Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:29])[CH:23]([F:28])[C:24]([F:27])([F:26])[F:25])[CH:3]=1.[Cl:31]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:17])([F:18])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:29])([F:30])[CH:23]([F:28])[C:24]([F:25])([F:26])[F:27])[C:3]=1[Cl:31]
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)cc2N)cc1SCC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 30 mL of acetonitrile, and 0.9g of N-chlorosuccinimide was added under cooling with ice. After stirring for 30minutes under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 3.12 g of 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole.
Reaction SMILES: [C:1](=[NH:26])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[C:8]([F:25])[CH:7]=1)[NH2:2].[OH:27]/[CH:28]=[C:29](/[CH2:35][C:36]1[CH:37]=[N:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=1)\[C:30](OCC)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:9]2[C:10]([F:12])=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:30]=[C:29]([CH2:35][C:36]4[CH:37]=[N:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=4)[C:28](=[O:27])[N:26]=3)=[CH:7][C:8]=2[F:25])=[CH:15][C:16]=1[C:21]([F:22])([F:24])[F:23]
Reactant: N=C(N)OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Reactant: CCOC(=O)/C(=C\O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncc(Cc2c[nH]c(OCCc3cc(F)c(Oc4ccc(Cl)c(C(F)(F)F)c4)c(F)c3)nc2=O)cn1
Yield: 14.9 %

Procedure:
The same procedure as E125 from 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl imidocarbamate (143 mg, 0.362 mmol), ethyl (2Z)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (129 mg, 0.543 mmol) and K2CO3 (125 mg, 0.906 mmol) in DMF (3 mL), except that the reaction temperature was 130° C., to afford the title compound (31 mg, 0.054 mmol, 15.04% yield) as white solid. LCMS: rt=3.61 min, [M+H+]=569
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:24])=[C:16]2[CH:15]=1.[S:31](N)([NH2:34])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]3[CH2:30][CH2:29][N:28]([S:31](=[O:33])(=[O:32])[NH2:34])[CH2:27]3)=[O:24])=[C:16]2[CH:15]=1
Reactant: O=C(N[C@H]1CCNC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: NS(N)(=O)=O
Product: NS(=O)(=O)N1CC[C@H](NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)C1

Procedure:
The title compound was prepared by the method substantially similar to that mentioned in Example-98, using 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-pyrrolidin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (Example-82) and Sulfamide to afford the crude, which was purified by Preparative HPLC [Column: 21.2×250×7 um, Zorbax, XDB,C-18(#22), Mobile phase-A: 10 mmol.NH4OAc in water, B:ACN, Gradient (Time/% B): 0/30, 2/30, 8/90 and Flow rate:20 mL/min] to afford 26 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[BrH:12].BrBr.CC(C)=O>C(O)(=O)C>[Br:12][CH2:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: O=C(CBr)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a solution of 1-(4-chlorophenyl)propan-2-one (25.0 g, 148 mmol) in acetic acid (37.9 mL) was added 48% aqueous HBr (19.0 mL, 168 mmol). A solution of bromine (16.3 mL, 316 mmol) in acetic acid (63.2 mL) was then added over 10 minutes and the resulting solution was stirred for 4 hours at room temperature. Acetone (190 mL) was added and the resulting solution was stirred at room temperature for 3 days. The reaction was concentrated in vacuo and the residue was taken up in DCM (300 mL) and brine (100 mL). The layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexanes=0/100→15/85) to give 25.4 grams of the title compound as a dark gray solid (69% yield). 1H NMR (400 MHz, CDCl3) δ: 7.34-7.31 (m, 2H), 7.18-7.15 (m, 2H), 3.94 (s, 2H), 3.91 (2, 2H).
Reaction SMILES: O[Li:2].O.C[O:5][C:6](=[O:46])[CH2:7][C:8]1[C:9]([CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)=[N:10][CH:11]=[CH:12][CH:13]=1>C1COCC1.O.CO>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:18]3[N:17]=[C:16]([CH2:15][CH2:14][C:9]4[C:8]([CH2:7][C:6]([O-:46])=[O:5])=[CH:13][CH:12]=[CH:11][N:10]=4)[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][N:19]=3)=[CH:28][CH:29]=2)[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44].[Li+:2]
Reactant: COC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(=O)[O-])n3)cc2)CC1
Product: [Li+]
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.4 %

