Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>C(OCC)C>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([Br:1])([F:8])[F:7])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)Br
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC(F)(F)Br
Temperature: 0 °C

Procedure:
A stirred solution of 4-bromo-4,4-difluorobutanol (0.57 g) in dry diethylether (5 cm3) was cooled to 0° C. Maintaining this temperature, triethylamine (1.7 cm3) was added. After ten minutes methanesulfonyl chloride (0.3 cm3) was added and the mixture stirred for a further hour at 0° C. The reaction mixture was poured into 2M hydrochloric acid (2 cm3) and diethylether (20 cm3). The organic phase was separated, washed with saturated brine, then passed through a plug of silica gel eluting with further diethylether. The diethylether fractions were evaporated under reduced pressure to give a light yellow oil (0.705 g). 1H NMR: δ 2.04-2.18(2H,m); 2.46-2.64(2H,m); 3.04(3H,s); 4.32(2H,t).
Reaction SMILES: [SH-].[Na+].[CH3:3][C:4]1([CH3:14])[O:8][N:7]=[C:6]([S:9]([CH2:12][CH3:13])(=O)=O)[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].C(S([O-])=O)O.[Na+].BrCC1[C:30]([Cl:37])=[N:31][N:32]([CH2:35][CH3:36])[C:33]=1[Cl:34]>CN(C)C=O.O>[Cl:37][C:30]1[C:13]([CH2:12][S:9][C:6]2[CH2:5][C:4]([CH3:14])([CH3:3])[O:8][N:7]=2)=[C:33]([Cl:34])[N:32]([CH2:35][CH3:36])[N:31]=1
Reactant: CCn1nc(Cl)c(CBr)c1Cl
Reactant: CCS(=O)(=O)C1=NOC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: O=S([O-])CO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Cl)c(CSC2=NOC(C)(C)C2)c1Cl
Reaction time: 1 h
Yield: 74.2 %

Procedure:
0.6 g of sodium hydrosulfide (purity: 70%, 10.7 mmoles) was added to a solution of 0.7 g (3.7 mmoles) of 5,5-dimethyl-3-ethylsulfonyl-2-isoxazoline dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto were added 0.51 g (3.7 mmoles) of anhydrous potassium carbonate and 0.56 g (3.6 mmoles) of Rongalit. The resulting mixture was stirred for 2 hours. Thereto was added, with ice-cooling, 0.9 g (3.5 mmoles) of 4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole. The resulting mixture was stirred at room temperature for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.8 g (yield: 70.8%) of 3-(3,5-dichloro-1-ethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a colorless transparent oily substance.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:38]([C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH:44]=O)([OH:40])=[O:39].Cl>C1COCC1.C(OCC)(=O)C>[C:13]1([CH:12]=[CH:44][C:43]2[CH:42]=[C:41]([CH:48]=[CH:47][CH:46]=2)[C:38]([OH:40])=[O:39])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(C=Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl) amide (3.3 mL, 3.3 mmol) in THF was added to a stirred suspension of benzyltriphenylphosphonium bromide (1.44 g, 3.6 mmol) in THF (35 mL) at 0° C. The resulting orange solution was added via cannula to a mixture of 3-carboxybenzaldehyde (500 mg, 3.3 mmol) and lithium bis(trimethylsilyl)amide (3.3 mL, 3.3 mmol) in THF (10 mL). The mixture was stirred overnight at room temperature. A 1N solution of HCl (75 mL) and ethyl acetate (75 mL) were added and the separated aqueous layer was extracted with ethyl acetate (3×50 mL), dried (MgSO4 anh.) filtered and evaporated. The residue was purified by HPLC (10:95 CH3CN:H2O, TFA 0.1%) to afford 130 mg of the title compound (17%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[CH:26]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.[CH3:35][CH2:36][OH:37]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:15]3[C:16](=[CH:17][N:18]=[C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][C:24]4=3)[CH:26]=[CH:35][C:36]2=[O:37])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1ccc2cnc3ccc(Cl)cc3c2n1-c1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4-(4-benzylphenylamino)-6-chloroquinoline-3-carbaldehyde (750 mg, 2.0 mmol) in EtOH (18 mL) was added triethyl phosphonoacetate (1.1 mL, 5.6 mmol) and K2CO3 (1.3 g, 9.3 mmol). The reaction mixture was stirred at 85° C. for 8 hours and then removed solvent. The reaction mixture was treated with 10 mL of water. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 97:3 v/v CH2Cl2: EtOH as solvent to afford title compound (510 mg, 64% yield) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1([OH:31])[CH2:8][O:7][CH:6]([C:9]2[C:13]3[CH:14]=[C:15]([N:18]4[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]4=[O:30])[CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)[O:5][CH2:4]1.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH3:29][N:20]1[C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][C:23](=[O:24])[N:18]([C:15]2[CH:16]=[CH:17][C:12]3[S:11][N:10]=[C:9]([CH:6]4[O:7][CH2:8][C:3]5([CH2:2][O:31]5)[CH2:4][O:5]4)[C:13]=3[CH:14]=2)[C:19]1=[O:30]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4OCC(O)(CBr)CO4)c3c2)c1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4OCC5(CO4)CO5)c3c2)c1=O
Yield: 16.3 %

