Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[OH:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C1C=CC=CC=1>[C:14]([NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[OH:13])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H]1Cc2ccccc2C[C@H]1O
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: O=C(N[C@@H]1Cc2ccccc2C[C@H]1O)c1ccccc1
Reaction time: 2 h

Procedure:
To a well stirred solution of 3.62 g of trans-3-amino-1,2,3,4-tetrahydro-2-naphthalenol, hydrochloride (1:1) in 30 ml of water at 0-5° C is added 2.1 ml of benzoyl chloride in 10 ml of benzene. To this stirred two-phase mixture is added, over 30 minutes at 0°-5° C, a solution of 1.45 g of sodium hydroxide in 30 ml of water--precipitation of a pink solid begins immediately. After stirring the mixture for an additional 2 hours at 0°-5° C, the solid is filtered, washed with ether, and dried in vacuo to give 4.2 g of crude trans-3-benzamido-1,2,3,4-tetrahydro-2-naphthalenol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[N:6]=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:3][CH:4]=2)=[N:12][N:11]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Br)cn2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCOCC3)cn2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
A mixture of 5-bromo-2-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.52 mmol), morpholine (455 μL, 5.22 mmol) and tetrabutylammonium iodide (41 mg, 0.10 mmol) was irradiated in the microwave for 1.5 h at 160° C. After cooling to ambient temperature the resulting suspension was diluted with ethyl acetate (15 mL) and stirred for 15 min at this temperature. Filtering off and washing with water (2 mL) and with ethyl acetate (1 mL) afforded the title compound (95 mg, 47%) which was obtained as a light brown solid. MS: m/e=390.3 [M+H]+.
Reaction SMILES: [NH:1]([C:8]([CH3:15])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[C:21](OCC)(=[O:26])[C:22]#[C:23][CH2:24][CH3:25]>>[CH2:13]([O:12][C:10]([C:9]1[C:23]([CH2:24][CH3:25])=[CH:22][C:21](=[O:26])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]=1[CH3:15])=[O:11])[CH3:14]
Reactant: CCC#CC(=O)OCC
Reactant: CCOC(=O)C=C(C)Nc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CC)cc(=O)n(-c2ccccc2)c1C

Procedure:
To a stirred solution of ethyl 3-anilinobut-2-enoate (50 mg, 0.2 mmol) in tetrahydrofuran (1 mL, 10 mmol) sodium hydride (60% NaH in mineral oil, 9.7 mg) was added. After 15 min ethyl 2-pentynoate (0.039 mL, 0.292 mmol) was added. After 60 min it was partitioned between ether (9 mL) and sat. aq. NaHCO3 (3 mL). The organic phase was washed twice with sat. aq. NaHCO3, dried (MgSO4) and evaporated. LC-MS (m/z) 286.3 (MH+); tR=1.27 (method C). 1H NMR (500 MHz, DMSO-d6): 1.13 (t, J=7.4 Hz, 3H, Me of Et), 1.28 (t, J=7.1 Hz, 3H, Me of EtO), 1.89 (s, 3H, 2-Me), 2.49 (q (overlapping with DMSO), J=7.4 Hz, 2H, CH2 of Et), 4.28 (q, J=7.1 Hz, 2H, CH2 of EtO), 6.28 (s, 1H, C5-H), 7.27 (t, J=7.3 Hz, 2H, two ortho-H of Ph), 7.47 (t, J=7.3 Hz, 1H, para-H of Ph), 7.53 (t, J=7.5 Hz, 2H, two meta-H of Ph).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[C:4]=1[F:10])[CH3:2].P(Cl)(Cl)([Cl:13])=O>C(N(CC)CC)C.ClCCl>[Cl:13][C:5]1[C:4]([F:10])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ncnc(O)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ncnc(Cl)c1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of the compound of part (iv) (40 kg), dichloromethane (120 L) and triethylamine (28.4 g) was slowly added phosphorus oxychloride (47.2 kg) over 3 hours maintaining the reaction temperature below 40° C. during the addition. The mixture was heated under reflux for 5 hours, cooled to 25° C. and cautiously quenched into 3N aqueous hydrochloric acid solution (176 L), maintaining the temperature below 20° C. during this operation. The layers were separated, the aqueous phase extracted with dichloromethane (50 L) and the combined organic layers washed with water (50 L). The organic layer was concentrated under reduced pressure to provide the product as an oil (40.69 kg).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[S:7][CH:8]=1)([CH3:3])[CH3:2].Cl[C:23]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:30]2[C:25](=[C:26]([CH3:45])[CH:27]=[C:28]([O:43][CH3:44])[CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([C:4]1[N:5]=[C:6]([C:23]2[CH:32]=[C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:30]3[C:25](=[C:26]([CH3:45])[CH:27]=[C:28]([O:43][CH3:44])[CH:29]=3)[N:24]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)cc(OC)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-c3nc(C(C)C)cs3)nc3c(C)cc(OC)cc23)cc1
