Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH2:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1cccn2nc(N)nc12
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ccccc1-c1cccn2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc12

Procedure:
[8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.312 mmol) and 1-(4-Bromo-phenyl)-4-methyl-piperazine (90.0 mg, 0.353 mmol) with 2,2′-Bis-dicyclohexylphosphanyl-biphenyl (34.0 mg, 0.0622 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a pale yellow foam (0.063 g, 49%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.39 (d, J=6.2 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.45 (d, J=7.5 Hz, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.09 (t, J=7.3 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.95 (d, J=7.6 Hz, 2H), 6.91-6.86 (m, 1H), 6.65 (s, 1H), 3.81 (s, 3H), 3.17-3.12 (m, 4H), 2.61-2.56 (m. 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].C1C=CC2N(O)N=[N:42]C=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:42])=[O:20])=[CH:21][CH:22]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(C(=O)O)cc2)c2cccc(Cl)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(C(N)=O)cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
185 mg of 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid, 25 mg of ammonium chloride, and 62 mg of HOBt were dissolved in 2.00 mL of DMF, and 78 mg of WSC was added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with water, an aqueous sodium hydrogen carbonate solution, and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80 to 0:100) to obtain a product, which was recrystallized from ethanol/water (95:5) to obtain 89 mg of 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH:22](OC)O)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.[C:27](=[O:34])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:28].C([SiH](CC)CC)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH2:22][NH:28][C:27](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:6][CH:7]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]
Reactant: CC(C)(C)OC(N)=O
Reactant: COC(O)C[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred mixture of 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-methoxyethanol (Example 5a, 36 mg, 0.1 mmol), tert-butyl carbamate (35 mg, 0.3 mmol), triethylsilane (0.1 mL), and acetonitrile (0.5 mL) was added trifluoroacetic acid (0.03 mL). The mixture was stirred at RT for 40 hr. Concentration and purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave tert-butyl 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)ethylcarbamate as a trifluoroacetic acid salt (23 mg, 0.043 mmol, 43% yield). MS found: (M+H)+=426.3.
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:46][O:47][C:48]1[CH:54]=[C:53]([O:55][CH3:56])[CH:52]=[C:51]([O:57][CH3:58])[C:49]=1[NH2:50].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([NH:50][C:49]2[C:51]([O:57][CH3:58])=[CH:52][C:53]([O:55][CH3:56])=[CH:54][C:48]=2[O:47][CH3:46])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCc1nnn(C(CCCCC)C(=O)O)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(CCCCC)C(=O)Nc2c(OC)cc(OC)cc2OC)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of (±)-5-dodecyl-α-pentyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained, mp 152°-155° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)=[CH:4][CH:3]=2)[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1nnc(-c2ccc(Br)cc2)n1
Product: Cn1nnc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1

