Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][N:23]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:29][CH2:28][C:25]3[CH:24]=[N:23][C:22]([CH3:21])=[CH:27][CH:26]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccccc1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccccc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-methyl-2-phenyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=O)[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH2:28]Br>C1COCC1>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:28][C:20]4[C:19](=[CH:24][CH:23]=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=4)[CH2:18]3)[CH:14]=[N:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CC1(C=Nc3ncnc(Cl)c31)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (0.29 ml, 0.74 mmol, 2.5 M) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition of butyllithium, N,N,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91 mg, 0.295 mmol, described in Intermediate 2) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O and the mixture was partitioned between EtOAc and H2O. The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317(M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1)[NH2:5].[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[Cl:1][C:2]1[C:3]([F:17])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:22]2[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=2)[CH:11]=1)[NH2:5]
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(Cl)c1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3Cl)ccn2)cn1
Temperature: 80 °C
Yield: 25.6 %

Procedure:
A solution of 3-chloro-4-(2-chloropyridin-4-yloxy)-2-fluoroaniline (10 g, 36.8 mmol) in DMF (140 mL) and water (30 mL) was treated with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.4 g, 40.5 mmol), K3PO4 (14.9 g, 73.6 mmol) and Pd(PPh3)4 (4.3 g, 3.7 mmol), sparged with N2 and heated at 80° C. for 12 h. The mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography to afford 3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (3.0 g, 26%). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J=6.0 Hz, 1 H), 8.24 (s, 1 H), 7.95 (s, 1 H), 7.15 (d, J=1.6 Hz, 1 H), 6.94 (d, J=8.8 Hz, 1 H), 6.80 (t, J=8.8 Hz, 1 H), 6.54-6.52 (m, 1 H), 5.51 (s, 2 H), 3.85 (s, 3H); MS (ESI): m/z 318.2 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[NH:11][CH2:10][CH2:9][NH:8][CH2:7]2)=[CH:2]1.[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]>N1C=CC=CC=1>[CH2:12]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:8]3[CH2:9][CH2:10][NH:11][CH:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[CH2:7]3)[CH:22]=2)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: c1cc(C2CNCCN2)co1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccoc4)C3)cc21
Yield: 32 %

Procedure:
A mixture of 592 mg of 3-(3-furanyl)piperazine, 329 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 8 ml of pyridine was heated in a pressure bottle at 95°-100° C. for 18 hours and then purified as described in Example 65, giving 160 mg of the desired product, mp 202°-204° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[CH:5][N:6]=2)=[O:32])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 30B-b, 102 mg, 0.23 mmol) in ethanol (10 mL) at 25° C. was treated with a solution of potassium hydroxide (40 mg, 0.69 mmol) in water (2.5 mL). This light yellow solution was stirred at 25° C. for 2 h and then concentrated in vacuo to remove ethanol. The resulting aqueous solution was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10/90 hexanes/ethyl acetate plus 1% acetic acid) afforded 6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-nicotinic acid (74 mg, 76%) as a white solid: FAB-HRMS m/e calcd for C26H26N2O4 (M+H)+ 431.1971, found 431.1987.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([NH:6][C@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[CH2:8]2)=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1.C(O[C:26](=[O:28])[CH3:27])(=O)C>N1C=CC=CC=1>[C:11]([O:12][C@@H:11]1[C@H:7]([NH:6][C:5]2[CH:16]=[C:17]([Cl:18])[C:2]([Cl:1])=[CH:3][C:4]=2[N+:19]([O-:21])=[O:20])[CH2:8][C@H:9]([CH2:14][O:15][C:14](=[O:15])[CH3:9])[C@@H:10]1[O:13][C:26](=[O:28])[CH3:27])(=[O:12])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@@H]1C[C@H](CO)[C@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1C[C@@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 89 %

