Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([O:36]CC5C=CC=CC=5)=[CH:33][CH:34]=4)[N:29]([CH3:44])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:45])=[CH:13]1>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=4)[N:29]([CH3:44])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:45])=[CH:13]1
Reactant: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCN)c3ccc(F)cc23)c2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCN)c3ccc(F)cc23)c2ccc(O)cc21
Yield: 69.5 %

Procedure:
The compound obtained in Example 63 (176 mg, 0.28 mmol) was dissolved in methanol (100 mL) and palladium (10 wt. % on activated charcoal, 200 mg) was added. The mixture was hydrogenated at ambient temperature at 60 psi over night, filtered through Celite® and concentrated in vacuo. The residue was purified by HPLC and lyophilized to give the title compound (104 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[N:21]=[C:22]([NH2:24])[CH3:23].CN1CCOCC1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([O:19][N:21]=[C:22]([NH2:24])[CH3:23])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: CC(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN1CCOCC1
Product: CC(N)=NOC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Preparation 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38], N′1-hydroxyethanimidamide [La Manna, et al, Theochem (1990), 69, 161-68], N-methyl morpholine, hydroxybenzotriazole hydrate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, to afford N′1-[((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)oxy]ethanimidamide as a colourless gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:3]=1[NH2:19].S(Cl)(Cl)(=O)=O.[CH2:25]([C:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1)[CH:26]=[CH2:27]>N1C=CC=CC=1>[F:9][C:5]1[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[C:3]([NH:19][S:31]([C:28]2([CH2:25][CH:26]=[CH2:27])[CH2:30][CH2:29]2)(=[O:33])=[O:32])[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: Nc1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(F)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a stirred solution of the amine, i.e., 3,5,6-trifluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine, (1 eq) in anhydrous pyridine (5 ml/mmole) was added the sulfonyl chloride, i.e., 1-allyl-cyclopropanesulfonyl chloride, (1-5 eq). The reaction mixture was stirred at 40° C. for 48 hours. The reaction mixture was partitioned with water and EtOAc. The organic layer was washed with brine, dried (MGSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica. 1H NMR (CDCl3, 300 MHz): δ 7.41 (dd, 1H), 7.38 (dd, 1H), 7.09 (s, 1H), 6.78 (m, 1H), 6.49 (m, 1H), 5.96 (s, 1H), 5.86 (m, 1H), 5.18 (d, 2H), 2.76 (d, 2H), 1.23 (m, 2H), 0.872 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:40][CH3:41])=[C:24]([CH:39]=1)[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32].O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:40][CH3:41])=[C:24]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:39]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: COc1ccc(CCl)cc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 4-(5-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (516 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (647 mg, yield: 83%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 109–110° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([NH:12][CH:13]1[CH2:19][C:18]2[CH:20]=[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])[CH:22]=[CH:23][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+].[CH2:36](O)[CH3:37]>>[CH2:5]([NH:12][CH:13]1[CH2:19][C:18]2[CH:20]=[C:21]([O:24][C:25]([CH3:30])([CH3:29])[C:26]([O:28][CH2:36][CH3:37])=[O:27])[CH:22]=[CH:23][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2)C(=O)O
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: -10 °C

