Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Br:19][CH2:20][CH2:21][CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)COc1ccccc1N1CCN(CCCBr)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine (2.37 g, 9.1 mmol), 1-bromo-3-chloropropane (14.34 g, 9 mL, 91.1 mmol), potassium carbonate (1.88 g, 13.6 mmol) and acetonitrile (40 mL) was heated 16 hours at reflux under argon. The reaction mixture was allowed to cool to 25° C., then filtered and concentrated in vacuo. The residue was further concentrated at 60° C. in vacuo to remove excess 1-bromo-3-chloropropane. The residue was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to give a mixture of 1-chloro- and 1-bromo-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane (1.4 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: C[O-]
Reactant: Oc1ccc(Cl)nc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(O)c(Br)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0° C. solution of 2-bromo-6-chloropyridin-3-ol (1 eq.) and DMF (0.2 M) is added NaOMe (2.2 eq.). The solution is allowed to warm to room temperature as the cooling bath expires and allowed to stir at room temperature for 24 h. The reaction is quenched with saturated NH4Cl and diluted with water. The aqueous solution is extracted with EtOAc. The combined EtOAc layers are dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH2:10][CH2:11][CH3:12])=[S:8])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[C:20](OC(OCC)OCC)(=O)C>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[N:3]=[C:2]3[N:1]=[CH:20][N:9]([CH2:10][CH2:11][CH3:12])[C:7](=[S:8])[N:6]3[N:5]=2)=[CH:18][CH:17]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCCNC(=S)n1nc(-c2ccc(Cl)cc2)nc1N
Product: CCCn1cnc2nc(-c3ccc(Cl)cc3)nn2c1=S
Yield: 71.5 %

Procedure:
The synthesis method of Example 55 was applied. The compound (280 mg) obtained in Example 44 and diethoxymethyl acetate (6.0 g) were used as reagents. The mixture was reacted at 100° C. for 2.5 hours to give 207 mg of white crystals (yield 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](=[O:19])[CH3:18]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH3:18])=[O:19])=[CH:4][CH:3]=1
Reactant: CC(=O)C(Br)c1ccccc1
Reactant: Sc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)C(Sc1ccc(Cl)cc1)c1ccccc1
Reaction time: 8 h

Procedure:
In a 100 ml round-bottomed flask, 1 eq. of 4-chlorothiophenol is dissolved in 4 eq. of pyridine and 50 ml of anhydrous ether, with magnetic stirring. 1.2 eq. of bromophenylacetone are then added dropwise and stirring is then carried out overnight at ambient temperature. The reaction mixture is then poured onto ice-cold water and is extracted with ethyl acetate. The organic phase is washed with 1M HCl solution and then with water, is dried over MgSO4 and is evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica gel column.
Reaction SMILES: N.CO.[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14](O)=[O:15])[CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][S:20](=[O:25])(=[O:24])[CH2:19]1.C[N:27](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14]([NH2:27])=[O:15])[CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][S:20](=[O:25])(=[O:24])[CH2:19]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(Br)cc2c(CC3CCCS(=O)(=O)C3)c[nH]c12
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2c(CC3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A solution of NH3/MeOH (40 mL) was added to a mixture of 5-bromo-3-((1,1-dioxo-tetrahydro-2H-thiopyran-3-yl)methyl)-1H-indole-7-carboxylic acid (1.30 g, 0.0034 mol), TEA (0.68 g, 0.0067 mol), and TBTU (2.16 g, 0.067 mol) in DCM (30 mL). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was washed with water and extracted with DCM (2×100 mL). The organic layers were dried, filtered, concentrated under reduced pressure, and purified by chromatography eluting with a mixture of DCM:MeOH (60:1), giving 0.94 g (72.5%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2([F:39])[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[N:17]=2)[CH2:11][CH2:10]1.Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:26]2([F:39])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([F:24])([F:22])[F:23])[N:17]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2cc(F)c(OC3CCN(Cc4nc(C(F)(F)F)no4)CC3)c(F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1cc(C2(F)CCNCC2)cc(F)c1OC1CCN(Cc2nc(C(F)(F)F)no2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-(3,5-difluoro-4-((1-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)oxy)phenyl)-4-fluoropiperidine-1-carboxylate D1i in dichloromethane (5 mL) is treated with hydrogen chloride in dioxane (4 M solution; 0.1 mL, 0.4 mL). The mixture is stirred at room temperature for 1 hour and concentrated to yield 5-((4-(2,6-difluoro-4-(4-fluoropiperidin-4-yl)phenoxy)piperidin-1-yl)methyl)-3-(trifluoromethyl)-1,2,4-oxadiazole D1j (hydrochloride salt) as an oil. LCMS calcd. for C20H23F6N4O2+ ([M+H]+): 465.2, found: 465.2.
Reaction SMILES: [CH3:1][N:2]([S:16]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:3][CH2:4]OS(C1C=C(C)C=CC=1)(=O)=O.[CH2:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH2:26]([N:33]1[CH2:38][CH2:37][N:36]([CH2:4][CH2:3][N:2]([CH3:1])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)(=[O:17])=[O:18])[CH2:35][CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(S(=O)(=O)OCCN(C)S(=O)(=O)c2cccc(C)c2)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(S(=O)(=O)N(C)CCN2CCN(Cc3ccccc3)CC2)c1