Procedure:
(1R,2S,3R,5R)-5-(4,5-Dichloro-2-nitroanilino)-3-(hydroxymethyl)-1,2-cyclopentanediol (1.30 g, 3.86 mmol) was stirred in pyridine (10 mL)-acetic anhydride (2.2 mL) at ambient temperature for 2 days. Volatiles were evaporated in vacuo and the residue partitioned between chloroform and saturated aqueous sodium bicarbonate. The chloroform layer was dried (sodium sulfate) and concentrated to an oil which was chromatographed on silica gel. Elution with 2% methanol-chloroform gave (1R,2S,3R,5R)-3-(acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate as yellow needles (1.60 g, 89%), after crystallization from ethyl acetate-hexanes, m.p. 125°-130° C.; 1H-NMR(DMSO-d6) and mass spectrum (CI) consistent with structure; [α]20589 -130.5°, [α]20578 -140°, [α]20546 -178° (c=0.275, methanol).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CO.ClCCl>[CH3:40][S:41]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:24][CH2:25][OH:26])[C:16]=2[CH2:22]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.4 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (40 mg, 0.09 mmol, Example 1) was dissolved in methanol (0.5 mL) and dichloromethane (3 mL). Triethylamine (0.013 mL, 0.09 mmol) and methanesulfonyl chloride (7.23 μL, 0.09 mmol) were added and the reaction mixture was stirred at room temperature, under nitrogen atmosphere, for 3 h. The solvent was evaporated under reduced pressure, the crude dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by preparative HPLC yielding 2-((6-(methylsulfonyl)-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (5.2 mg, 10.15%).
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O>>[S:11]1[CH:12]=[C:8]([C:2]([CH2:3][CH2:4][C:5]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:7])=[O:1])[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)c1csc2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1csc2ccccc12
Yield: 78 %

Procedure:
The γ-oxo-benzo[b]thiophene-3-butyric acid is coupled to L-proline with 1,1'-carbonyldiimidazole to give 1-[3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline (78%) as a glass. As for Example 1, the preceding compound is reacted with bromine in acetic acid to give 1-[3-bromo-3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline as a glass (97%). Reaction with sodium thioacetate in ethanol gives the product (92%) of the Example as a glass.
Reaction SMILES: [CH3:1][C:2]12[CH2:27][CH:6]([N:7]([C:9]([C:11]3[CH:26]=[CH:25][C:14]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:29])([CH3:28])[CH2:3]2.S(Cl)(Cl)=O.C[N:35](C=O)C>C(Cl)Cl>[CH3:1][C:2]12[CH2:27][CH:6]([N:7]([C:9]([C:11]3[CH:26]=[CH:25][C:14]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([C:22]([NH2:35])=[O:23])[CH2:18][CH2:17]4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:29])([CH3:28])[CH2:3]2
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(OC3CCC(C(=O)O)CC3)cc2)C1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(OC3CCC(C(N)=O)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 4-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexanecarboxylic acid (4 g, 10.01 mmol) in DCM (75 mL) was added thionylchloride (1.5 mL) and dry DMF (0.5 mL). The resulting mixture was stirred for 16 hrs at room temperature and the volatiles evaporated in vacuo. The residue was dissolved in DCM (50 mL), added dropwise to an ice cooled solution of conc. aqueous ammoniac (150 mL) and TEA (7 mL) and stirred for 1 hr. The phases were separated and the organic phase dried (Na2SO4), filtered and evaporated which afforded 3.5 g (88%) of the title compound as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nccs2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nccs2)cc1
Temperature: -78 °C

Procedure:
Prepared according to the method described in Example 36b) from 2-(4-methoxyphenyl)thiazole (1.7 g), dichloromethane (20 ml) and boron tribromide (1.0 M in dichloromethane, 17.8 ml) with stirring at -78° C. After work up the residue was triturated with ether to give the sub-title compound a pale yellow solid (1.2 g).
Reaction SMILES: C(OC(O[CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:22]([O:21][C:19]([NH:18][C:13](=[CH2:12])[C:14]([O:16][CH3:17])=[O:15])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H](COC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 65 °C
Yield: 80.4 %