Procedure:
To a mixture of 3-[3-[5-(bromomethyl)-5-hydroxy-m-dioxan-2-yl]-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil (0.580 g, 1.11 mmol) and tetrahydrofuran at 5° C. is added sodium hydride (60% dispersion in mineral oil, 0.0400 g, 1.11 mmol). The resultant mixture is stirred overnight at ambient temperature and treated with additional sodium hydride (0.0400 g, 1.11 mmol). The mixture is poured into saturated ammonium chloride and extracted twice with diethyl ether. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with diethyl ether-methylene chloride to afford the title compound (0.0800 g, 16.3%, mp 203-206° C.) which is identified by NMR spectral analysis.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([N:11]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[C:30]([Cl:42])[CH:29]=3)[O:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:12]4[O:13][CH:14]5[CH2:15][NH:8][CH2:9][CH:10]5[N:11]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CC(C)(C)OC(=O)N1CC2N=C(Nc3ccc4ncnc(Nc5ccc(OCc6ccccn6)c(Cl)c5)c4c3)OC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cc(Nc2ncnc3ccc(NC4=NC5CNCC5O4)cc23)ccc1OCc1ccccn1

Procedure:
N4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydro-pyrrolo[3,4-d]oxazole-5-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS APCI (+) m/z 488, 490 (M+1, Cl pattern) detected; 1H NMR (400 mHz, CD3OD) δ 8.56 (d, 1H), 8.44 (s, 1H), 8.21 (br. s, 1H), 7.91 (m, 2H), 7.70 (m, 2H), 7.63 (d, 1H), 7.57 (d, 1H), 7.39 (m, 1H), 7.16 (d, 1H), 5.28 (s, 2H), 5.17 (m, 1H), 4.78 (m, 1H), 3.34 (d, 1H), 3.16 (d, 1H), 2.84 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]#[CH:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:42]#[C:41][CH2:40][NH:39][C:37](=[O:38])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: C#CCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1

Procedure:
Following the procedure outlined for Example 152, 2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (Example 69) was coupled to N-(tert-butoxycarbonyl)propargylamine (Aldrich, St. Louis, Mo.) to afford tert-butyl (3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-yl)carbamate after purification via column chromatography on silica gel (10 to 40% EtOAc in hexanes). 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.08 (dd, J=1.00, 5.09 Hz, 1H), 7.69 (dd, J=0.98, 3.72 Hz, 1H), 7.51-7.56 (m, 2H), 7.32 (dd, J=3.91, 4.89 Hz, 2H), 7.07 (d, J=9.39 Hz, 1H), 3.94 (d, J=5.48 Hz, 2H), 3.26-3.29 (m, 4H), 3.12-3.18 (m, 4H), 1.40 (s, 9H); m/z (ESI, +ve ion) 628.1 (M+H)+. GK-GKRP IC50 (Binding)=0.695 μM.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O>[CH:17]1([N:23]2[CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCN(C4CCCCC4)CC3)cc2)[nH]c1=O

Procedure:
From 11.7 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 18.4 g. of N-cyclohexylpiperazine in 150 ml. of dimethyl sulfoxide, there is obtained 6-[p-(4-cyclohexyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinonitrile; m.p. 306°-312° (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C=O)C.S(Cl)([Cl:22])=O>>[Cl:22][C:8]1[C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1