Yield: 63 %

Procedure:
Compound 219 (100 mg, 0.29 mmol), compound 221f (242 mg, 0.35 mmol), and potassium carbonate (48 mg, 0.35 mmol) in degassed anhydrous DMF were stirred under microwave radiations at 80° C. for 1 hr. Solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel (Petroleum ether/DCM) to yield compound 222f as yellow powder in 63% yield. 1H NMR (CDCl3, 400 MHz) δ 1.40 (s, 3H), 1.42 (s, 3H), 2.80 (s, 3H), 3.17-3.24 (m, 1H), 3.85 (s, 3H), 3.89 (s, 3H), 5.31 (s, 2H), 6.99 (d, J=9.10 Hz, 2H), 7.00 (s, 1H), 7.21 (m, 1H), 7.31 (d, J=2.93 Hz, 1H), 7.49 (d, J=9.10 Hz, 2H), 7.79 (s, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1COCC1.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>[C:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)s1
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: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2)s1
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
5-bromothiophene-2-carboxaldehyde (1.0 g, 5.2 mmol) is added to a solution of tetrakis(triphenylphosphine)palladium(0) (180 mg, 0.16 mmol) in degassed THF (10 mL). The resulting solution is stirred for 5 minutes. A solution of phenylboronic acid (760 mg, 6.2 mmol) in THF (10 mL) is added followed by aqueous Na2CO3 (2M, 5.2 mL). The mixture is heated at reflux for 24 hours. The reaction mixture is allowed to cool, poured into ether, and washed twice with water. The ether layer is dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (1:1 hexanes:CH2Cl2) to yield the desired product (900 mg, 91%). 1H NMR (300 MHz, CDCl3) δ 7.38-7.45, 7.65-7.68, 7.73, 9.88.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Reactant: C1=COCCC1
Solvent: ClCCl
Product: O=C(NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (1.00 g) was dissolved in dichloromethane (10 mL). To this solution, 3,4-dihydro-2H-pyran (1.20 mL) and p-toluenesulfonic monohydrate (6.3 mg) were sequentially added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was sequentially washed with a saturated aqueous solution of sodium bicarbonate and saturated brine. The mixture was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant:hexane:ethyl acetate=4:1) to give 2-tetrahydropyranyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (1.18 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.Cl.[CH3:16][N:17]([CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1)[C:18]([C:20]1[N:25]=[C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=1)=[O:19].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:16][N:17]([CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1)[C:18]([C:20]1[N:25]=[C:24]([CH:26]2[CH2:27][CH2:28][N:29]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:30][CH2:31]2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: CN(C(=O)c1cccc(C2CCNCC2)n1)C1CCCc2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(C(=O)N(C)C3CCCc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (81 mg, 0.39 mmol), 1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide hydrochloride salt (150 mg, 0.39 mmol), and diisopropylethylamine (0.41 mL, 0.39 mmol) in DMF (10 mL) was added dropwise BOP (191 mg, 0.39 mmol) at RT. After stirring overnight at RT, the reaction mixture was poured on water (10 mL) and extracted with ethylacetate (20 mL). The aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with aq. sat. sodium bicarbonate solution (30 mL), 1M HCl solution (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate) to give 1′-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (150 mg, 71%). M.p 62-65° C. 1H-NMR (400 MHz, CDCl3): δ=1.67-2.02 (m, 6H), 2.18-2.22 (m, 1H), 2.30 (s, 3H), 2.71 (s, 3H), 2.72-2.75 (m, 2H), 3.17-3.27 (m, 2H), 3.97-4.05 (m, 2H), 4.58-4.78 (m, 2H), 4.96 (s, 2H), 5.05-5.15 (m, 1H), 6.33 (s, 1H), 7.10-7.24 (m, 4H), 7.28-7.32 (m, 1H), 7.57-7.58 (m, 1H), 7.76-7.78 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH3:2].[CH2:35](O)[CH2:36][CH2:37][CH2:38][CH2:39]CC.Cl.O1CCOCC1>>[CH2:1]([O:3][C:4](=[O:34])[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:22][CH:23]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH2:2][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCO
