Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[CH:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH:16]2[O:21][CH:20]([CH2:22][OH:23])[CH:19]([OH:24])[CH:18]([OH:25])[CH:17]2[OH:26])[CH:7]=1.NCC(O)=O.[OH-].[Na+]>>[CH:10]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:6][CH:7]=[C:8]([O:15][C@@H:16]2[O:21][C@H:20]([C:22]([OH:3])=[O:23])[C@@H:19]([OH:24])[C@H:18]([OH:25])[C@H:17]2[OH:26])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OC2OC(CO)C(O)C(O)C2O)cc1
Reactant: CC(=O)[O-]
Agent: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
The reagent solutions were: NaAc buffer: 200 mM sodium acetate buffer pH 4.5; Substrate: 50 mM p-nitrophenyl-α-D-glucopyranoside (Sigma N-1377) in NaAc buffer (0.3 g/20 ml) and stop solution: 800 mM glycine-NaOH buffer pH 10. 30 μl filtered supernatant was placed in a fresh 96-well flat bottom MTP. To each well 50 μl NaAc buffer and 120 μl substrate was added and incubated for 30 minutes at 50° C. (Thermolab systems iEMS Incubator/shaker HT). The reaction was terminated by adding 100 μl stop solution. The absorbance was measured at 405 nm in a MTP-reader (Molecular Devices Spectramax 384 plus) and the activity was calculated using a molar extinction coefficient of 0.011 μM/cm.
Reaction SMILES: C(O)C.C([O:6][C:7](=[O:35])[CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:20]=3[CH:19]=[C:18]([CH3:34])[CH:17]=2)[CH:13]=[N:12]1)C.[OH-].[Na+].Cl>O>[OH:33][C:21]1([C:29]([F:31])([F:32])[F:30])[C:20]2[CH:19]=[C:18]([CH3:34])[CH:17]=[C:16]([C:14]3[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][C:7]([OH:35])=[O:6])[CH:15]=3)[C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: CCOC(=O)CCCn1cc(-c2cc(C)cc3c2-c2ccccc2C3(O)C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2cnn(CCCC(=O)O)c2)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.2 %

Procedure:
To a mixture of ethanol (5.4 ml) and an optically active form (3.55 g) of 4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid ethyl ester was added 2N aqueous sodium hydroxide solution (18 ml), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was acidified with 2N hydrochloric acid (36 ml). To this mixture was added water (36 ml), and the mixture was extracted 3 times with ethyl acetate (30 ml). The combined organic layer was washed 3 times with water (50 ml) and once with saturated brine (50 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (3.40 g, 100%).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[CH:15]=[N:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[N:12][C:11]2=[O:29])=[CH:7][C:6]=1[O:32]C.B(Br)(Br)Br>O>[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[CH:15]=[N:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:20][CH2:21]3)=[N:12][C:11]2=[O:29])=[CH:7][C:6]=1[OH:32]
Reactant: COc1cc(Cn2cnc(N3CCN(c4ccc(F)cc4)CC3)nc2=O)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)c(O)c1
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a dichloromethane solution (1.0 mL) of 1-(4-chloro-3-methoxybenzyl)-4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (10.0 mg, 0.0232 mmol) synthesized in Synthesis Example 141, 1M boron tribromide (1.00 mL, 1.00 mmol) was added at −78° C. and while elevating gradually the temperature of the resultant mixture to room temperature, the mixture was stirred for 3 hours. After the completion of the reaction, to the reaction solution, water was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was dried and was concentrated under reduced pressure and the resultant solid was washed with ethyl acetate to obtain the title compound (6.00 mg, yield: 62%).