Procedure:
LiOH.H2O (19.1 mg, 0.455 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I122) (90.9 mg, 0.152 mmol) in THF (7 mL), water (1.5 mL) and methanol (1 mL). The resulting mixture was allowed to stir at room temperature for 20 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL), the organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (I123) (81.3 mg, 91%) as a pale yellow viscous oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH2:15]1[CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:19]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:18][C:17]=2[O:16]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][CH:25]([C:19]4[CH:20]=[CH:21][C:22]5[O:23][CH2:24][CH2:15][O:16][C:17]=5[CH:18]=4)[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc2c(cc1C1CCNCC1)OCCO2
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: c1cc(OCCCN2CCC(c3ccc4c(c3)OCCO4)CC2)c2cc[nH]c2c1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(3,4-ethylenedioxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 59% overall yield as a foam. FDMS m/e=392 (M+ of free base).
Reaction SMILES: [CH2:1]=O.[CH3:3][NH:4][CH3:5].[C:6](O)(=O)[CH2:7][C:8]([OH:10])=[O:9]>O>[CH3:3][N:4]([CH2:1][C:7](=[CH2:6])[C:8]([OH:10])=[O:9])[CH3:5]
Reactant: C=O
Reactant: O=C(O)CC(=O)O
Reactant: CNC
Solvent: O
Product: C=C(CN(C)C)C(=O)O

Procedure:
Formaldehyde solution (150 ml of 40% solution) was added with stirring to a solution of dimethylamine (218g of 26% solution) and malonic acid (104g) in water (250 ml). The reaction temperature was kept at 20° C during the addition and for a further 2 hours. The solution was then heated on a steam bath for 2 hours and the water was removed under reduced pressure to give a pale yellow syrup which was dried further by azeotropic distillation with benzene.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: N#Cc1cccc(F)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(F)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (3.66 g, 22.1 mmol) and 2-amino-3-fluorobenzonitrile (3.0 g, 22.05 mmol) in DCM (73 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (9.1 mL, 66.0 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 13.15 mL, 13.15 mmol). The reaction mixture was stirred at 0° C. for 2 hours, then at room temperature overnight. The resultant mixture was concentrated under reduced pressure to afford the title compound as a beige residue (5.19 g, 83% yield). This material was used in the next step without purification. LCMS (Method C): RT=3.49 min, m/z: 257 [M−N2].
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][SH:37])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:8]([S:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CS)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(CO[Si](C)(C)C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5-chloro 3(2H)-pyridazinone (1.5 g, 4.54 mmol) in DMF (10 ml) is added anhydrous cesium carbonate (2.9 g, 9.09 mmol) and 4-tert-butybenzyl mercaptan (1.02 g, 4.54 mmol). The mixture is stirred for 2 hours at 70° C. and then cooled to room temperature and ethyl acetate is added to it. The solution is then washed with water, dried and concentrated and the residue subjected to purification by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[CH2:12][CH2:11]3)=[O:14])[CH2:16][CH2:17]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O=C(C1CCNCC1)N1CCN(c2ccncn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1)N1CCN(c2ccncn2)CC1
Reaction time: 20 h
Yield: 30 %

Procedure:
4-(1-(4-Pyrimidinyl)piperazin-4-ylcarbonyl)piperidine (385 mg; 1.4 mmol) in CH2Cl2 (20 ml) was stirred at room temperature as a solid suspension and treated dropwise with 4-Bromobenzenesulfonyl chloride (385 mg; 1.5 mmol) and Et3N (0.4 ml; 3 mmol) in CH2Cl2 (15 ml). The resulting clear yellow solution was stirred at the same temperature for a further 20 h then treated with saturated NaHCO3(aq) (40 ml). The mixture was extracted twice with CH2Cl2 and the combined organic extracts washed twice each with water and brine then dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to a yellow solid. The solid was chromatographed through a 10 g silica bond elut prepacked column, eluting with 1% methanol, 1% ammonium hydroxide and 98% CH2Cl2 to give 1-(4-bromophenylsulphonyl)-4-(1-(4-pyrimidinyl)piperazin-4-ylcarbonyl)piperidine (209 mg; 30% yield based on the amine), a white solid, m.p. 171-174° C.;
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH:10]([NH:12][CH:13]([C:19]([O-])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])[CH:13]([NH:12][CH:10]=[O:11])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C(NC=O)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(NC=O)C(=O)Nc1ccc(Br)cc1C
Yield: 18.8 %