Procedure:
Prepared in analogy to example 4.4 (a) from 5-(4-Bromo-phenyl)-2-methyl-2H-tetrazole and N-BOC-piperazine. MS (m/e): 345.1 (MH+, 41%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=S)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][NH2:17]>CC(O)C.C1COCC1>[CH2:1]([N:8]1[CH2:14][CH2:13]/[C:12](=[N:16]/[NH2:17])/[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C1CCN(Cc2ccccc2)CCN1
Reactant: NN
Solvent: CC(C)O
Solvent: C1CCOC1
Product: N/N=C1/CCN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from Step A (1.00 g, 4.54 mmol) in 2-propanol (8.0 mL) and THF (20 mL), hydrazine (0.68 g, 21.7 mmol) was added. The mixture was stirred at room temperature overnight. The crude product was concentrated, and the residue purified by preparative TLC (silcia gel, 1:9 10% ammonium hydroxide in methanol:dichloromethane) to yield the desired compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O>CC(N(C)C)=O>[NH:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]=[C:1]1[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(C=O)cc2)C1
Reactant: Nc1ccccc1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(-c3nc4ccccc4[nH]3)cc2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
tert-Butyl 2-(4-formylphenyl)morpholine-4-carboxylate (300 mg, 1.03 mmol) was dissolved in dimethylacetamide (4.5 ml). 1,2-Diaminobenzene (134 mg, 1.24 mmol) and sodium metabisulfite (294 mg, 1.54 mmol) were added and the reaction mixture was stirred at 90° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (20 g silica gel, 40 to 70% ethyl acetate in heptane) to yield a white solid (333 mg, 85%). MS (ISP): 280.3 (100%, [M-BOC+H]+), 380.2 (20%, [M+H]+).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([O:20][CH:21]([O:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH2:24][NH2:25])[CH3:19].CCN(CC)CC>C(Cl)Cl>[CH2:27]([O:26][CH:21]([O:20][CH2:18][CH3:19])[CH2:22][CH2:23][CH2:24][NH:25][S:1]([C:4]1[C:16]2[C:8](=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:28]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CCOC(CCCN)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of dansyl chloride (270 mg, 1.00 mmol) in CH2Cl2 (10 mL) was added 4-aminobutyraldehyde diethyl acetal (237 μL, 1.20 mmol) and Et3N (170 μL, 1.20 mmol). The solution was stirred for 1 h at 25° C. and was then evaporated to dryness under reduced pressure. The material left was processed and purified under conditions identical to those described for the processing and purification of 11. Fractions containing the product were collected and evaporated to dryness under low pressure affording 13 (366 mg, 930 μmol) as a solid in a yield of 93%. 1H NMR (300 MHz, DMSO-d6): δ 8.45 (dt, J=8.5, 1.1 Hz, 1H), 8.30 (dt, J=8.8, 0.9 Hz, 1H), 8.09 (dd, J=7.3, 1.2 Hz, 1H), 7.89 (t, J=5.5 Hz, 1H), 7.61 (t, J=8.5 Hz, 1H), 7.58 (t, J=8.5 Hz, 1H), 7.25 (dd, J=7.6, 0.7 Hz, 1H), 4.19 (t, J=5.3 Hz, 1H), 3.36 (m, 2H), 3.23 (m, 2H), 2.81 (s, 6H), 2.77 (t, J=5.5 Hz, 2H), 1.31 (m, 4H), 0.99 (t, J=7.0 Hz, 6H). 13C NMR (75 MHz, DMSO-d6): δ 151.2, 136.1, 129.2, 128.9, 128.1, 127.7, 123.5, 119.1, 114.9, 101.6, 60.2, 44.9, 42.2, 30.1, 24.4, 15.1. +ESI-HRMS: Calcd for C20H30N2O4S [M+H]+ 395.1999. found 395.2000.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cnc2ccc(Br)cc2c1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc2ccc(-c3ccc(Cl)cc3)cc2c1
Temperature: 150 °C