Procedure:
A solution of D1 (22 g, 89 mmol) and N-benzylpiperazine (15.7 g, 89 mmol) was heated to reflux in toluene for 96 hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo and the residue was purified by chromatography on silica gel to afford the title compound. MH+ 388.
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C([Sn](CCCC)([C:53]([O:55]CC)=[CH2:54])CCCCC)CCC.[F-].[K+]>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.O1CCCC1>[C:53]([C:2]1[CH:42]=[CH:41][C:5]([O:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:11][CH2:12]2)=[CH:4][CH:3]=1)(=[O:55])[CH3:54]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(Br)cc3)CC2)c2ncnn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](Oc3ccc(C(C)=O)cc3)CC2)c2ncnn12

Procedure:
A mixture of 4′-({4-[trans-4-(4-bromophenoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.67 g), dibutyl(1-ethoxyethenyl)pentylstannane (0.45 mL), dichlorobis(triphenylphosphine)palladium (0.038 g) and tetrahydrofuran (3 mL) was heated under reflux for 64 hr. Aqueous potassium fluoride solution was added, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11](=O)[CH3:12].Cl.[CH3:15][O:16][NH2:17].O.[OH-].[Na+]>CO>[CH3:15][O:16][N:17]=[C:11]([CH3:12])[CH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9]
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 50 °C

Procedure:
1-(2,4,6-trichloro-phenyl)-propan-2-one (273 g, 1.118 mol) was suspended in methanol (544 g) at ambient temperature. The resulting suspension was then heated under stirring to a temperature of 50° C. (most of the solid is dissolved). Then O-methyl-hydroxylamine hydrochloride as a 30% solution in water (358 g, 1.286 mol) was fed within 30-60 min. maintaining the temperature between 50-52° C. During the course of O-methyl-hydroxylamine hydrochloride addition the reaction mass turned into a two-phase system (liquid-liquid). At the end of O-methyl-hydroxylamine hydrochloride feed the pH was adjusted to 4-5 by slow addition of NaOH 30% (264 g 1.981 mol). The mixture was then stirred for 1-2 hours at 50-52° C. to allow the reaction to go to completion. Subsequently the pH was adjusted to 7-8 by adding NaOH 30% (8.5 g, 0.064 mol).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[S:5][C:6]=1[CH3:7].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:9](=[O:15])[N:10]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[C:11](=[O:14])[NH:12][CH:13]=2)[S:5][C:6]=1[CH3:7]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(-c2c[nH]c(=O)[nH]c2=O)sc1C
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(-c2c[nH]c(=O)n(C(=O)c3ccccc3)c2=O)sc1C
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
(5-(4,5-dimethyl-1,3-thiazol-2-yl)-2,4(1H,3H)-pyrimidinedione) (Prep 15, 100 mg) suspended in Pyridine (2 mL) was slowly added to a stirring solution of benzoyl chloride (0.156 ml, 1.344 mmol) in Pyridine (1 mL) under nitrogen atmosphere. The resulting yellow solution was stirred at rt for 5.5 hours. Water was added (3 mL) and the mixture was extracted with EtOAc (10 mL). The organic was washed with NH4Cl saturated aqueous solution (2×2 mL) dried (Na2SO4, vacuo) to afford 340 mg of a yellowish solid that was dissolved in EtOAc (30 mL) and washed with NaHCO3 aqueous saturated solution. The organic was dried (Na2SO4, vacuo) to afford the title compound as a yellowish solid (180 mg)
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[C:9]1([NH:15][C:16](=[O:30])[NH:17][N:18]=[C:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.C(O)C>[N:2](=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[C:19]1=[N:18][NH:17][C:16]([NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:30])[OH:3]
Reactant: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NN=c1c(=O)c2ccccc2c1=NO)Nc1ccccc1