Procedure:
Thionyl chloride (0.2 ml) was added dropwise to ethanol (5 ml) with stirring at -10° C. After stirring for ten minutes, 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-2-methylpropionic acid (0.49 g) was added portionwise to the mixture. The reaction mixture was stirred at ambient temperature for 1 hour and then refluxed for 3 hours. After cooling, the mixture was poured into an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with chloroform-methanol (100:1) to give ethyl 2-(8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy)-2-methylpropionate (0.43 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]2[N:21]=[CH:22][CH:23]=[C:4]2[N:3]=1.[CH:24]([O:27][C:28]1[CH:34]=[C:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:32]([CH3:41])=[CH:31][C:29]=1[NH2:30])([CH3:26])[CH3:25].Cl>C(O)(C)C.O1CCOCC1>[CH:24]([O:27][C:28]1[CH:34]=[C:33]([CH:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[C:32]([CH3:41])=[CH:31][C:29]=1[NH:30][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:5]2[N:21]=[CH:22][CH:23]=[C:4]2[N:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)nc2ccnn12
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccccc3S(=O)(=O)C(C)C)n3nccc3n2)c(OC(C)C)cc1C1CCNCC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-N-(2-(isopropylsulfonyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.1 mmol) and 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (0.1 mmol) in 2 mL of isopropanol, was added 25 uL of HCl in dioxane (2 N). The suspension was stirred at 150° C. for 3 hours. After work-up and prep-HPLC, product was obtained. 1H NMR (CDCl3, 400 MHz) δ 7.88-7.95 (m, 3H), 7.73-7.75 (d, 1H), 7.61-7.64 (m, 1H), 7.23-7.26 (m, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 6.17-6.18 (d, 1H), 6.09 (s, 1H), 4.46-4.54 (m. 1H), 3.30-3.34 (m, 2H), 3.12-3.21 (m, 1H), 2.79-2.83 (m, 3H), 2.27 (s, 3H), 1.77-1.79 (m, 4H), 1.15-1.28 (m, 12H); MS (ES+): 563.28 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:14]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH:13]=[CH2:12]
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc([N+](=O)[O-])cc1F
Yield: 99.6 %

Procedure:
A solution of compound 1 (20 g, 127.3 mmol), allyl bromide (16.19 mL, 190.96 mmol) and potassium carbonate (44 g, 318.25 mmol) in acetone (300 mL) was refluxed overnight. The solvent was removed in vacuo. The residue obtained was suspended in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate. The filtrate was concentrated to yield the desired compound 2 (25 g, yield 99.6%).
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C>[C:7]([O:6][C:4](=[O:5])[C:3](=[N:12][OH:13])[C:2](=[O:1])[CH3:11])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)C(=NO)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 3-oxobutyrate and sodium nitrite (1 equiv.) in acetic acid was stirred at room temperature to give tert-butyl-2-hydroximino-3-oxobutyrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21](SC)[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[NH2:25][NH2:26]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([NH:25][NH2:26])[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: NN
Reactant: CSc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Product: NNc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1

Procedure:
A solution of 6-(3-fluoropyridin-4-yl)-2-(methylthio)-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridine (Example 47, 0.05 g, 0.15 mmol) in hydrazine (0.5 mL) was heated in a sealed tube at 100° C. for 30 hours. The solvent was evaporated and the residue (0.05 g) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:23]2)=[CH:19][CH:18]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2)n1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4ccc(Cl)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-chloro-benzyl)-1H-pyrazol-3-yl amine. The title compound was obtained as a light yellow solid (Yield=28%). MS ISP (m/e): 389.2 (100) [(M+H)+].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[C:20]([Cl:21])=[CH:19][C:16]([CH2:17]Br)=[CH:15][C:14]=1[Cl:22])=[O:12].[N-:23]=[N+:24]=[N-:25].[Na+]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[C:20]([Cl:21])=[CH:19][C:16]([CH2:17][N:23]=[N+:24]=[N-:25])=[CH:15][C:14]=1[Cl:22])=[O:12]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc2ccccc2c1)c1c(Cl)cc(CBr)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc3ccccc3c2)c(Cl)c1
Yield: 103.6 %

Procedure:
A suspension of 4-(2-naphthoyl)-3,5-dichlorobenzyl bromide (0.633 g, 1.61 mmol) and sodium azide (0.245 g, 3.77 mmol) in 10 ml of ethanol was heated at reflux for 3 hours. The reaction mixture was filtered and the precipitate rinsed with ethanol. The filtrate was concentrated and the residue redissolved in ether. The resulting precipitate was collected and washed thoroughly with ether. Concentration afforded 0.594 g of an oil which slowly crystallized. The crude azide was used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[OH-].[Na+]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Reactant: Nc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Nc2ccccn2)c(C(F)(F)F)c1
Yield: 81 %