Procedure:
4-Bromo-2-methylaniline (1.48 grams, 0.008 mole), mono-ethyl formamidomalonate (1.39 grams, 0.008 mole), prepared in Part A of this Example, and 1,3-dicyclohexylcarbodiimide (1.64 grams, 0.008 mole) were reacted in a manner similar to that described in Example LVII to give 0.53 gram (0.0015 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-2-formamido-3-oxopropanoate as white crystals having a melting point of 174.5° C.-176° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.CCCCCC.C([O:25][C:26](=O)[C:27]([F:30])([F:29])[F:28])C>C(OCC)C.C1CCCCC1.C(OCC)C>[F:28][C:27]([F:30])([F:29])[C:26]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[CH:4]=1)=[O:25]
Reactant: C[Si](C)(C)c1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(C(=O)C(F)(F)F)c1
Temperature: -78 °C
Yield: 52.7 %

Procedure:
To a solution of 3-trimethylsilyl-bromobenzene (7.62 g, 33.3 mmol) in diethyl ether (35 ml) was added at 0° C. 1.5M n-butyllithium in hexane (22.2 ml, 33.3 mmol) over 10 min. Then the mixture was allowed to react 15 min at room temperature, cooled to -78° C. and ethyltrifluoroacetate (14.2 g, 100 mmol) was added over 5 min. Then the mixture was allowed to react 15 min at -78° C., the cooling bath was removed and when the temperature rose to 0° C. 3N HCl (35 ml) was added dropwise. The organic layer was separated, washed with water, brine, dried over MgSO4 and concentrated. Chromatography (silica gel, cyclohexane/diethyl ether: 90/10) followed by distillation under reduced pressure afforded the expected compound as a colorless oil (4.32 g, 53% yield), b.p. 120° C., Rf: 0.28 (cyclohexane/diethyl ether: 95/5).
Reaction SMILES: [CH:1]1([C:6]2([CH2:26][CH2:27][C:28]3[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH2:34][N:35](C)[C:36](=O)OC(C)(C)C)=[C:30]([CH2:46][CH3:47])[CH:29]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[C:8](=[O:25])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(OCCNC(=O)OC(C)(C)C)=C(CC)C=3)CC(O)=C(CC3N=C4N=C(C)C=C(C)N4N=3)C(=O)O2)CCCC1>>[CH:1]1([C:6]2([CH2:26][CH2:27][C:28]3[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH2:34][NH:35][CH3:36])=[C:30]([CH2:46][CH3:47])[CH:29]=3)[O:7][C:8](=[O:25])[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)=[C:10]([OH:12])[CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCN(C)C(=O)OC(C)(C)C
Agent: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCNC(=O)OC(C)(C)C
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1OCCNC

Procedure:
The title compound was prepared analogously to example A(71) where tert-butyl 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethyl(methyl)carbamate (Example A(69)) was substituted in place of tert-butyl 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-ethylphenoxy]ethylcarbamate in that example. 1H NMR (300 MHz, MeOD): δ 1.16 (t, J=8.54 Hz, 3 H) 1.32–2.35 (m, 11 H), 2.40 (s, 3H), 2.59–2.75 (m, 14 H), 2.92 (t, J=16.54 Hz, 2 H), 3.84 (t, J=7.54 Hz, 2 H), 6.55 (d, J=2.08 Hz, 1 H), 6.65 (d, J=2.56 Hz, 1 H), 6.95 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH:16]([CH2:20][N:21]3[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[N:23]([CH3:29])[C:22]3=[O:30])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH:31]OS([O-])=O.[K+].[OH2:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH2:15][CH:16]([CH2:20][N:21]3[C:25](=[O:26])[C:24]([CH3:28])([CH3:27])[N:23]([CH3:29])[C:22]3=[O:30])[C:17]([OH:19])=[O:18])(=[O:31])=[O:37])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(CC(CSc2ccc(-c3ccc(Cl)cc3)cc2)C(=O)O)C(=O)C1(C)C
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(CC(CS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)C(=O)O)C(=O)C1(C)C
Reaction time: 2 h

