Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH:14]([CH3:16])[CH3:15])[C:6]=2[N:7]=1.[NH:18]1[CH:22]=[CH:21][C:20](B(O)O)=[N:19]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]2[CH:11]=[C:10]([C:20]3[NH:19][N:18]=[CH:22][CH:21]=3)[C:9](=[O:13])[N:8]([CH:14]([CH3:16])[CH3:15])[C:6]=2[N:7]=1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C(C)C
Reactant: OB(O)c1cc[nH]n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(N)nc2c1cc(-c1ccn[nH]1)c(=O)n2C(C)C
Temperature: 100 °C
Yield: 13.6 %

Procedure:
In a 350 mL pressure tube 2-amino-6-bromo-8-isopropyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.50 g, 5.05 mmol), 1H-pyrazol-3-yl boronic acid (1.12 g, 10.09 mmol), K2CO3 (336 mg, 15.1 mmol), and tetrakis(triphenylphosphine) palladium (0) (583 mg, 0.0504 mmol) were dissolved in 50 mL dioxane and 5 mL H2O. The tube was sealed, heated to 100° C. and allowed to react overnight. A color change was observed. LCMS indicated no presence of starting material. Sample was filtered through a syringe filter and evaporated to dryness. Compound was dissolved in ethyl acetate and triturated in hexane. Light yellow powder of 2-amino-8-isopropyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (195 mg, 13.7% yield) was found to be 98% pure by HPLC. 1H NMR (400 MHz, CDCl3) δ 12.97 (br s, 1H), 8.35 (s, 1H), 7.60 (br s, 1H), 7.21 (s, 2H), 6.94 (s, 1H), 5.86 (br s, 1H), 2.50 (m, 6H), 1.54 (s, 3H), MS (EI) for C14H16N6O: 285.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:20]=[C:19](I)[C:16]2=[N:17][CH:18]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][N:40](C(OC(C)(C)C)=O)[CH:41]=2)O1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[N:21]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:20]=[C:19]([C:37]3[CH:38]=[N:39][NH:40][CH:41]=3)[C:16]2=[N:17][CH:18]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cnc3c(I)nn(C4CCCCO4)c3c2)c1Cl
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2cnc3c(-c4cn[nH]c4)nn(C4CCCCO4)c3c2)c1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 105.4 %

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (60 mg, 0.1 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (40. mg, 0.13 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (7 mg, 0.009 mmol), and potassium phosphate (48 mg, 0.22 mmol) in 1,4-dioxane (0.5 mL) and water (0.07 mL) in a reaction vial was degassed and sealed. It was stirred at 85° C. overnight. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (50 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:10][C@@:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][C@H:12]1[CH2:14][O:15]CC1C=CC=CC=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].C(O)C>[OH:15][CH2:14][C@@H:12]1[CH2:13][C@@:11]1([CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1CO)C(=O)OC(C)(C)C
Yield: 76.3 %

Procedure:
1,1-dimethylethyl methyl[((1S,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]carbamate (20.65 g, 54 mmol), accessed via the method of Preparation 12A, was combined with 10% palladium on activated carbon (2.00 g) in 250 mL ethyl alcohol and hydrogenated under 1 atm H2(g) for 3 h at ambient temperature. The catalyst was filtered off through celite and the filtrate concentrated to a yellow oil. The crude material was purified by flash chromatography on silica eluted with 5→25% EtOAc/DCM. Appropriate fractions were combined and concentrated to give the title compound (12.02 g, 41.2 mmol, 76%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6, 90° C.) δ 7.30-7.22 (m, 9H), 7.15 (m, 1H), 4.41 (t, J=5.1 Hz, 1H), 3.87 (d, J=14.5 Hz, 1H), 3.74 (m, 1H), 3.52 (m, 1H), 3.31 (d, J=14.4 Hz, 1H), 2.63 (s, 3H), 1.21 (s, 9H), 1.20-1.07 (m, 2H), 0.77 (m, 1H). ES-LCMS m/z 314.21 (M+Na).
Reaction SMILES: Cl[O-:2].[Na+].[C:4]([C:7]1[C:8]([CH3:23])=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[S:13](=[O:19])(=[O:18])[CH2:12][C:11]([CH3:21])([CH3:20])[C:10]2=[O:22])(=[O:6])C>O1CCOCC1.O>[C:4]([C:7]1[C:8]([CH3:23])=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[S:13](=[O:19])(=[O:18])[CH2:12][C:11]([CH3:20])([CH3:21])[C:10]2=[O:22])([OH:6])=[O:2]
Reactant: [O-]Cl
Reactant: CC(=O)c1cc(C)c2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CC(C)(C)C2=O
Temperature: 30 °C
Yield: 84 %