Procedure:
0.01 mol of hydroxylamine hydrochloride and 0.01 mol sodium acetate in solution in 20 ml water were added to a solution of 0.01 mol of 2-(4-phenyl semicarbazono)-indan-1,3-dione in 150 ml ethanol. The reaction mixture was refluxed for 1 hour, then the ethanol was eliminated at reduced pressure. The resulting crystals were dried on suction pump, washed in water, dried and recrystallised from isopropanol.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:40])[C:8]1=[O:41])=O.O[Li].O>C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:40])[C:8]1=[O:41]
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(C(F)(F)F)cc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(C(F)(F)F)cc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
To a solution of 3-(1-methyl-2,4-dioxo-5-(4-(trifluoromethyl)benzyl)-6-(3-(trifluoromethyl) phenoxy)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (150 mg, 0.258 mmol) in THF (2 mL) was added aq. LiOH.H2O (1 mL, 0.5 M). The reaction was stirred at RT for 10 min then extracted with EA (50 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1-methyl-5-(4-(trifluoromethyl)benzyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (20 mg, 8% yield over 3 steps) as a white solid. 1H NMR (CDCl3) δ: 8.37 (s, 1H), 7.42 (m, 3H), 7.35 (m, 1H), 7.31 (m, 2H), 7.02 (m, 2H), 4.83 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 3.73 (s, 3H), 3.56 (s, 2H), 2.95 (s, 1H), 1.98-1.87 (m, 2H). LCMS: MH+ 554 and TR=3.39 min.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[N:15]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:14]=2)=[N:5][C:6](S(C)(=O)=O)=[N:7][CH:8]=1)#[N:2].[CH:43]([NH2:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([C:3]1[C:4]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[N:15]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:14]=2)=[N:5][C:6]([NH:46][CH:43]([CH3:45])[CH3:44])=[N:7][CH:8]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Yield: 81.6 %

Procedure:
Benzyl 3-(5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (0.826 g, 1.372 mmol) in THF (30 mL) was treated with isopropylamine (0.234 mL, 2.744 mmol, 2.0 Eq) and DIPEA (0.478 mL, 2.744mmol, 2.0 Eq) and allowed to heat at reflux for I hour. The mixture was concentrated in vacuo and purified by column chromatography (ISCO Companion™, 40 g column, 0-100% EtOAc/Petroleum ether) to give 0.651 g (82%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:36])[CH2:11][CH2:12][N:13]([CH:33]([CH3:35])[CH3:34])[C:14](=[O:32])[C:15]1[CH:20]=[C:19]([O:21][CH2:22][CH2:23][NH:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:18]=[C:17]([CH3:31])[CH:16]=1.[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:33]([N:13]([C:14](=[O:32])[C:15]1[CH:20]=[C:19]([O:21][CH2:22][CH2:23][NH:24][C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[CH:18]=[C:17]([CH3:31])[CH:16]=1)[CH2:12][CH2:11][C:10]([OH:36])=[O:9])([CH3:35])[CH3:34]
Reactant: COC(=O)CCN(C(=O)c1cc(C)cc(OCCNc2ccncc2)c1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(CCC(=O)O)C(C)C)c1
Yield: 89.5 %

Procedure:
To a solution of 3-(isopropyl-{3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-amino)-propionic acid methyl ester trifluoroacetate (0.031 g) in dioxan (1 ml) was added 2M aqueous sodium hydroxide (0.078 ml), and the resultant solution was stirred at room temperature for 3 h. 1M Aqueous hydrochloric acid (ca 0.5 ml) was added and the resultant solution was concentrated under reduced pressure. Th residue was subjected to preparative hplc and the title compound (0.027 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][CH2:7][CH2:8][CH:9]([N:10]=[C:11]=[S:12])[C:2]1=2.Cl.[CH3:14][O:15][NH:16][CH3:17]>>[CH3:17][N:16]([O:15][CH3:14])[C:11]([NH:10][CH:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH2:6][CH2:7][CH2:8]1)=[S:12]
Reactant: S=C=NC1CCCc2ccsc21
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=S)NC1CCCc2ccsc21

Procedure:
In the manner described in Example 5, 4,5,6,7-tetrahydrobenzo[b]thien-7-yl isothiocyanate is allowed to react with O,N-dimethylhydroxylamine hydrochloride to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[O:12])[N:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH2:33][N:32](C(OC(C)(C)C)=O)[CH:31]([C:44](OCC)=[O:45])[CH2:30]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:49][CH2:50][CH:51]([OH:54])[CH2:52][OH:53]>Cl.CO>[OH:54][CH:51]([CH2:52][OH:53])[CH2:50][NH:49][C:44]([CH:31]1[C:30]2[C:29](=[CH:28][C:27]([N:7]3[C:8]([NH:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:15]=4)=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]3)=[CH:36][CH:35]=2)[CH2:34][CH2:33][NH:32]1)=[O:45]
Reactant: NCC(O)CO
Reactant: CCOC(=O)C1Cc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Oc4cccnc4)c3)ccc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3cccnc3)c2)n(-c2ccc3c(c2)CCNC3C(=O)NCC(O)CO)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91 %