Reaction SMILES: [CH:1]1([Tl])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:7]1([P:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)C>[C:15]1([P:13]([C:2]2[CH2:1][CH:5]=[CH:4][CH:3]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: [Tl]C1C=CC=C1
Solvent: CCOCC
Product: C1=CCC(P(c2ccccc2)c2ccccc2)=C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 g (0.186 mol) of cyclopentadienyl-thallium (obtained from Fluka) were introduced together with 300 ml of diethyl ether into a 500 ml flask. The suspension was cooled to 0° C. and 34.2 ml (0.186 mol) of diphenylchlorophosphine were added dropwise in the course of 10 minutes. The suspension was then warmed to room temperature and stirred for one hour, and finally filtered through a frit. The solvent was then stripped off in vacuo and left behind 39.5 g (85% of the theoretical yield) of the intermediate product diphenylphosphino-cyclopentadiene, compound 5. A content of 18.6 g (0.074 mol) of the compound 5 was then diluted with toluene and cooled to 0° C. 33.2 ml of a 2.24 molar solution of butyllithium in hexane (0.074 mol) were added to this solution in the course of 10 minutes. After warning to room temperature and after stirring for 2 hours, the yellow solution gave a precipitate, which was filtered off and washed with toluene and then with hexane. After drying in vacuo, 13.2 g of the compound 6 (70% of the theoretical yield) were obtained as a brownish powder (cf. J. Am. Chem. Soc. 105 (1983), 3882; Organometallics 1 (1982), 1591).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:22][CH:21]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:29]2[CH2:30][CH2:31][C@H:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[C@H:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: Clc1ccc([C@H]2CCNC[C@H]2c2ccccc2)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccc(Cl)cc2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=512.2 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-4-(4-chloro-phenyl)-3-phenyl-piperidine hydrochloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]3[C:20]4([CH2:24][S:23][C:22]([N:25](COCC[Si](C)(C)C)COCC[Si](C)(C)C)=[N:21]4)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[CH:18]=4)[O:13][C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[C:9]3[C:20]4([CH2:24][S:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[CH:18]=4)[O:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1=NC2(CS1)c1cc(-c3cccnc3)ccc1Oc1ncc(N3CCOCC3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(CS1)c1cc(-c3cccnc3)ccc1Oc1ncc(N3CCOCC3)cc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 3-morpholino-7-(pyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.066 g, 0.095 mmol) in 5 mL of DCM was treated with TFA (0.5 ml, 6.49 mmol). The reaction was stirred for 3 hrs at 50° C. The mixture was cooled to RT and was diluted with DCM (25 mL). The derived solution was washed with saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (3×15 mL) and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (RediSep 12 g, gradient elution 0-100% DCM: 100:10:1 DCM, MeOH, NH4OH) to provide 3-morpholino-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine as a racemic mixture. Chiral separation provided (S)-3-morpholino-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine and (R)-3-morpholino-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine, both isomers as a white solid. MS m/z=432.3.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Cl[CH2:10][C:11]1[O:15][C:14]([C:16]2[CH:24]=[C:23]([C:25]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:26]=3[CH:27]=[CH:28][NH:29]4)[CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3S(C2C=CC=CC=2)(=O)=O)=[N:13][N:12]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].[OH-].[Na+]>C(#N)C.C(O)(C)C>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:10][C:11]2[O:15][C:14]([C:16]3[CH:24]=[C:23]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH:22]=[C:21]4[C:17]=3[CH:18]=[N:19][NH:20]4)=[N:13][N:12]=2)[CH2:5]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(Cc2nnc(-c3cc(-c4cccc5[nH]ccc45)cc4[nH]ncc34)o2)C[C@H](C)O1
Temperature: 70 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