Procedure:
17.8 Grams (about 15 mmol) of a 6.4 wt % sodium hypochlorite aqueous solution was placed in a 100-ml three-necked round-bottomed flask, and cooled to 15~20° C., and then a solution of 1.26 g (4.26 mmol) of 6-acetyl-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide in 8 ml of dioxane was gradually added. The mixture was stirred at 15~20° C. with external cooling for 30 minutes, and then stirred at room temperature (temperature-increased to about 30° C.) for 3 hours. The reaction mixture was diluted with about 50 ml of water and washed with chloroform twice. A sodium sulfate aqueous solution was added to an aqueous layer to decompose excess hypochlorite, and then the aqueous solution was neutralized and acidified with a 5 wt % hydrochloric acid aqueous solution to give a white solid. The solid was extracted with ethyl acetate, and an organic layer was washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 1.06 g (yield 84%) of 6-carboxy-3,3,5,8-tetramethylthiochroman-4-one-1,1-dioxide in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=O.[CH3:16][N:17]1[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[N:18]1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[Si](C#N)(C)(C)C.[C-]#N.[K+]>C(#N)C>[NH2:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([C:20]1[C:19]([CH3:23])=[N:18][N:17]([CH3:16])[C:21]=1[OH:22])=[O:7]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1N
Reactant: Cc1cc(O)n(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C)c(O)c1C(=O)c1ccc(S(C)(=O)=O)c(N)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under nitrogen, 0.50 g (2.2 mmol) of 3-amino-2-methyl-4-(methylsulfonyl)benzoic acid, 0.32 g (2.8 mmol) of 1,3-dimethyl-5-hydroxypyrazole and 0.50 g (2.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were dissolved in dry acetonitrile. The mixture was stirred at RT for 1 day and allowed to stand for 2 days. 0.61 ml (4.4 mmol) of NEt3, 0.12 ml (0.9 mmol) of Me3SiCN and a spatula tip of KCN were added, and the mixture was stirred at RT for 2 days. The solvent was removed under reduced pressure, and the residue was taken up in CH2Cl2 and 10% strength H2SO4. The organic phase was separated off and dried over MgSO4, and the solvent was removed under reduced pressure. The residue was crystallized from acetonitrile. The mother liquor was purified by preparative HPLC. This gave 0.10 g in a purity of 97%.
Reaction SMILES: I[C:2]1[O:3][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:6]=1.[OH:15][N:16]([CH:20]([C:22]#[CH:23])[CH3:21])[C:17]([NH2:19])=[O:18].CN(C)C=O.[NH4+].[OH-]>C(NCC)C.CC#N.CC#N.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH:8]=[CH:7][C:4]2[O:3][C:2]([C:23]#[C:22][CH:20]([N:16]([OH:15])[C:17]([NH2:19])=[O:18])[CH3:21])=[CH:6][CH:5]=2)[CH:10]=1
Reactant: C#CC(C)N(O)C(N)=O
Reactant: Ic1ccc(C=Cc2cccnc2)o1
Agent: Cl[Pd]Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C#Cc1ccc(C=Cc2cccnc2)o1)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a stirred solution of 2-iodo-5-[2-{3-pyridyl}ethenyl]furan (1.4 g, 4.7 mmol), prepared as in step 5, and N-hydroxy-N-(butyn-2-yl)urea (0.64 g, 5 mmol), prepared as in step 2, in diethylamine (10 mL) was added dimethylformamide (1 mL), triphenylphosphine (0.026 g, 0.1 mmol), cuprous iodide (5 mg, 25 mmol) and bis(acetonitrile)palladium(II) chloride (13 mg, 50 mmol). The mixture was stirred overnight at ambient temperature. Aqueous NH4OH was added and the mixture extracted thoroughly with CH2Cl2. The combined organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with 5% MeOH--CH2Cl2 to afford an off-white solid. Recrystallization from ethyl acetate-hexanes gave 530 mg of the title compound. m.p. 166° C. 1H NMR (DMSO-d6, 300 MHz) δ1.38 (d, J=7 Hz, 3H), 5.19 (q, J=7 Hz, 1H), 6.61 (bs, 2H), 6.82 (d, J=3 Hz, 1H), 6.82 (d, J=3 Hz, 1H), 7.09 (d, J=16 Hz, 1H), 7.25 (d, J=16 Hz, 1H), 7.39 (m, 1H), 7.77 (m, 1H), 8.03 (m, 1H), 8.45 (m, 1H), 8.77 (m, 1H), 9.43 (s, 1H). MS (DCI/NH3) m/e 298 (M+H)+. Anal calcd for C16H15N3O3 : C, 64.63; H, 5.08; N, 14.13. Found: C, 64.01; H, 5.09; N, 14.06.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:16]1([NH:19][C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(NC2CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)bromobenzene (10 g), cyclopropylamine (2.4 g) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.3 g) in toluene (100 mL) was added palladium acetate (0.16 g) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 20 min. To this mixture was added sodium tert-butoxide (4.7 g), and the mixture was stirred at 100° C. for 2 hr. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried, filtered through silica gel (eluted with 20% ethyl acetate/hexane), and concentrated under reduced pressure. The residue was diluted with hexane, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give N-cyclopropyl-3,5-bis(trifluoromethyl)aniline (7.0 g, 74%) as an orange oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:24]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:23][O:22][N:21]=2)=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:27](=[O:28])[CH2:26][CH2:25][C:24]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:21][O:22][CH:23]=1
Reactant: O=C(O)CCc1conc1-c1ccc(Cl)cc1
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1conc1-c1ccc(Cl)cc1)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 3-trifluoromethylbenzylamine (0.75 ml), 3-[3-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.90 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.82 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.03 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(3-trifluoromethylbenzyl)-3-[3-(4-chlorophenyl)-4-isoxazolyl]propionamide (1.27 g, yield 87%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from isopropyl ether-hexane. melting point: 80–81° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:24]1[CH2:25][CH2:26][CH2:27][C@@H:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(O[C@@H]5CCCNC5)nc34)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13.2 %