Reactant: CCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
(R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid ethyl ester (100 mg, 0.2 mmol) was dissolved in 1-heptanol (6 g, 50 mmol), followed by the addition of 4 M HCl in dioxane (1 mL, 4 mmol). The resulting mixture was stirred at room temperature for 8 hours, then evaporated under reduced pressure and purified (Interchim reverse phase chromatography column). The pure fractions were lyophilized to yield the title compound (27 mg, 95% purity). MS m/z [M+H]+ calc'd for C28H33ClFN3O6, 562.20; found 562.2.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15](C3C=CC=CC=3Cl)=[O:16])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC([C:55]1[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=1)=O>>[C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:29])([F:30])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=3)=[O:16])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3Cl)nc2n1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccc(Cl)cc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 2-[5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl]-1-(2-chloro-phenyl)-ethanone (example 47), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(4-chlorophenyl)ethanone and isolated as light yellow solid. MS (m/e): 435.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:4][C:3]=1[O:14][CH3:15].[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:16][CH:11]([CH3:12])[C:10]([C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:14][CH3:15])[CH:4]=1)=[O:13]
Reactant: CCC(=O)c1cc(OC)c(Br)c(OC)c1
Reactant: [Br-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)C(C)Br)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one (1.50 g, 5.49 mmol) in anhydrous THF (20 mL) was added pyridinium tribromide (1.93 g, 6.04 mmole). The reaction was stirred at room temperature for 2 hrs then neutralized with a solution of saturated aqueous NaHCO3. The mixture was extracted with EtOAc the combined organics were washed with saturated aqueous NaHCO3 and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (10-20% EtOAc-hexanes) gave 2-bromo-1-(4-bromo-3,5-dimethoxyphenyl)propan-1-one as an orange oil (1.09 g, 56% yield).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[C:26]([F:25])[CH:27]=3)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: Nc1cccc(F)c1
Product: CCc1ccc(C2CC(C(=O)Nc3cccc(F)c3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 24 mg (0.22 mmol, 1.1 eq.) of 3-fluoroaniline were reacted according to General Method 1. Yield: 38 mg (45% of theory)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[CH:21][CH:20]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 3-bromo-2-chloropyridine (4.1292 g, 21.46 mmol), 4-(pyridin-2-ylamino)phenol (4.7912 g, 25.75 mmol), and cesium carbonate (2.082 mL, 25.75 mmol) in dimethyl sulfoxide at 80° C. to stir. Reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (2×10 mL), satd sodium chloride solution (2×10 mL), dried with magnesium sulfalte, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 0.5% to 4% methanol in DCM, to provide N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 343.0 (M+1). IC50 (uM) 0.96.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[CH:6](=O)[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>>[O:11]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:6][NH:1][CH2:2][CH:3]([NH:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1)[CH3:4]
Reactant: O=Cc1ccco1
Reactant: CC(N)CN
Agent: [BH4-]
Agent: [Na+]
Product: CC(CNCc1ccco1)NCc1ccco1
Yield: 7.5 %

Procedure:
This compound was prepared as described in the general method (Method A) with 1,2-diaminopropane (1.00 g, 13.5 mmol), furfural (2.20 g, 22.9 mmol) and NaBH4 (0.52 g, 13.7 mmol) to give 1.90 g of the crude diamine Plug filtration (SiO2, ethyl acetate/ethanol 95:5) of 0.50 g afforded 0.20 g (24%) of the pure product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][CH2:12][CH:11]1/[CH:22]=[CH:23]/[C:24](=[O:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][CH2:12][CH:11]1/[CH:22]=[CH:23]/[CH:24]([OH:32])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)CCCCCCC1C(/C=C/C(=O)CC2CCCCC2)CCC1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCCCCCC1C(/C=C/C(O)CC2CCCCC2)CCC1OC1CCCCO1