Procedure:
A mixture of (S)-methyl 3-(benzyloxycarbonyloxy)-2-(tert-butoxycarbonylamino)propanoate (36.0 g, 102 mmol), K2CO3 (28.2 g, 204 mmol) and DMF (204 mL) was heated at 65° C. for 1 hour. After cooling, the reaction mixture was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10:1 hexanes/EtOAc) to give methyl 2-(tert-butoxycarbonylamino)acrylate (16.5 g, 81%) as a colorless oil, which was used directly in the next step.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH3:10].I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:10]
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 93.4 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of 0.31 M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.70 g, 93%) as a yellow oil: EI-HRMS m/e calcd for C16H21ClO2 (M+) 280.1230, found 280.1238.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH2:13].[O:15]1[CH2:18][C:17](=O)[CH2:16]1.C([BH3-])#N.[Na+].[NH4+].[Cl-]>CO.[Cl-].[Zn+2].[Cl-].CCOC(C)=O>[O:15]1[CH2:18][CH:17]([NH:13][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:14])[CH2:16]1
Reactant: Cc1ccccc1-c1ccncc1N
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccccc1-c1ccncc1NC1COC1

Procedure:
A solution of 4-o-tolylpyridin-3-amine (0.125 g, 678 μmol) and oxetan-3-one (147 mg, 2.04 mmol, CAS RN 6704-31-0) in methanol (2 mL) was treated with zinc chloride (370 mg, 2.71 mmol). The reaction mixture got slightly warm and a solution formed. Then, molecular sieves 4 Å (100 mg, 678 μmol) were added and the reaction mixture refluxed for 19 hours. After cooling to room temperature another batch of oxetan-3-one (147 mg, 2.04 mmol) was added and the reaction mixture was heated again to reflux for another 24 hours before zinc chloride (185 mg, 1.36 mmol) was added. After stirring for another 2 hours sodium cyanoborohydride (128 mg, 2.04 mmol, CAS RN 25895-60-7) was added and the reaction mixture was stirred at reflux for 2 hours. After stirring at room temperature overnight, the reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the mixture was filtered over dicalite. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified twice by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Off-white foam (0.072 g; 42%). MS (ESI): m/z=241.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[CH:29]=[N:28][NH:27][C:24]2=[N:25][CH:26]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[CH:29]=[N:28][N:27]([CH2:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[C:24]2=[N:25][CH:26]=1)=[O:20]
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Reactant: COC(=O)c1cnc2[nH]ncc2c1
Product: COC(=O)c1cnc2c(cnn2Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Yield: 53 %

Procedure:
Compound 33 was prepared following general method 3A, using compound 17 as a starting material and 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester as the heterocycle. Yield: 53%.
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1>CO.[Pd]>[OH:1][CH:2]1[CH:8]([NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C(NC(=O)C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(NC1CCNCCC1O)C(F)(F)F
Yield: 75.7 %

Procedure:
A solution of benzyl 4-hydroxy-5-(2,2,2-trifluoroacetamido)azepane-1-carboxylate (935 mg, 3.0 mmol) in MeOH (100 mL) was passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give 4-hydroxy-5-(2,2,2-trifluoroacetamido)azepane as a pale yellow solid (514 mg). To a solution of this solid (500 mg, 2.21 mmol) in dry DMSO (10 mL) was added 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (150 mg, 0.93 mmol) and potassium fluoride (513 mg, 8.85 mmol). The reaction mixture was heated at 65° C. for 16 hr. The mixture was poured into water (200 mL) and extracted with EtOAc (5×50 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (70% EtOAc/isohexane) gave 2,2,2-trifluoro-N-(5-hydroxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide as a yellow solid (640 mg). A portion of this solid (200 mg, 0.57 mmol) was dissolved in MeOH (25 mL) and passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyazepan-4-yl)-2,2,2-trifluoroacetamide as an orange foam (172 mg, 68% over 3 steps). 1H NMR (400 MHz, DMSO) δ 9.22 (d, J=8.1 Hz, 1H), 6.83 (s, 1H), 4.84 (d, J=5.0 Hz, 1H), 3.91-3.73 (m, 2H), 3.32 (s, 3H), 3.28-2.96 (m, 4H), 2.00-1.75 (m, 4H). Exchangeable NH2 not observed.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13](C(OCC)=O)[CH2:12][CH2:11]1.[BrH:21].C(=O)=O>>[BrH:21].[BrH:21].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1
Agent: Br
Agent: O=C=O
Product: Cc1cccc(C)c1NC1CCNCC1

