added dropwise and the mixture allowed to warm to the ambient temperature for 18 hours. The reaction was heated under reflux for 1 hour, cooled, diluted with water (250 cm3), extracted with diethyl ether (2×100 cm3), dried (MgSO4) and evaporated under reduced pressure to give N,N-diethyl 2-amino-4-methylthiazole-5-sulfonamide (0.48 g). M+ 249; 1H NMR: δ 1.20(6H,t); 2.48(3H,s); 3.28(4H,q); 5.25(2H,br s); (solid).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:15]([O-])(O)=O.[Na+]>>[CH:3]1[N:2]=[CH:15][N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=12
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1cccnc1CN
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1cccn2cncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 44.8 mL of acetic anhydride and 19.2 mL of formic acid was heated in a 50-60° C. oil bath temperature for 3 h and then cooled to rt to give formic-acetic anhydride, which was then slowly added to the solid ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl and then stirred at rt for 8 h. Excess reagent was evaporated to give a residue, which was neutralized by very slow addition of sat. NaHCO3 solution. Solution was extracted with DCM, dried and evaporated to provide ethyl imidazo[1,5-a]pyridine-8-carboxylate as a yellow solid (crude weight 2.7 g). MS: exact mass calculated for C10H10N2O2, 190.07; m/z found, 191 [M+H]+.
Reaction SMILES: [P:1]([O-:40])([O:36][CH2:37][CH2:38]Br)([O:3][CH2:4][CH:5]([O:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2].[S:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>C1(C)C=CC=CC=1>[P:1]([O-:40])([O:36][CH2:37][CH2:38][C:42]1[S:41][CH:45]=[CH:44][NH+:43]=1)([O:3][CH2:4][CH:5]([O:24][C:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][N:26]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:2]
Reactant: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)Oc1cc(-c2ccccc2)on1
Reactant: c1cscn1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCc1[nH+]ccs1)Oc1cc(-c2ccccc2)on1
Reaction time: 120 h

Procedure:
A mixture of 0.925 g of the crude (2RS)-3-hexadecyloxy-2-(5-phenyl-3-isoxazolyloxy)propyl 2-bromoethyl phosphate obtained as described in the first part of Example 7 and 0.51 ml of thiazole in 0.8 ml of toluene was heated on an oil bath kept at 70° C. for 5 days, whilst stirring. The mixture was then cooled and freed from toluene by evaporation under reduced pressure. 15 ml of chloroform were then added to the residue, followed by 0.296 g of silver carbonate. The mixture was then heated under reflux for 1 hour. At the end of this time, the mixture was cooled, an insoluble material was filtered off and the solvent was stripped off from the filtrate by evaporation under reduced pressure. The residue was subjected to column chromatography through 20 g of silica gel. 0.117 g of the title compound was obtained as a viscous oil from the fractions eluted with a 1:1 by volume mixture of methanol and methylene chloride and with a 35:60:5 by volume mixture of methanol, methylene chloride and water.
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:7]([C:13]([NH:15][C:16]2[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:24][CH3:25])=[O:14])=[C:6]1[CH3:26])[CH2:2][CH2:3][CH3:4].[Br:27]N1C(=O)CCC1=O>ClCCl>[Br:27][C:9]1[C:8](=[O:12])[C:7]([C:13]([NH:15][C:16]2[C:17]([CH2:24][CH3:25])=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:22][CH3:23])=[O:14])=[C:6]([CH3:26])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10]=1[CH3:11]
Reactant: CCCCn1c(C)cc(=O)c(C(=O)Nc2c(CC)cccc2CC)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCCCn1c(C)c(Br)c(=O)c(C(=O)Nc2c(CC)cccc2CC)c1C
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of 3.0 g (8.5 mmol, m.p. 110°-112° C.) of 1-butyl-N-(2,6-diethylphenyl)-1,4-dihydro-2,6-dimethyl-4-oxo-3-pyridinecarboxamide and 1.7 g (9.6 mmol) of N-bromosuccinimide was dissolved in 100 ml of dichloromethane, and the mixture was stirred for a day at room temperature. The reaction mixture, transferred to a separatory funnel, was washed with water, saturated sodium bicarbonate and water. The organic layer was dried and concentrated in a known manner to give a crystalline residue, and the residue was recrystallized from a mixture of ethyl acetate and hexane, affording 2.25 g of the title compound having m.p. 158°-160.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([Br:18])[CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.CCN(CC)CC>C(Cl)Cl>[Br:18][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:17]=[CH:16][C:6]=1[O:7][CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)COc1ccc(CN)cc1Br
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a solution of t-butyl 2-(4-(aminomethyl)-2-bromophenoxy)acetate (6) (88 mg, 1 eq, 0.28 mmol) in DCM (15 mL) was added 4-fluoro-benzenesulfonyl chloride (65 mg, 0.33 mmol, 1.2 eq) and Et3N (56 mg, 0.56 mmol, 2 eq). The mixture was stirred at room temperature for 2 h, filtered, concentrated in vacuo and purified by preparative TLC to give 64 mg (48%) of t-butyl 2-(2-bromo-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (7).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C:17]=2[CH3:29])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C:17]=2[CH3:29])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)Cc1cccc(-c2ccc(O)cc2)c1C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1cccc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
tert-Butyl(dimethyl)silyl chloride (370 mg, 2.48 mmol) was added to a solution of allyl (4′-hydroxy-2-methyl-1,1′-biphenyl-3-yl)acetate (830 mg, 2.48 mmol) obtained in Example (98-1) and imidazole (170 mg, 2.48 mmol) in N,N-dimethylformamide (12 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was diluted with ethyl acetate and successively washed with water and a saturated aqueous NaCl solution, it was dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=95/5-90/10) to give allyl (4′-{[tert-butyl(dimethyl)silyl]oxy}-2-methyl-1,1′-biphenyl-3-yl)acetate (675 mg, yield: 69%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](Br)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=2)[CH2:38][CH2:37]1>>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[CH:43]=2)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Reactant: CN1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(N2CCN(C)CC2)c1
Yield: 83 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide (38 mg, 0.07 mmol) and 1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperazine (31 mg, 2 equiv.) were coupled together using the suzuki method previously described to provide 37 mg (83% yield) of the crude as a brown oil which was taken on to the deprotection step.
Reaction SMILES: C[O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][Br:10])[CH2:5][CH2:4]1.C[Si](I)(C)C>C(Cl)(Cl)Cl>[Br:10][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([OH:2])[CH2:4][CH2:5]1
Reactant: COC1CCC(CBr)CC1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: OC1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 4-methoxycyclohexylbromomethane compound (C-4) (2.6 g) in chloroform (7.8 g) was cooled with ice. Then trimethylsilyliodide (2.2 ml) was transferred to the C-4 solution. It was stirred at ambient temperature for 8 h, and then quenched with methanol. Then, volatiles were removed to obtain the desired alcohol in almost quantitative yield.
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:14]=[C:13]([C:15]([C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)=[O:16])[C:8]2[O:9][CH2:10][O:11][CH2:12][C:7]=2[CH:6]=1.[Cl-].[NH4+].O>C(OCC)C.O1CCCC1>[Cl:4][C:5]1[CH:14]=[C:13]([C:15]([CH3:1])([C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[OH:16])[C:8]2[O:9][CH2:10][O:11][CH2:12][C:7]=2[CH:6]=1
Reactant: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cc(Cl)cc2c1OCOC2
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cc(Cl)cc2c1OCOC2
Temperature: 40 °C
Yield: 79.8 %