Procedure:
A solution of 3-[(4′-chloro[1,1′-biphenyl]-4-yl)sulfanyl]-2-[(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl]propanoic acid (4.6 g) in 30 ml of DMF was added dropwise to a stirred solution of Oxone® (13.5 g) in 75 mL of DMF and 20 mL of water at 45° C. After stirring for 2 h, the solvent was removed and the residue was partitioned between ethyl acetate and brine. The residue was columned on a small pad of silica gel eluting with chloroform to furnish 3.9 g of the title compound as a white foam.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:35][CH:36]3[CH2:38][CH2:37]3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[C:25]([O:27]CC5C=CC=CC=5)[N:24]=[CH:23][N:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:49][C:50]([O:52][CH3:53])=[O:51].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([NH:35][C:11]2[C:12]3[N:13]([C:15]([C:18](=[O:19])[NH:20][C:21]4[CH:26]=[C:25]([OH:27])[N:24]=[CH:23][N:22]=4)=[CH:16][N:17]=3)[N:14]=[C:9]([NH:8][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH2:7][CH2:6]3)[CH:10]=2)[CH2:38][CH2:37]1
Reactant: COC(=O)CBr
Reactant: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(OCc5ccccc5)ncn4)n3n2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(O)ncn4)n3n2)CC1
Temperature: 45 °C
Reaction time: 14 h

Procedure:
To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(6-(benzyloxy)pyrimidin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (30.0 mg, 0.058 mmol) in DCM (2 mL) was added DIEA (0.041 mL, 0.234 mmol) and methyl 2-bromoacetate (13.40 mg, 0.088 mmol). The reaction solution was stirred at 45° C. for 14 hrs. The reaction mixture was concentrated and treated with TFA (0.270 mL, 3.50 mmol) at 65° C. for 1 hr. The reaction mixture was concentrated and diluted with MeOH, and purified by HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to obtain methyl 2-((trans)-4-(8-(cyclopropylamino)-3-(6-hydroxypyrimidin-4-ylcarbamoyl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylamino)acetate (11 mg, 0.022 mmol, 38.0% yield). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.295 minutes. [M+H]=496.19. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43-12.79 (1H, m), 11.67 (1H, s), 9.11 (2H, d, J=4.77 Hz), 8.31 (1H, s), 7.96 (1H, s), 7.63 (1H, s), 6.90-7.18 (2H, m), 5.95 (1H, s), 4.14 (2H, t, J=5.65 Hz), 3.80 (3H, s), 3.53-3.79 (1H, m), 2.91-3.21 (1H, m), 2.21 (2H, d, J=10.79 Hz), 2.10 (2H, d, J=11.54 Hz), 1.61 (2H, br. s.), 1.24 (2H, d, J=12.30 Hz), 0.76 (2H, d, J=5.02 Hz), 0.62 (2H, d, J=2.51 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:16][O:17][CH2:18][CH2:19][CH:20]([CH3:37])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:36])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])(=[O:7])=[O:6].[CH3:38][N:39]([CH3:41])[CH3:40]>C1(C)C=CC=CC=1>[S:12]([O-:14])(=[O:13])(=[O:11])[CH3:15].[CH3:1][O:2][CH:3]([CH2:16][O:17][CH2:18][CH2:19][CH:20]([CH3:37])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:36])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:4][S:5]([CH2:8][CH2:9][CH2:10][N+:39]([CH3:41])([CH3:40])[CH3:38])(=[O:7])=[O:6]
Reactant: CN(C)C
Reactant: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)CS(=O)(=O)CCCOS(C)(=O)=O
Solvent: Cc1ccccc1
Product: COC(COCCC(C)CCCC(C)CCCC(C)CCCC(C)C)CS(=O)(=O)CCC[N+](C)(C)C
Product: CS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In 20 ml of toluene containing 4 g of trimethylamine is dissolved 3.1 g of 3-mesyloxypropyl 2-methoxy-3-(3,7,11,15-tetramethylhexadecyloxy)propyl sulfone, and the mixture is stirred at room temperature for 3 days. The reaction mixture is concentrated under reduced pressures to leave a residue which in turn is purified by silica gel column chromatography to yield 2.49 g of the captioned compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22]([NH:14][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[C:12]([CH3:13])[N:11]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1nc(N)ccc1COCC1CC1
Product: Cc1nc(NS(=O)(=O)c2cccc(Cl)c2C)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.053 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.058 g) as a light brown solid (0.046 g). MS (ESI−): 379.1 ([M−H]−)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=[C:10]2[CH:9]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1
Reactant: ClCOCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COCc1ccccc1

Procedure:
The title compound was prepared from 2.06 g (7.06 mmol) of 7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (Example 2, Step A) and benzyl chloromethyl ether essentially following the procedure outlined in Example 2, Step B. Purification by flash chromatography (silica gel, 5 to 10% ethyl acetate/hexane gradient) gave the title compound as a white foam. LC/MS 357 (M+1-tBu).