Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:45][O:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:49](=[O:50])[CH2:48][CH2:47][O:46][CH3:45])[CH2:20]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCCC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NCC4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC(=O)N1CCC[C@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reaction time: 12 h

Procedure:
To a solution of 2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-ylmethyl)pyrimidin-4-amine, 11c, (0.04 g, 0.11 mmol) in a 10:1 mixture of CH2Cl2/DMF (1 mL) was added iPr2NEt (0.058 mL, 0.33 mmol) and 3-methoxypropanoyl chloride (0.02 g, 0.17 mmol). After 12 hours, the solvent was concentrated in vacuo and the resulting crude was and the crude was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 327.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[C:13](=[O:20])[CH2:12]1)(OCC1C=CC=CC=1)=O>C(O)C.[Pd]>[OH:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:20]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1CCO
Agent: [Pd]
Solvent: CCO
Product: O=C1CNCCN1CCO
Reaction time: 6 h

Procedure:
A solution of 1-carbobenzoxy-4-(2-hydroxyethyl)piperazine-3-one (1.0 g, 35.9 mmol) in absolute ethanol (75 ml) was hydrogenated over a 10% palladium on carbon catalyst (1.0 g) at 20°-25° and an initial pressure of 40 psi for 6 hours. Catalyst was removed by filtration through diatomaceous earth and the filtrate concentrated under reduced pressure to give 4-(2-hydroxyethyl)piperazine-3-one.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:22])=[O:21].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: NC(=O)CCCCCl
Reactant: CC1=C2CCNCC2c2ccccc21
Agent: Cl
Product: CC1=C2CCN(CCCCC(N)=O)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and 5-chlorovaleric acid amide are reacted in accordance with the process described in Example 1. Reaction period 19 hours at 60°. The hydrochloride of the title compound has a M.P. of 194°-196° from ethanol.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:11](C(OCC1C=CC=CC=1)=O)[NH:12]C(OCC1C=CC=CC=1)=O)[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CO.[OH-].[OH-].[Pd+2]>[NH:11]([CH:3]([CH2:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH2:2][OH:1])[NH2:12]
Reactant: O=C(NN(C(=O)OCc1ccccc1)[C@H](CO)CC1CCOCC1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NNC(CO)CC1CCOCC1
Yield: 94.4 %

Procedure:
To a solution of (S)-dibenzyl 1-(1-hydroxy-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)hydrazine-1,2-dicarboxylate (16.52 g, 0.0374 mol) in methanol (320 mL) was added Pd(OH)2/C (1.65 g). The reaction flask was evacuated and filled with H2. Stirring was continued until the starting material had disappeared. The mixture was filtered through celite, and the filter cake was washed with MeOH (2×30 mL). The combined organic solvent was dried over Na2SO4, and concentrated in vacuum to give 2-hydrazino-3-(tetrahydro-pyran-4-yl)-propan-1-ol (6.15 g, 94%), which was used for the next step without purification. 1H NMR (CD3OD) δ 1.2-1.7 (m, 7H), 2.2-2.7 (s, 4H), 2.8-2.9 (m, 1H), 3.3-3.4 (m, 3H), 3.7-3.8 (m, 1H), 3.9-4.0 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([C@@H:17]([CH:24]([CH3:26])[CH3:25])[CH2:18][O:19]C(OC)=O)[CH:11]=[C:10]([C:27]([O:29]CC)=[O:28])[C:9]2=[O:32].[OH-].[Na+].Cl>CC(O)C>[Cl:1][C:2]1[C:3]([F:36])=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([C@@H:17]([CH:24]([CH3:26])[CH3:25])[CH2:18][OH:19])[CH:11]=[C:10]([C:27]([OH:29])=[O:28])[C:9]2=[O:32]
Reactant: CCOC(=O)c1cn([C@H](COC(=O)OC)C(C)C)c2cc(F)c(Cc3cccc(Cl)c3F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)[C@@H](CO)n1cc(C(=O)O)c(=O)c2cc(Cc3cccc(Cl)c3F)c(F)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 19 (270 mg, 0.52 mmol) in 2-propanol (5 mL) was added 4N sodium hydroxide (1 mL) and the solution was stirred at rt for 3 h. The reaction mixture was acidified with 2N HCl (10 mL) and extracted with EtOAc (15 mL). The phases were separated and the aqueous phase was extracted with EtOAc (15 mL). The combined organic solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give 220 mg (95%, 98% purity) of 20 as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[CH3:29][C:30]([OH:34])([C:32]#[CH:33])[CH3:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:33]#[C:32][C:30]([OH:34])([CH3:31])[CH3:29])[N:3]=[C:4]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:5]4=[N:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:19]1
Reactant: C#CC(C)(C)O
Reactant: O=C(NC1CC1)c1ccc(-c2cnc3c(NCCCCO)nc(Br)cn23)cc1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C#Cc1cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc2c(NCCCCO)n1
Yield: 2.3 %