Procedure:
A suspension of 0.148 mole of methyl magnesium iodide in 150 ml of diethyl ether at a temperature of 30° C., is added at ambient temperature to 17.3 g (0.033 mole) of (6-chloro-4H-1,3-benzodioxin-8-yl)(1-triphenylmethyl-1H-imidazol-4-yl)ketone dissolved in 200 ml of tetrahydrofuran. The temperature of the reaction mixture increases to 40° C. When the addition is complete, stirring is maintained for 1 hour at ambient temperature. There is then added 8 g of ammonium chloride and stirring is continued for a further hour. Subsequently, 100 ml of water are added and the reaction mixture is extracted twice with dichloromethane. The organic phases are dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The residue is recrystallized from 100 ml of ethyl acetate. 13.77 g of alpha-(6-chloro-4H-1,3-benzodioxin-8-yl)-alpha-methyl-1-triphenylmethyl-1H-imidazole-4-methanol are obtained. Yield: 80% of theory; M.P.: 248°-250° C. (decomposition).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[N:12][CH:13]=[N:14][C:15]([NH2:16])=[C:10]3[CH:9]=[N:8]2)[CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH2:26][C:27](O)=[O:28])[CH:21]=[C:22]([Cl:24])[CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:16][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:7]([CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:27](=[O:28])[CH2:26][NH:25][C:20]4[CH:19]=[C:18]([Cl:17])[CH:23]=[C:22]([Cl:24])[CH:21]=4)[CH2:2]3)[N:8]=[CH:9][C:10]=12
Reactant: Nc1ncnc2c1cnn2C1CCCNC1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1cnn2C1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 50 °C
Yield: 6.8 %