Procedure:
1.91 g (10 mmol) of 3-nitrobenzotrifluoride, 1.88 g (20 mmol) of 2-aminopyridine and 1.2 g (30 mmol) of sodium hydroxide in the form of microbeads are heated at 50° C. for 6 h in 30 ml of abs. DMSO while passing through dry air. After cooling, the mixture is diluted with ethyl acetate and extracted several times by shaking with water. After drying and stripping off the organic solvent, 3.8 g of crude product are obtained which is purified by chromatography on silica gel using petroleum ether and ethyl acetate (volume ratio 1:1). 2.3 g (8.1 mmol, 81%) of 2-(4-nitro-2-trifluoromethylphenylamino)-pyridine of m.p. 83°-84° C. are thus obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH2:19][CH3:20])[N:15]=[N:14]3)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:26]#[N:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[F:35].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH2:12][N:13]4[CH:17]=[C:16]([C@:18]([OH:25])([C:21]([F:22])([F:24])[F:23])[CH2:19][CH3:20])[N:15]=[N:14]4)=[CH:9][CH:10]=3)[N:5]=[C:4]([C:26]#[N:27])[CH:3]=2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: CCC(O)(c1cn(Cc2ccc3c(Cl)cc(C#N)nc3c2)nn1)C(F)(F)F
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)c(F)c4)cc(C#N)nc3c2)nn1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carbonitrile (100 mg, 0.25 mmol) in DME (3 mL) was added tetrakis(triphenylphosphine)palladium (14 mg, 0.013 mmol), 3,4-difluorophenylboronic acid (59 mg, 0.38 mmol) and aq. 2M Na2CO3 (0.38 mL, 0.75 mmol). After 2 h at 100° C., the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with EtOAc/hexanes, 4:6) gave the title compound. MS (+ESI): 474 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:3]1
Reactant: CN1CCOC(CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCOC(CN2CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-(4-methylmorpholin-2-ylmethyl)piperazine-1-carboxylate (5.00 g, 17.0 mmol) prepared according to Process Step 2 was dissolved in dichloromethane (60 mL), and the solution was mixed with trifluoroacetic acid (20 mL) added dropwise under ice-cooling. After stirring at room temperature for one hour, the solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in dioxane (100 mL), and the solution was mixed with triethylamine (20 mL) to thereby yield 4-methyl-2-piperazin-1-ylmethylmorpholine.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][CH2:62][NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](=[O:20])[NH:63][CH2:62][CH2:61][S:60][C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
351 mg (0.63 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 200 mg (0.63 mmol) 2-(Tritylsulfanyl)ethanamine, 0.11 ml (0.63 mmol) N,N-diisopropylethyl-amine and 238 mg (0.63 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 98 mg (0.110 mmol, 16% of theory) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[C@@H:19]1([C:25](O)=[O:26])[CH2:21][C@H:20]1[C:22]([OH:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:25]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([OH:24])=[O:23])=[O:26])[CH:7]=1)=[O:18]
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1ccnc(NC(=O)[C@@H]2C[C@H]2C(=O)O)c1)c1c(Cl)cccc1Cl
Temperature: 70 °C
Yield: 67 %