Procedure:
To a solution of 90 mg (203 μmol) 4-{6-bromo-8-[(4-hydroxybutyl)amino]imidazo[1,2-a]pyrazin-3-yl}-N-cyclopropylbenzamide which was prepared according to intermediate example 8a in 2.0 mL tetrahydrofuran were added 68.1 mg 2-methylbut-3-yn-2-ol, 1.0 mL tetrabutylammonium fluoride (1 molar in tetrahydrofuran) and 42.8 mg bis(triphenylphosphine)palladium (II) chloride. The mixture was subjected to microwave radiation for 2 hours at 130° C. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 2.1 mg (2%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:18][C:15]2=[CH:16][N:17]=1.[F:27][C:28]([F:39])([F:38])[C:29]1([CH2:32]OS(C)(=O)=O)[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:32][C:29]4([C:28]([F:39])([F:38])[F:27])[CH2:31][CH2:30]4)[CH2:23][CH2:22]3)[O:18][C:15]2=[CH:16][N:17]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCN(CC5(C(F)(F)F)CC5)CC4)oc3cn2)c(F)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (80 mg), methanesulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester (120 mg), KI (21 mg), K2CO3 (92 mg), and N-methylpyrrolidinone (3 mL) is stirred at 100° C. for 4 h. After cooling to room temperature, water is added and the mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the title compound. Mass spectrum (ESI+): m/z=497 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([C:16](=[CH:24][C:25]3([CH3:28])[CH2:27][CH2:26]3)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1>[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][C:25]3([CH3:28])[CH2:27][CH2:26]3)[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(=CC2(C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cn(C(CC2(C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 257 mg (583 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)prop-2-enoate (isomer mixture) were admixed with 30 ml of a “Hot Stryker's” reagent solution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292]. The reaction mixture was stirred at RT for 2 h, and 20 ml of saturated aqueous ammonium chloride solution were then added. The phases were separated and the aqueous phase was extracted three times with 25 ml of ethyl acetate. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (40 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 247 mg (96% of theory)
Reaction SMILES: C1([N:7]=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]=1/[CH:25]=[CH:26]/[C:27](/[CH3:37])=[CH:28]/[CH:29]=[CH:30]/[C:31](/[CH3:36])=[CH:32]/[C:33](O)=[O:34].ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]=1/[CH:25]=[CH:26]/[C:27](/[CH3:37])=[CH:28]/[CH:29]=[CH:30]/[C:31](/[CH3:36])=[CH:32]/[C:33]([NH2:7])=[O:34]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(N)=O)C(C)(C)CCC1
Reaction time: 8 h
Yield: 208.3 %

Procedure:
3.41 g (0.0165 mole) of dicyclohexylcarbodiimide (DCC) was added to 50 ml of dry dichloromethane solution of 6.98 g (0.0126 mole) of 1-amino-polyethyleneglycol-monomethyl ether (formula (IIIa), mean molecular weight 550), 4.54 g (0.0151 mole) of retinoic acid and 1.7 g (0.0126 mole) of 1-hydroxybenzotriazole and then stilled at room temperature for 8 hours in nitrogen atmosphere under shading and anhydrous condition. The reaction solution was filtered and then the solvent was removed by distillation under reduced pressure. The residue was separated by column chromatography (SiO2, mesh size 270-400, dichloromethane/methanol=15:1, v/v) to obtain 9.42 g (Yield 75%) of the title compound (pale yellow liquid in the form of wax, Tm=−15° C., Rf=0.22).
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.S(Cl)([Cl:18])(=O)=O>>[Cl:18][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)(F)c1ccc2nc(S)sc2c1
Product: FC(F)(F)c1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Sulfuryl chloride (40 mL) was added with stirring to 2-mercapto-6-(trifluoromethyl)-benzothiazole (18.0 g, 76.7 mmol) at <20° C. under a nitrogen atmosphere, and the suspension was then stirred at rt for 2 h. The reaction mixture was poured into ice water with stirring. Precipitation was formed, and stirring was continued for 2 h. The solid precipitate was filtered, and rinsed with water. The wet filter cake was dissolved in 100 mL EtOAc, and the solution was washed with 100 mL water and 50 mL saturated aqueous NaHCO3 solution, then dried over Na2SO4. EtOAc was removed by rotary evaporation, and the residue was dried in vacuo to afford the desired product as a light yellow solid (16.5 g, 91%). GC-EIMS m/z 237 (M+); 1H NMR (CDCl3) δ 8.10 (s, 1H), 8.00 (d, 1H), 7.70 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]([OH:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][C:25]=2[OH:40])[N:21]=[C:20]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([OH:56])[CH2:50][O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:43][C:42]=2[OH:57])[N:19]=1.[OH-].[K+].S(OC)(O[CH3:64])(=O)=O>COCCOCCOC>[OH:57][C:42]1[CH:43]=[C:44]([O:47][CH2:48][CH:49]([OH:56])[CH2:50][O:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:45]=[CH:46][C:41]=1[C:20]1[N:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]([OH:39])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][C:25]=2[OH:40])[N:23]=[C:18]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][C:2]=2[O:1][CH3:64])[N:19]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCCCC)cc3O)nc(-c3ccc(OCC(O)COCCCC)cc3O)n2)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCCCC)cc3O)nc(-c3ccc(OCC(O)COCCCC)cc3OC)n2)c(O)c1
Temperature: 80 °C
Yield: 57.6 %