Procedure:
To a solution of 7-nitroquinazolin-4(3H)-one (2.0 g, 10.5 mmol) in 40 ml thionyl chloride was added 0.8 ml of DMF and the mixture was heated at reflux overnight then evaporated to dryness to provide crude 4-chloro-7-nitroquinazoline.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([O:33]CC)=[O:32])[C:3]=12.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)[CH:7]=[CH:6][C:5]=2[N:4]2[CH2:27][CH2:28][C@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C:3]=12
Reactant: CCOC(=O)C[C@H]1CCn2c1c(Cl)c1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)Oc1ccc(COc2ccc3c(c2)c(Cl)c2n3CC[C@@H]2CC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.4 %

Procedure:
To a solution of (R)-ethyl 2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (54.6 g, 107 mmol) in dioxane (750 mL) and MeOH (75 mL) was added NaOH (aq. 3N, 89.0 mL, 268 mmol). The mixture was stirred at room temperature for 17 h, concentrated in vacuo to approx 150 mL, and acidified with aqueous 3N HCl (300 mL). The resulting slurry was shaken and the solid filtered, washed with H2O (twice), hexanes and dried in a vacuum oven (50° C., 2 Torr, 15 h) to give (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid (51.3 g, 101 mmol, 94% yield, >98% ee) as a white solid. Exact mass calculated for C24H23ClF3NO4: 481.1, found: LCMS m/z=482.2, [M+H+]; 1H NMR (400 MHz, CD3CN) δ ppm 1.33 (d, J=6.0 Hz, 6 H), 2.34 (m, 1 H), 2.58 (dd, J1=16.5, J2=9.7 Hz, 1 H), 2.86 (m, 1 H), 3.06 (dd, J1=16.5, J2=4.2 Hz, 1 H), 3.73 (m, 1 H), 4.01 (m, 1 H), 4.14 (ddd, J1=9.9, J2=8.5 Hz, J3=4.9 Hz 1 H), 4.75 (sep, J=6.0 Hz, 1 H), 5.08 (s, 2 H), 6.87 (dd, J1=8.8, J2=2.4 Hz, 1 H), 7.01 (d, J=2.4 Hz, 1 H), 7.18 (d, J=8.6 Hz, 1 H), 7.21 (d, J=8.8 Hz, 1 H), 7.63 (dd, J1=8.6, J2=2.1 Hz, 1 H), 7.68 (d, J=2.1 Hz, 1 H), 9.10 (bs, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.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]>[CH2:14]([C@H:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][N:11]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:34])([CH3:33])[C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: c1ccc(C[C@H]2CN(Cc3ccccc3)CCN2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(O)(c1ccc(N2CCN(Cc3ccccc3)C[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Temperature: 100 °C
Yield: 33.7 %

Procedure:
In a sealable vial (S)-1,3-dibenzylpiperazine (0.617 g, 2.316 mmol, Alfa Aeser, Ward Hill, Mass.), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (0.623 g, 2.316 mmol, Example 27, Step 1), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.071 g, 0.058 mmol, Strem Chemicals, Newburyport, Mass.), Pd2(dba)3 (0.067 g, 0.116 mmol, Strem Chemicals, Newburyport, Mass.), and sodium tert-butoxide (0.556 g, 5.79 mmol) were combined and suspended in toluene (5 mL). The vial was purged with N2 for 5 min and was then heated at 100° C. for 15 h. The mixture was diluted with EtOAc (20 mL), the layers were separated and the organics were washed with water (10 mL) and brine (10 mL). The organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give 2-(4-((2S)-2,4-dibenzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.355 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]2)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][CH2:30][C@@H:29]([O:32][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28]2)=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](O)C3)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(N3CC[C@@H](OS(C)(=O)=O)C3)cc2)C1
Reaction time: 0.33 h
Yield: 101.7 %

Procedure:
To a solution of (S)-1,4-di(t-butoxycarbonyl)-2-(4-((R)-3-hydroxy pyrrolidino)phenyl)piperazine (733 mg, 1.64 mmol) and triethylamine (0.34 mL, 2.46 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.152 mL, 1.97 mmol) at 0° C. After stirring for 20 min, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford (S)-1,4-di(t-butoxycarbonyl)-2-(4-((R)-3-(methansulfonyloxy)pyrrolidin-1-yl) phenyl)piperazine (877 mg, quant.) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]34[CH2:25][CH:24]3[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20]4)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1>[Pd]>[C:19]12([NH:18][C:16]([C:12]3[N:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]5[C:2]([F:1])=[CH:39][CH:38]=[CH:37][C:36]=5[F:40])[C:7]4=[N:14][C:13]=3[CH3:15])=[O:17])[CH2:25][CH:24]1[CH2:23][CH2:22][NH:21][CH2:20]2
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC12CC1CCN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC12CNCCC1C2