Temperature: 0 °C

Procedure:
To an ice cold solution of trans-2-(4-cyclohexyl-3-oxo-1-butenyl)-5-[(tetrahydropyran-2-yl)oxy]cyclopentaneheptanoic acid methyl ester (43 g), prepared in Example 7, in 200 ml of methanol, sodium borohydride (3.8 g) is added portionwise. After stirring for 30 min. acetic acid (4.2 ml) is added. The mixture is concentrated under reduced pressure. The residue is taken up in ether. The ether solution is washed to neutral with water and saturated NaCl solution, dried and evaporated to yield trans-2-(4-cyclohexyl-3-hydroxy-1-butenyl)-5-[(tetrahydropyran-2-yl)oxy]cyclopentaneheptanoic acid methyl ester, νmaxCHCl3 3,450, 1,735, 1,030 cm- 1.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.C(Cl)Cl.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.[OH-].[Na+]>O>[CH3:12][C:9]1[C:8]2=[C:13]3[C:4](=[CH:5][CH:6]=[C:7]2[S:11][CH:10]=1)[NH:2][C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]3=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1csc2ccc(NN)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(C)CC4
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
15,75 g of 5-hydrazino-3-methylbenzothiophene hydrochloride are suspended in 500 ml of water, a layer of methylene chloride is introduced under the suspension and 10.5 g of 1-methyl-4-piperidone are added at about 0° C. The mixture is then adjusted to pH 9.5 with N NaOH and is stirred for 30 minutes. The organic phase is separated off and washed with saturated NaCl solution, dried and mixed with 500 ml of ethylene glycol and the methylene chloride is distilled off under a vacuum of 12 mm. Some of the glycol is then distilled off under 0.01 mm and at 100° C. and the concentrated solution is heated to 200° C. (bath temperature) in an N2 atmosphere for 1/2 hour. The crystals which precipitate on cooling the mixture are filtered off, washed and recrystallised from ethyl acetate. Melting point: 224°-227° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:14]([F:25])[CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=2)O1.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>[F:25][C:14]1[CH:13]=[C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=3)=[CH:3][N:4]=2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2F)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
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: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4)n4ccnc34)cc2F)CC1
Yield: 16.5 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[3-fluoro-4-(4-methyl-piperazin-1-yl)-phenyl]-amine (60.0 mg, 0.15 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (49.5 mg, 0.30 mmol), Pd(PPh3)4 (43.0 mg, 0.038 mmol) and 1.5 M Na2CO3 (0.80 mL, 1.20 mmol) in dioxane (3 mL). The crude material is purified by silica gel column chromatography eluting with 95:5 and 90:10 DCM:MeOH to afford the title compound (11 mg, 16%). LCMS: Rt 1.86 min (96%), m/z (ES+) 446 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.52 (4H, m), 3.01 (4H, m), 7.05 (1H, t), 7.52 (1H, br s), 7.59 (1H, s), 7.75 (1H, s), 7.79-7.85 (3H, m), 8.04 (1H, s), 8.09-8.11 (3H, m), 8.15 (1H, br s), 9.86 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:33][C:34](=[O:48])[NH:35][C@@H:36]1[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:26])([F:27])[F:25])[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:33][C:34]([NH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:48]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
To a stirring solution of (R)-tert-butyl 3-(3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)ureido)pyrrolidine-1-carboxylate (0.289 mmol, 200 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (7.23 mmol, 824 mg) and the mixture allowed to stir at room temperature for 5 hours. The reaction mixture was purified by strong cation exchange column chromatography to afford the title compound (146 mg). MS (ESI) m/z 592.3 [M+H]+