Procedure:
To a 2-5 mL microwave vial fitted with a stirbar was added methyl 6-bromoquinoline-3-carboxylate (Int-1, 0.15 g, 0.564 mmol), 4-chlorophenylboronic acid (0.114 g, 0.733 mmol), sodium carbonate (0.179 g, 1.69 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0651 g, 0.056 mmol). The vial was capped and 1,4-dioxane (1.6 mL) and water (0.47 mL) were added by syringe. The mixture was purged with argon for 5 min. The contents of the vial were heated in a microwave at 150° C. for 30 min. The reaction mixture was cooled to room temperature and the vial was opened. The mixture was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted twice with water. The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was used as obtained in the following step. LC-MS: (FA) ES+ 298.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:27]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 50 g (0.41 mole) of p-hydroxybenzaldehyde, 22.2 g (0.41 mole) of sodium methoxide and 500 ml of dried dimethylformamide was added 114 g (0.41 mole) of 1-bromotetradecane. The mixture was refluxed for 3 hours, then allowed to stand at room temperature overnight after which it was poured into ice-water and extracted with diethyl ether. The ether layer was washed with water, 5% potassium hydroxide, and saline, and dried over sodium sulfate, filtered and evaporated. The residue is recrystallized from hexane to give 4-tetradecyloxybenzaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:6]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2nn(CCN3CCCC3)cc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
4-Nitroindazole (3.00 g, 18.4 mmol) was dissolved in 60 mL of N,N-dimethylformamide and potassium carbonate (7.50 g, 54.3 mmol) was added. The mixture was stirred for 30 minutes and then 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (4.80 g 28.2 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature and the mixture filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo to remove N,N-dimethylformamide and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.64 (m, 4H), 2.48 (m, 4H), 3.01 (t, 2H, J=6.44), 4.67 (t, 2H, J=6.44), 7.49 (t, 1H, J=8.14), 8.19 (d, 2H, J=7.80), 8.92 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:48])[O:10][CH2:11][C@@H:12]([O:14][C:15]1[CH:16]=[C:17]([CH:33]=[C:34]([O:36][C:37]2[CH:42]=[N:41][C:40]([C:43](=[O:47])[N:44]([CH3:46])[CH3:45])=[CH:39][N:38]=2)[CH:35]=1)[C:18]([NH:20][C:21]1[CH:25]=[CH:24][N:23](C(OC(C)(C)C)=O)[N:22]=1)=[O:19])[CH3:13]>C(Cl)Cl>[F:48][CH:9]([F:8])[O:10][CH2:11][C@@H:12]([O:14][C:15]1[CH:35]=[C:34]([CH:33]=[C:17]([C:18](=[O:19])[NH:20][C:21]2[CH:25]=[CH:24][NH:23][N:22]=2)[CH:16]=1)[O:36][C:37]1[N:38]=[CH:39][C:40]([C:43]([N:44]([CH3:46])[CH3:45])=[O:47])=[N:41][CH:42]=1)[CH3:13]
Reactant: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 3-[[3-[(2S)-1-(difluoromethoxy) propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoyl]amino]pyrazole-1-carboxylate (150 mg, 0.26 mmol) in DCM (16 mL) and stirred at RT for 2 hours. The solvent was removed in vacuo, DCM (20 mL) added and the mixture washed with water (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL), dried (MgSO4) and reduced in vacuo to give the desired compound (94 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[C:6]=1[F:13])[CH3:2].[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([N:24]2[CH2:25][CH2:26][CH:22]([NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:27])[CH2:23]2)=[C:7]([F:12])[C:6]=1[F:13])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1ccc(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 70.1 %

Procedure:
A solution of 2,3,4-trifluorobenzoic acid ethyl ester (Example 1g, 3.70 g, 18.1 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under nitrogen atmosphere for 4.5 hours. The solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and the mixture concentrated in vacuo. The resulting residue is then purified by column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (4.70 g). 1H NMR (CDCl3): δ 7.59-7.49 (m, 1H), 6.35-6.26 (m, 1H), 4.88-4.84 (bd, 1H), 4.39-4.28 (m, 3H), 3.81-3.50 (m, 3H), 3.48-3.34 (m, 1H), 2.32-2.15 (m, 1H), 2.02-1.76 (m, 1), 1.45 (s, 9H), 1.40 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:24]#[C:23][C:25]1[CH:31]=[CH:30][CH:29]=[C:27]([NH2:28])[CH:26]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To the reaction vessel containing methyl 5-{N-[(6-amino-5-iodopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}pentanoate (2.0 g, 4.56 mmol, 1 eq), 3-ethynylaniline (0.715 mL, 1.5 eq), and bis(triphenylphosphine)palladium(II) dichloride (320 mg, 0.1 eq) in anhydrous DMF (10 mL) under anhydrous nitrogen atmosphere was added triethylamine (2.54 mL, 4 eq) and copper(I) iodide (173 mg, 0.2 eq). The reaction mixture was stirred at RT for 15 minutes and then partitioned between saturated aq NaHCO3 and EtOAc. The organic layer was separated, washed with aq NH4Cl (1×) and brine (1×), followed by drying with anhydrous Na2SO4. The upper clear liquid was decanted, concentrated, and the brown oily residue was subject twice to a gradient column chromatography (EtOAc-Hex from 1:3 to MeOH-EtOAc-Hex 1:30:6). Concentration of the product eluting fractions provided the title compound as a white foam (1.32 g, 68%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1)(=[O:3])[CH3:2].[C:12]1([CH2:18][S:19][CH:20]([C:24](O)=[O:25])[C:21](O)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:10][C:8]1[CH:9]=[C:4]([C:1]2[O:3][C:21](=[O:22])[C:20]([S:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:24]([OH:25])[CH:2]=2)[CH:5]=[C:6]([CH3:11])[N:7]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)nc(C)c1
Product: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)n1