Procedure:
To a solution of (R)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate (117 mg, 0.25 mmol) in DCM (3.0 mL) at 0° C. was added TFA (0.5 mL, 6.73 mmol). The reaction was stirred at RT for 20 min. The solution was concentrated, the residue was dissolved in DCM and washed with a saturated aq. solution of NaHCO3. The aq. layer was extracted with DCM (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO (3.0 mL). Purification by rpHPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 5-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min.), followed by drying in a Genevac Series II Evaporator afforded (R)-2-(2-(piperidin-3-yloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (15.7 mg, 0.033 mmol, 13.0% yield) as an amorphous yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (br. s., 1H), 8.76 (s, 1H), 8.80 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.03 (br. s., 1H), 5.52 (br. s., 1H), 3.39-3.55 (m, 4H), 3.15 (br. s., 2H), 2.89 (t, J=6.7 Hz, 2H), 2.13-2.24 (m, 1H), 1.93-2.07 (m, 2H), 1.82-1.92 (m, 1 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.47 (s, 3F). m/z (ESI, +ve ion) 363.0 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[CH3:11]O>>[NH2:2][C@H:3]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: CO
Agent: Cl
Product: COC(=O)C1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
Hydrogen chloride gas was bubbled through a solution of (1R,3S)-3-aminocyclopentanecarboxylic acid (5.00 g, 38.7 mmol, Peptech) in MeOH (100 mL) for about 15 min to give a tan solution, and the reaction mixture was stirred at ambient temperature for about 24 h. The solvent was removed under reduced pressure to give (3S)-methyl 3-aminocyclopentanecarboxylate (5.5 g, 25.5 mmol, 66%) which was dissolved in DMF (100 mL) and then K2CO3 (17.6 g, 127 mmol) and (bromomethyl)benzene (6.05 mL, 50.9 mmol) were added. The reaction mixture was stirred overnight at ambient temperature. The solid was collected by filtration and washed with DMF (100 mL). The filtrate was concentrated under high vacuum and the crude material was purified by silica gel chromatography eluting with 10% EtOAc in heptane to give (3S)-methyl 3-(dibenzylamino)cyclopentanecarboxylate (7.3 g, 89%) as a yellow oil: LC/MS (Table 2, Method a) Rt=2.97 min; MS m/z: 324 (M+H)+.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([F:15])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:14])([CH3:13])[C:4]3[CH:3]=[CH:2][N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:5]=32)=[CH:10][CH:9]=1
Reactant: CC1(C)c2ccc(F)cc2C(=O)C1CC=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1cc(F)ccc1C2(C)C
Reaction time: 0.75 h
Yield: 55.9 %