Procedure:
Using the same procedureas for Example 179, 2-t-butyl 3-ethyl 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (0.029 g, 0.044 mmol), available from experimental 184) in 3N hydrochloric acid in MeOH (10.0 mL) was stirred at RT for 1 h. The solvent was evaporated and the residue was dissolved in 3-amino-1,2-dihydroxypropane (0.200 g, 2.2 mmol) in MeOH (0.5 mL) and the solution was stirred at RT for 2 d. The solvent was evaporated and the residue was purified by reverse phase chromatography and coevaporated with THF/4N HCl to yield 1-(1-(1-((2,3-dihydroxypropyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (24 mg, 81% yield) as a pale yellow solid. 1H-NMR (MeOH-d4): δ 8.68 (d, 1H, J=3.2 Hz), 8.60 (d, 1H, J=7.6 Hz), 8.23 (ddd, 1H, J=8.8, 2.6, 1.0 Hz), 8.06 (dd, 1H, J=8.4, 1.4 Hz), 7.70 (dd, 1H, J=−9.0, 1.8 Hz), 7.58-7.54 (m, 3H), 7.42 (t, 1H, J=8.0 Hz), 7.22 (dt, 1H, J=8.4, 1.0 Hz), 6.90 (dd, 1H, J=6.8, 1.6 Hz), 6.58 (d, 1H, J=1.2 Hz), 5.29 (s, 1H), 3.84-3.63 (m, 2H), 3.63-3.51 (m, 5H), 3.30-2.87 (m, 2H), 1.37 (s, 9H), urea, amine, hydroxy and amide protons not visible. MS expected 600.3 found 600.2.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[O:28]=[C:29]([CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:30]>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:32]([CH3:34])([CH3:33])[CH2:31][C:29](=[O:28])[CH3:30])=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: CC(=O)C=C(C)C
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)C(C)(C)CC(C)=O
Yield: 75.7 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (1 g, 0.0044 mole) in chloroform (40 ml) was added triethylamine (0.68 ml, 0.0049 mole), trimethyl silylchloride (0.62 ml, 0.0049 mole) and mesityl oxide (0.56 ml, 0.0049 mole). The reaction mixture was stirred at reflux for 18 hours. The solution was washed with H2O, followed by extraction with 5% HCl solution and brine, dried over Na2So4 ; solvent was removed in vacuo to give 1.08 g of an oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[OH:16])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOP(=O)(OCC)c1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(I)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94.6 %

Procedure:
To a mixture of (2-hydroxy-5-iodo-phenyl)-phosphonic acid diethyl ester (14.7 g, 41.2 mmol) and cesium carbonate, (17.4 g, 53.5 mmol) in DMF (150 mL) was added benzyl bromide (6.40 mL, 54 mmol). The reaction was allowed to stir for 2.5 days at rt at which point the reaction was concentrated under reduced pressure, the residue diluted in 0.5 N HCl (30 mL) and extracted twice with EtOAc. The pooled organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 17.4 g (91%) of a colorless solid after recrystallization (EtOAc-hexanes). Rf 0.36 (1:1 EtOAc-hexanes). Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 447 (M+H).
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][N:11]=[C:7]2[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=2)[N:4]=1.[OH-:29].[Na+].Cl>O1CCOCC1>[OH:29][C:3]1[N:8]2[CH:9]=[N:10][N:11]=[C:7]2[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[C:5]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[CH:23]=2)[N:4]=1
Reactant: [OH-]
Reactant: CSc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1nc(-c2ccnc(Cl)c2)c(-c2cccc(C(F)(F)F)c2)c2nncn12

Procedure:
1 g of crude 5-methylthio-7-(2-chloro-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine and 15 ml of 2M NaOH in 15 ml 1,4-dioxane in a 150-ml r.b.flask with a stir bar was stirred at 80° C. The basic solution was cooled down to room temperature and neutralized to pH 7.5 with 10% HCl. A precipitate was formed, filtered off and washed with water (2×10 ml). The solid was dried under vacuum at 70° C. overnight to give a solid product; MS m/z (M+H)+ 392.1.