Procedure:
The title compound was prepared from the condensation of the trimethylsilyl enol ether of 4-acetyl-2,6-dimethylpyridine and the diethyl ester of [(phenylmethyl)thio]propanedioic acid following the same procedure outlined in Method A; m.p. 88°-90° C. NMR (DMSO-d6) δ 2.55 (s, 6 H), 4.02 (s, 2 H), 6.85 (s, 1 H), 7.16-7.28 (m, 5 H), 7.40 (s, 2 H).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:22][O:23][C:24](=[O:59])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[CH2:34][CH:35]1[CH:40]([C:41]2[O:42][CH2:43][CH:44]([C:46](=[O:57])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[N:45]=2)[CH:39]2[O:58][CH:36]1[CH2:37][CH2:38]2>ClCCl.[Cu](Br)Br>[CH3:22][O:23][C:24](=[O:59])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[CH2:34][CH:35]1[CH:40]([C:41]2[O:42][CH:43]=[C:44]([C:46](=[O:57])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[N:45]=2)[CH:39]2[O:58][CH:36]1[CH2:37][CH2:38]2
Reactant: CCCCCCCCCNC(=O)C1COC(C2C3CCC(O3)C2Cc2cc(F)ccc2CCC(=O)OC)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCNC(=O)c1coc(C2C3CCC(O3)C2Cc2cc(F)ccc2CCC(=O)OC)n1
Reaction time: 0.25 h

Procedure:
To a suspension of Copper bromide (6.27 g, 28.08 mmol) in dichloromethane (90 mL), under nitrogen atmosphere and in a water bath, was added HMTA (3.94 g, 28.08 mmol) followed by DBU (4.17 mL, 28.08 mmol) and the resulting mixture was stirred for 15 minutes. Then, a solution of (3-{4-Fluoro-2-[3-(4-nonylcarbamoyl-4,5-dihydro-oxazol-2-yl)-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl]-phenyl}-propionic acid methyl ester (3.72 g, 7.02 mmol) in dichloromethane (40 ml) was added and the resulting mixture was stirred at room temperature for 16 h.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[N:7][CH:8]=1.[Br:13]P(Br)Br.O>C(Cl)Cl>[Br:13][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(C(F)(F)F)cn1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(CBr)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [5-(trifluoromethyl)pyridin-2-yl]methanol (5.0 g, 28.24 mmol) in DCM (50 ml) was added tribromophosphane (0.58 g, 3.50 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was then poured into water (50 ml) and the organics were extracted with DCM (2×50 ml), washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]1[O:18][C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[O:11][CH2:10]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:15]2[CH2:16][CH2:17][C:12]3([O:18][CH2:9][CH2:10][O:11]3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nccc(N2CCC3(CC2)OCCO3)n1
Reaction time: 2.5 h

Procedure:
A solution of 18.5 g 2,4-dichloropyrimidine in 150 ml ethanol is added dropwise to a solution of 16 ml 4-piperidone-ethylene ketal and 17.5 ml triethylamine in 100 ml ethanol while cooling on ice. Subsequently the reaction mixture is stirred for a further 2.5 hours, the ethanol is then removed in a vacuum, the residue is admixed with 100 ml water and the aqueous mixture is extracted three times with 50 ml methylene chloride each time. After drying the combined organic phases over sodium sulfate and removing the solvent, the solid residue is recrystallized from ethyl acetate/isohexane. In this way 11 g 8-(2-chloro-pyrimidin-4-yl)-1,4-dioxa-8-aza-spiro[4.5]decane is obtained as a white powder. f.p.: 135-137° C.