Procedure:
A mixture of 11.9 g (15.0 mmol) of 2,4,6-tris[2-hydroxy-4-(3-n-butoxy-2-hydroxypropoxy)phenyl]-1,3,5-triazine in 80 ml of diglyme (Fluka 99.5%) is heated under nitrogen to 80° C. To the solution there are added in succession 1.0 g (15.1 mmol) of pulverized KOH (Fluka, 85%) and 2.5 g (19.8 mmol) of dimethyl sulfate (Fluka, 99%), with stirring. After stirring at 80° C. for 20 h the mixture is cooled, the precipitate is filtered off and the solvent is stripped off from the filtrate. The crude product is purified by column chromatography (silica gel 60, 230-60 mesh, Ø=5 cm, h=30 cm; CH2Cl2/methanol 95:5). Stripping the solvent from the main fraction and drying at 100° C./0.9 mmHg for 3 h give 7.0 g (57.8%) of the title compound (Compound 1).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.[Br:22][CH:23]1[S:31][C:30]2[C:25]([N:26](Cl)[CH:27]=[C:28]([C:32]#[N:33])[CH:29]=2)=[CH:24]1.C(OCC)C>C(OCCO)C>[Br:22][C:23]1[S:31][C:30]2[C:25](=[N:26][CH:27]=[C:28]([C:32]#[N:33])[C:29]=2[NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[CH:24]=1
Reactant: N#CC1=CN(Cl)C2=CC(Br)SC2=C1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#Cc1cnc2cc(Br)sc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A mixture of 4-phenoxyaniline (430 mg, 2.32 mmol), pyridine hydrochloride (244 mg, 2.11 mmol) and 2-bromo-4-chlorothieno[3,2-b]pyridine-6-carbonitrile (578 mg, 2.11 mmol) in 10 mL of 2-ethoxyethanol is heated at 125° C. for 4 hours. The mixture is poured into diethyl ether and the solids are collected by filtration. The solids are stirred with saturated aqueous sodium bicarbonate for 1 hour. The solids are collected by filtration, washed with water and diethyl ether to give 717 mg of 2-bromo-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a tan solid, mp 248-250° C.; 1H NMR (DMSO-d6) δ 7.01-7.19 (m, 5H), 7.23-7.47 (m, 4H), 7.66 (s, 1H), 8.57 (s, 1H), 9.62 (s, 1H); MS 422.1, 424.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)([CH3:11])([CH3:10])[CH3:9]>C(O)(C)(C)C>[C:8]([O:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:23][CH2:22]2)=[CH:16][CH:15]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: Brc1ncccn1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(NC2CCN(c3ncccn3)CC2)cc1
Temperature: 90 °C
Yield: 90.3 %