Procedure:
A solution of 3.04 g of (RS)-2-(2-oxoethyl)-6-fluoro-3,3-dimethyl-1-indanone and 110 mg of p-toluenesulfonic acid in 100 ml of anhydrous toluene was heated on a water separator. A solution of 4.14 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.0 g (56%) of (R)-1-(7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:1][CH:2]2[CH2:6][CH2:5][CH2:4][CH:3]2[NH:7][C:8](=[O:23])[C:9]2[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:19])([F:20])[F:18])=[CH:11][C:10]=2[O:21][CH3:22])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Reactant: O=C1CCCC1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC1CCCC1

Procedure:
The title compound, off-white solid, MS: m/e=417.3 [(M+H)+], was prepared in accordance with the general method of example 11 from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and cyclopentanone.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)O1.C(=O)([O-])[O-].[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>[CH3:12][O:11][C:7]1[C:6]2[C:2]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[CH:3][N:4]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)[C:5]=2[CH:10]=[CH:9][N:8]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(I)cn2C1CCOC1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2C1CCOC1
Temperature: 130 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrrolo[3,2-c]pyridine (60.0 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (74.0 mg), tetrakis(triphenylphosphine)palladium(0) (20.1 mg) and potassium carbonate (48.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.6 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([C:29](=[O:31])[CH3:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:26]5[CH2:27][CH2:28][N:23]([C:29](=[O:31])[CH3:30])[CH2:24][CH2:25]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(piperazin-1-yl)ethanone (1.2 equiv) to give 179 (13.5 mg, M+1 424.1)
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:39]1[C:43]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.CN.Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:43][NH:39][C:34](=[O:35])[CH2:33][CH:30]1[S:29][C:28]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][C:19]=3[O:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:32][CH2:31]1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a solution of (2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (365 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (158 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg), methylamine hydrochloride (70 mg), and triethylamine (0.144 mL), and the mixture was stirred at room temperature for 1 hr. 1N HCl was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and crystallized from acetonitrile. The obtained crystals were recrystallized from ethyl acetate and diethyl ether to give the title compound (115 mg, yield 31%) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11]
Reactant: O=[N+]([O-])O
Reactant: N#CCc1c(F)cccc1F
Agent: O=S(=O)(O)O
Product: N#CCc1c(F)ccc([N+](=O)[O-])c1F
Yield: 98.8 %

Procedure:
To a solution of (2,6-difluorophenyl)acetonitrile (5 g, 32.7 mmol) in conc. Sulphuric acid (15 mL) at −78° C. was added dropwise a solution of nitric acid (65%, 2.25 mL, 32.7 mmol) in conc. sulphuric acid (5 mL). On completion of addition the reaction mixture was poured onto ice and the precipitate that formed collected by filtration, washed with water and dried in vacuo to give the title product as a white solid (6.4 g, 100%). 1H NMR 400 MHz δ (CDCl3): 8.24-8.16 (1H, m), 7.17 (1H, ddd, J=9.6, 7.8, 1.9 Hz), 3.84 (2H, t, J=1.2 Hz).