Procedure:
To a solution of N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide (141 mg, 0.50 mmol), trans-cyclopropane-1,2-dicarboxylic acid (325 mg, 2.5 mmol), and disiopropylethylamine (339 mg, 2.63 mmol) in dry DMF (5 mL) was added HATU (1951 mg, 2.5 mmol). The reaction mixture was heated at 70° C. for 6 hours and then quenched with sat. NH4Cl (100 mL). The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by prep HPLC (10-50% CH3CN/H2O with 0.1% formic acid) to give trans-2-(4-(2,6-dichlorobenzamido)pyridin-2-ylcarbamoyl)cyclopropanecarboxylic acid (132 mg, 67% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 10.86 (s, 1H), 8.38 (s, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.62-7.55 (m, 2H), 7.54-7.45 (m, 2H), 1.90-1.82 (m, 1H), 1.25 (dt, J=8.0, 5.4 Hz, 3H). LCMS (ESI) m/z: 394.0 [M+H+].
Reaction SMILES: [CH2:1]([N:3]1[C:11](Br)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N:4]1)[CH3:2].[Li]C(C)(C)C.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][C:19]([OH:18])([C:11]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]3[C:10]=2[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCn1nc2ccccc2c1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCn1nc2ccccc2c1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 22.5 %

Procedure:
To a solution of 2-ethyl-3-bromoindazole (3.4 g, 15.18 mmol) in THF (30 mL) was added t-BuLi (1.7 M in pentane, 10.72 mL, 18.22 mmol) dropwise at −78° C. After stirring at −78° C. for 20 min., was added tert-butyl 4-oxo-1-piperidinecarboxylate (3.03 g, 15.18 mmol) in THF (10 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 10 min. and at rt for 18 h. After the reaction was quenched with aq. NH4Cl , the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. Concentration followed by purification by flash chromatography (hexanes ethyl acetate=4:1, then 1:1) to give 1.18 g of the title compound as a foamy solid.
Reaction SMILES: [F:1][CH:2]([O:7][C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[O:10][C:11]([F:19])([F:18])[CH2:12][O:13][CH2:14][CH2:15][CH2:16]Br)[C:3]([F:6])([F:5])[F:4].[CH2:24]([O:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[N:36][CH:37]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([O:31][C:32]1[CH:37]=[N:36][C:35]([C:38]2[CH:39]=[CH:40][C:41]([O:44][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O:10][C:9]([F:21])([F:20])[C:8]([F:23])([F:22])[O:7][CH:2]([F:1])[C:3]([F:6])([F:5])[F:4])([F:19])[F:18])=[CH:42][CH:43]=2)=[N:34][CH:33]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(OC(F)(F)C(F)(F)OC(F)(F)COCCCBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)C(F)(F)F)cc2)nc1

Procedure:
Using essentially the procedure of Comparative Example A, the title compound was prepared by combining 3-(2-(2-(tetrafluoroethoxy)tetrafluoroethoxy)-2,2 -difluoroethoxy)-l-bromopropane (5.1 g, 38.5 mmol), 5 -heptyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 11.0 mmol), potassium carbonate (1.6 g, 12.7 mmol), and acetonitrile (58 mL). The resulting crude product was isolated and purified essentially as in Comparative Example A to yield 5.1 g.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([CH3:25])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH3:25][C:17]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)cc(C(F)(F)F)nc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
A suspension of sodium hydride (150 mg of 60% in mineral oil, 3.7 mmol) was formed in THF (10 mL) and cooled in an ice bath. 2,2,2-Trifluoroethanol (0.34 mL, 4.7 mmol) was added dropwise, then the mixture was stirred at 0° C. for 5 mins. A solution of ethyl 2-chloro4-methyl-6-(trifluoromethyl)nicotinate (500 mg, 1.9 mmol) in THF (10 mL) was added and the mixture heated at reflux for 18 hours then cooled to room temperature. The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried over magnesium sulphate, filtered and evaporated to give an oil. Purification by flash column chromatography on silica gel using 40% hexane: 60% DCM as eluent gave ethyl 4-methyl-2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)nicotinate as a colourless oil (350 mg): 1H NMR (500 MHz, CDCl3): δ 7.24 (1H, s), 4.83-4.77 (2H, q, J 8.3), 4.43 (2H, q, J 7.1), 2.43 (3H, s), 1.38 (3H, t, J 7.1).