Procedure:
A mixture of 10 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate and 135 parts of hydrobromic acid solution 48% is stirred at a temperature between 80° and 110° C. until the evolution of gaseous carbon dioxide is ceased (about one hour). The red-coloured reaction mixture is evaporated in vacuo. The residue is taken up in 56 parts of methylbenzene and the latter is evaporated again. Then evaporation is repeated in a mixture of 24 parts of 2-propanone and 40 parts of methylbenzene. The resulting semi-solid residue is triturated in 80 parts of hot 2-propanone and on cooling, the solid product is precipitated. It is filtered off, washed successively with small amounts of absolute ethanol and 2-propanone and dried, yielding 13 parts of N-(2,6-dimethylphenyl)-4-piperidinamine dihydrobromide; mp. +300° C.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][C:20]=2C)=[CH:4][N:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C1C=CN2C(=NC=C2Br)C=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:7]2[CH:2]=[N:3][CH:4]=[C:5]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:6]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: Cc1nc2ccccn2c1-c1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Agent: Brc1cnc2ccccn12
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cncc(-c2cnc3ccccn23)c1)c1ccc(F)cc1
Temperature: 120 °C

Procedure:
N-(5-(H-imidazo[1,2-a]pyridin-3-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide. A suspension of N-(5-bromopyridin-3-yl)-4-fluorobenzenesulfonamide (from Example 1) (200 mg, 604 μmol), bis(pinacolato)diboron (169 mg, 664 μmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (44.2 mg, 60.4 μmol), potassium acetate (119 mg, 1208 μmol) in 1,4-dioxane (2.5 mL) was sparged with argon for 5 min, appropriately sealed, then heated to 120° C. for 1 h. The reaction vessel was then charged with 3-bromoH-imidazo[1,2-a]pyridine (Alfa Aesar (USA), 149 mg, 755 μmol), sodium carbonate (192 mg; 1.82 mmol) and water (0.5 mL)-sparged with argon-then heated to 100° C. for 3 h. The reaction was then partitioned between 9:1 CHCl3/i-Pr (25 mL) and 5% NaHCO3 (10 mL). The remaining residue in the reaction vessel was dissolved in DMF (3 mL) and added to the separatory funnel. The aqueous layer was then adjusted to a pH of about 8 with 5M HCl, and aqueous further extracted with 9:1 CHCl3/i-Pr (10 mL). The combined organics were dried over MgSO4 then concentrated under reduced pressure. The product was purified on silica (24 g) eluting with 3 to 8% of 2M NH3 in MeOH/CH2Cl2. Product then further purified on reverse phase HPLC eluting with water/acetonitrile (0.1% TFA). The desired fractions were then concentrated under reduced pressure, dissolved in CH3OH/CH2Cl2 (1:1; 5 mL), and stirred with Si-Carbonate (250 mg; 0.2 mmol) for 15 min. The filtrate was isolated by filtration then concentrated to a white solid. MS (ESI positive) m/z: calcd exact mass for C18H13FN4O2S: 368.1; found 369.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.97-7.04 (m, 1H) 7.33-7.39 (m, 1H) 7.41-7.49 (m, 2H) 7.70 (d, J=9.00 Hz, 1H) 7.73 (t, J=2.15 Hz, 1H) 7.84 (s, 1H) 7.87-7.93 (m, 2H) 8.31 (d, J=2.35 Hz, 1H) 8.36 (d, J=6.85 Hz, 1H) 8.59 (d, J=1.76 Hz, 1H) 10.79 (br. s., 1H).