Procedure:
216 mg of rac-benzyl 1-[({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-3-azabicyclo[4.1.0]heptan-3-carboxylate (Example 176A, 0.4 mmol, 1 equivalent) were reacted [0.2 equivalents of palladium on activated carbon (10%), reaction time: 16 h] and worked up analogously to Example 121 [After the separation by HPLC, the residue was taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated]. This gave 123 mg (74% of theory; 98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=2)=[C:4]([I:17])[CH:3]=1.[CH2:18]([OH:21])[CH2:19][OH:20].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:20][CH2:19][CH2:18][OH:21])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:17])[CH:3]=1
Reactant: OCCO
Reactant: Clc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: OCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
A mixture of 2-(4,5-dichloro-2-iodophenoxy)-4-chloropyridine (0.45 g, 1.128 mmol), ethane-1,2-diol (4 mL, 71.89 mmol), K2CO3 (0.45 mg, 3.26 mmol) in acetone (6 mL) was stirred at 120° C. for 5 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed withed brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1 to 4:1) to afford the desired product (160 mg, 33% yield). ESI-MS m/z: 426.0[M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([C:19]#[N:20])[CH:17]=2)[NH:12][C:11](=O)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)([Cl:29])=O.C1(C)C=CC=CC=1.O>CN(C)C=O>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]=[C:11]([Cl:29])[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1cc2c(cc1C(F)(F)F)nc(Cl)c(=O)n2OCc1ccccc1
Reaction time: 20 h
Yield: 89 %

Procedure:
To a solution of 7.0 g (~19.4 mmol) of 1-benzyloxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 250 ml of dry N,N-dimethylformamide was added at 0° C. 38.5 ml of 1.93M phosgene in toluene (~74.3 mmol). Stirring was continued at 24° C. for 20 h. The evaporated reaction mixture was stirred with water to give the title compound (6.6 g; 89%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C=O)C>[Si:12]([O:1][CH2:2][CH2:3][C:4](=[O:6])[CH3:5])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)CCO[Si](C)(C)C(C)(C)C
Yield: 94 %

Procedure:
4-Hydroxybutan-2-one (1.0 g, 11.35 mmol), imidazole (1.16 g, 17 mmol) in DMF (15 ml) was reacted with tert-butyldimethylsilyl chloride (1.7 g, 11.35 mmol) for three hours at room temperature. The reaction was partitioned with ether and water. The aqueous phase was extracted several times with ether. The combined organics were washed several times with water then dried over magnesium sulfate and concentrated in vacuo to give the title compound as a clear oil (2.16 g, 94%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=3)[CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 51.8 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 0.15 mmol), 4-hydroxyphenylboronic acid (0.025 g, 4 mmol), Pd(dba)2 (0.02 g, 0.035 mmol), X-Phos (0.02 g, 0.042 mmol) and Na2CO3 (0.032 g, 0.3 mmol) in dioxane/H2O (20 mL/2 mL) was stirred at 95° C. for 18 h under N2. The solvent was removed in vacuo and the residue purified by chromatography (silica gel, petroleum ether/ethyl acetate 3:1) to give 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (0.03 g, 51%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.85 (s, 1H), 9.54 (s, 1H), 8.70 (s, 1H), 8.14 (s, 1H), 7.78-7.75 (m, 2H), 7.62 (s, 1H), 7.43 (t, 1H, J=8.0 Hz), 6.91-6.88 (m, 2H), 6.70 (d, 1H, J=7.8 Hz), 6.07 (d, 1H, J=8.1 Hz), 4.22 (brs, 1H), 3.57 (brs, 2H), 2.08-1.98 (m, 3H), 1.69 (brs, 1H), 1.15 (d, 3H, J=6.3 Hz). LC/MS: 387 [M+H]+, 385 [M−H]−, tR=1.59 min. HPLC: 96.77% at 214 nm, 97.82% at 254 nm, tR=6.12 min.