Procedure:
A mixture of 1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (620 mg, 2.2 mmol), 2-((3,5-dichlorophenyl)amino)acetic acid (475 mg, 2.2 mmol, 1 eq), HBTU (822 mg, 2.2 mmol, 1 eq) and DIPEA (560 mg, 4.4 mmol, 2.0 eq) in THF (10 mL) was heated to 50° C. for 16 h. The mixture was concentrated in vacuo and purified by silica gel column with EA in PE (20% to 100%, v/v) to give the title product (63 mg, yield: 7%). 1H NMR (400 MHz, DMSO-d6) δ: 8.21 (d, 1H), 8.11 (d, 1H), 7.85-7.65 (m, 2H), 6.76 (s, 1H), 6.73 (s, 1H), 6.60 (d, 1H), 6.32 (t, 1H), 4.76-4.71 (m 0.5H), 4.61-4.54 (m, 1H), 4.48 (d, 0.5H), 4.19 (d, 0.5H), 4.11-4.08 (m, 1H), 4.02-3.94 (m, 1.5H), 3.86-3.81 (m, 0.5H), 3.17-3.09 (m, 1H), 2.95-2.90 (m, 0.5H), 2.20-2.12 (m, 1H), 2.08-2.05 (m, 1H), 1.89-1.82 (m, 1H), 1.72-1.51 (m, 1H). ESI-MS: 420.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=1[F:40].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:27]1[C:28]2[C:24](=[C:23]([NH:1][CH2:2][C@:3]([OH:21])([CH2:8][C:9]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5])[CH:31]=[C:30]([CH3:32])[CH:29]=2)[CH:25]=[N:26]1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CN)C(F)(F)F
Reactant: Cc1cc(Br)c2cnn(-c3ccc(F)cc3F)c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1F)C(F)(F)F
Yield: 20.7 %

Procedure:
A solution of (2R)-2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 21, 20 mg, 0.065 mmol), 4-bromo-1-(2,4-difluorophenyl)-6-methyl-1H-indazole (Intermediate 13, 18.3 mg, 0.057 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.6 mg, 0.0028 mmol), racemic-BINAP (3.6 mg, 0.0056 mmol) and sodium tert-butoxide (7.7 mg, 0.081 mmol) in toluene (0.4 mL) was heated in a microwave at 120° C. for 15 min. The mixture was then cooled, partitioned between ethyl acetate (20 mL) and aqueous ammonium chloride (20 mL). The organic layer was separated, washed successively with aqueous sodium bicarbonate, water and brine, passed through a hydrophobic frit and evaporated. The residue was purified by mass-directed autopreparation to give the title compound (6.5 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][C:15](=[O:18])[CH2:16][Cl:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][C:15]2([CH2:16][Cl:17])[O:21][CH2:20][CH2:19][O:18]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CCOC(=O)C(CC(=O)CCl)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC1(CCl)OCCO1)c1ccc(Br)cc1

Procedure:
To a solution of ethyl 2-(4-bromophenyl)-5-chloro-4-oxopentanoate (1-2) (35 g, 105 mmol) and ethylene glycol (19.5 g, 315 mmol) in toluene (300 mL) was added para-toluenesulfonic acid (100 mg) and the reaction was heated to reflux with a dean stark trap for 6 hours. The reaction mixture was concentrated was purified by column chromatography eluting with 0-50% EtOAc/Hexane. The appropriate fractions were combined, concentrated, and the resulting solid was recrystallized from EtOAc and hexane to give ethyl 2-(4-bromophenyl)-3-[2-(chloromethyl)-1,3-dioxolan-2-yl]propanoate (1-3) as a white solid MS (M+H)+: 378.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:32][O:33][C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38]([CH:41](Br)[CH3:42])=[CH:37][CH:36]=1>C1COCC1>[CH3:32][O:33][C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH3:42])[CH:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Reactant: CC(C)(C)c1ccc(CC(=O)OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)C(C(=O)OCc2ccccc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (4-tert-butyl-phenyl)acetic acid benzyl ester (Step C, 1.8 g, 6.38 mmol) in anhydrous THF (15 mL) was added LiHMDS (9.57 mL, 9.57 mmol, 1.0 M solution in toluene) at −78° C. The reaction mixture was stirred for 1.5 h at −78° C., and then 4-(1-bromo-ethyl)-benzoic acid methyl ester (1.7 g, 7.02 mmol, in THF 5.0 mL) was added dropwise, stirred for 2 h at −78° C. and then allowed to warm to rt for 1 h. After completion of the reaction quenched with saturated NH4Cl solution (20 mL) and stirred for 10 min. The reaction mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was recrystallization from minimum amount of EtOAc and hexane at room temperature to afford 4-[2-benzyloxycarbonyl-2-(4-tert-butyl-phenyl)-1-methyl-ethyl]-benzoic acid methyl ester as a mixture of diastereomers (2.3 g, 80%), d/r (2:1): 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.30-7.38 (m, 7H), 7.06 (d, J=6.9 Hz, 2H), 5.11 (dd, J=6.0, 12.9 Hz, 2H), 3.92 (s, 3H), 3.75 (d, J=7.5 Hz, 1H), 3.49-3.46 (m, 1H), 1.29 (s, 9H), 1.24 (d, J=6.9, Hz, 3H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:4); Rf=0.6.