Procedure:
2-Bromopyrimidine (0.016 g, 0.1 mmol) was added to a solution of (49) (0.032 g, 0.12 mmol) in tert-butyl alcohol (2 mL) at 25° C. The mixture was heated to 90° C. and was maintained at that temperature for 12 h. The reaction mixture was then cooled to room temperature and concentrated to a yellow oily residue. Purification of the residue by flash column chromatography (gradient elution 0 to 20% EtOAc in hexanes) provided the title compound (0.032 g, 89%): TLC (Rf =0.41; 40% EtOAc/hexanes); 1H NMR (CDCl3) δ 8.29 (d, 2H, J=4.7), 7.80 (d, 2H, J=8.8), 6.54 (d, 2H, J=8.8), 6.46 (t, 1H, J=4.7), 4.66 (d, 2H, J=13.7), 3.96 (d, 1H, J=7.8), 3.63 (m, 1H), 3.13 (t, 2H, J=12.0), 2.12 (d, 2H, J=12.0), 1.54 (s, 9H), 1.43 (m, 2H); 13C NMR (CDCl3) δ 166.1, 161.6, 157.8, 150.3, 131.5, 120.5, 111.8, 109.8, 79.9, 50.1, 42.6, 32.1, 28.3; HRMS (FAB) m/z 355.2126 (M+H)+ (C20H26N4O2 requires 355.2134).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[N:13][CH:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OCCc1ccc(O)cc1
Product: OCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D3 starting from 4-(2-hydroxyethyl)phenol and 2-chloro-5-(trifluoromethyl)pyridine. LC-MS (ESI): m/z 284 [M+H]+; 2.97 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14](CC(O)=O)[C:13](=[O:19])[C:12](CC)(CC)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:19])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1CCC[C@@H](c2cc(F)cc(F)c2)N1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl (5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)pentanoate from Step A (4.42 g, 12.2 mmol) in MeOH (200 mL) was cooled to 0° C. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 1 minute, after which time the reaction vessel was sealed and allowed to sit in the ice bath for 15 minutes. Dry nitrogen was then bubbled through the solution for 30 minutes, prior to removal of solvent in vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. After dissolving in a third volume of MeOH (100 mL), triethylamine (6.78 mL, 48.9 mmol) was introduced and the mixture was heated to 65° C. for 3 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between diethyl ether (100 mL) and 1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=212 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13]2)=[CH:8][CH:7]=1)C.[OH-].[Na+]>>[F:17][C:15]1[CH:14]=[N:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:18])=[O:3])=[CH:11][CH:10]=2)[CH:16]=1
Reactant: CCOC(=O)Cc1ccc(-n2cc(F)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(-n2cc(F)cn2)cc1
Yield: 94.9 %

Procedure:
4.4 g (17.7 mmoles) of 4-(4-fluoropyrazol-1-yl)phenylacetic acid ethyl ester in 60 ml of 1 N solution of sodium hydroxide are heated to 100° C. for 2 hours. After cooling and extraction with benzene, clarification (effected with activated charcoal) is followed by acidification with concentrated hydrochloric acid to produce 3.7 g (95% of theory) of 4-(4-fluoropyrazol-1-yl)phenylacetic acid, m.p. 165° to 167° C. (from acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:25][O:18][C:17](=[O:19])[CH2:16][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)[NH:13][CH:14]=1
Reactant: Cn1cc(-c2cnc3[nH]cc(CC(=O)O)c3c2)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c[nH]c2ncc(-c3cnn(C)c3)cc12
Yield: 70 %

Procedure:
[5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid (200 mg, 0.78 mmol) was suspended in Methanol (4 mL). Next, sulfuric acid (125 uL) was added and the solution was heated to reflux for 2 hours. The solution was concentrated under vacuum and the crude material was dissolved in dichloromethane, transferred to a separatory funnel and washed with sat. NaHCO3 (aq). The organic layer was dried over Na2SO4 and concentrated down. The crude product was purified by flash chromatography (0-10% Methanol/dichloromethane gradient) to afford the title compound (148 mg, 70% yield). MS m/z=271 [M+H+]+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[F:14])(=[O:3])[CH3:2].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[F:14])=[O:3]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(C(C)=O)c(F)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C(=O)CBr)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
N-(4-Acetyl-3-fluoro-phenyl)-acetamide (10.2 g, 51.2 mmol) is dissolved in 50 mL chloroform. At room temperature bromine (1.98 mL, 38.4 mmol) is added drop wise. The reaction mixture is stirred at room temperature for 1.5 hours. Subsequently the precipitated product is filtered off, washed first with chloroform and then with ethyl acetate to yield N-[4-(2-bromo-acetyl)-3-fluoro-phenyl]-acetamide (8.7 g, 43%); LCIMS at 254 nm; [M+H] 275; Rt 2.918 min)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14]C(=O)C)=[CH:6][CH:7]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccccc1-c1ccc(Cl)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1ccccc1-c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 3-chloro-6-(2-acetoxyphenyl)pyridazine (23.1 g), aqueous sodium hydroxide (2N, 56 ml) and ethanol (10 ml) was stirred at room temperature for 1 hour. The mixture was diluted with an equal volume of water, adjusted to pH 2 with concentrated hydrochloric acid and was filtered to give 3-chloro-6-(2-hydroxyphenyl)pyridazine (18.7 g) m.p. 187.5°-188.5°. A sample recrystallised from ethanol had m.p. 187.5°-188.5°.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O>>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc(OC)c1O
Reactant: OB(O)c1ccco1
Product: COc1cc(-c2ccco2)cc(OC)c1O
Yield: 79 %

Procedure:
4-Bromo-2,6-dimethoxyphenol (Lee, H.; et al. Tetrahedron Letters, 2004, 45, 1019) was coupled with 2-furylboronic acid according to the procedure used in the synthesis of Example 21. Purification by chromatography (20-40% EtOAc-hexanes) gave 4-(furan-2-yl)-2,6-dimethoxyphenol as a light orange solid (1.95 g, 79% yield).