(2R,6S)-2,6-Dimethylmorpholine (12.57 mg, 0.11 mmol) and 4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (51 mg, 0.104 mmol) were dissolved in acetonitrile (0.5 ml) and N,N-diisopropylethylamine (0.0262 ml, 0.15 mmol) was added, followed by sodium iodide (14.99 mg, 0.1 mmol). The solution was stirred at 70° C. for 18 h and blown to dryness under a stream of nitrogen. Isopropanol (0.5 ml) was added followed by 2M sodium hydroxide (0.5 ml) and stirred for 18 h when the mixture was neutralised and the solvent removed under a stream of nitrogen. The crude product was dissolved in dimethylsulphoxide (0.5 ml) and purified by Mass Directed Automated Preparative HPLC (Method F) and the solvent was evaporated in vacuo using Genevac to give the title compound (4 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:40]([OH:43])([CH3:42])[CH3:41])[CH:37]=[N:38][CH:39]=2)O1>>[OH:43][C:40]([C:36]1[CH:35]=[C:34]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:39]=[N:38][CH:37]=1)([CH3:42])[CH3:41]
Reactant: CC(C)(O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C(C)(C)O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G) and 2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propan-2-ol (Stage 215.1.1) to give the title compound as a white foam. (HPLC: tR 2.13 min (Method A); M+H=457 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.69-8.66 (m, 1H), 8.46-8.44 (m, 1H), 8.21 (s, 1H), 8.16-8.12 (m, 1H), 7.98-7.91 (m, 2H), 7.58-7.56 (m, 1H), 5.26 (s, 1H), 4.53 (hp, 1H), 3.59 (s, 3H), 1.97 (s, 3H), 1.49 (s, 6H), 1.44 (d, 6H))
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(Cl)cc1
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (99 mg, 1.05 mmol) was added in one charge to a stirred solution of 5-bromo-2-(4-chlorobenzyloxy)benzoic acid (may be prepared as described in Description 16, 180 mg, 0.53 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol) and 1-Hydroxybenzotriazole (85 mg, 0.63 mmol) in DMF (15 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=1.5:1) to yield the title compound as a white solid. 200 mg.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)=[O:20])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)=[O:20])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CCCCNC(=O)C1CC(=O)C1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CCCCNC(=O)C1CC(=O)C1

Procedure:
(S)-methyl 2-(tert-butoxycarbonylamino)-6-(3-oxocyclobutanecarboxamido)hexanoate (0.501 g) was treated with 20 mL 4M HCl in 1,4-dioxane at ambient temperature for 20 minutes and the solvent was removed under reduced pressure. The resulting viscous oil was taken up in 10 mL CH3CN, and seeded with small amount of crystals of the title compound prepared in a smaller scale. The resulting crystals were collected by vacuum filtration, washed with CH3CN, and dried under reduced pressure, affording (S)-methyl 2-amino-6-(3-oxocyclobutanecarboxamido)hexanoate (TU3205-016) as color less solid. MS (ESI+): calcd. 257.15. found 257.20 (MH+). H-NMR (400 MHz, DMSO-d6):1.267 (1H, m), 1.419 (3H, m), 1.753 (2H, m), 3.114 (7H, m), 3.752 (3H, m), 4.023 (1H, t, J=6.4 Hz), 8.169 (1H, t, J=5.5 Hz), 8.365 (3H, br.s). C-NMR (100 MHz, DMSO-d6): 21.499, 27.160, 28.390, 29.548, 38.067, 50.858, 51.721, 52.727, 169.949, 173.034, 205.586.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1([CH2:25][CH3:26])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[N:12]=2)[C:7]1=[O:24])C.[OH-].[Na+].O>C(O)C>[CH2:25]([C:6]1([CH2:5][C:4]([OH:27])=[O:3])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[N:12]=2)[C:7]1=[O:24])[CH3:26]
Reactant: CCOC(=O)CC1(CC)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC1(CC(=O)O)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of ethyl(3-ethyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidin-3-yl)acetate (270 mg) obtained in Step E in ethanol (5 mL) was added dropwise 2M aqueous sodium hydroxide solution (1.4 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was washed with diethyl ether. The aqueous layer was neutralized with 2M hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[C:16]3Cl)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)O1.C([O-])(=O)C.[K+].C(O)CCC>CC(P(C(C)(C)C)C1C=CC=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC=CC=1)(C)C.Cl[Pd]Cl.O>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[C:16]3[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Nc1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1)C(C)(C)C
Solvent: CCCCO
Solvent: O
Product: CS(=O)(=O)Nc1cc(-c2ccc3nccc(-c4cccnc4)c3c2)cnc1Cl
Temperature: 105 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
To a 5 mL microwave vial, N-(2-chloro-5-(4-chloroquinolin-6-yl)pyridin-3-yl)methanesulfonamide (0.0500 g, 0.136 mmol, Example 9), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.0334 g, 0.163 mmol), potassium acetate (0.0333 g, 0.339 mmol) and dichlorobis(di-tert-butylphenylphosphine)palladium(II) (0.0042 g, 0.0068 mmol) were mixed into 1 mL of nBuOH along with 0.1 mL of water. The reaction mixture was stirred at 105° C. for 3 h. The reaction mixture was partitioned between water (10mL)/brine (10 mL) and 25% IPA/CHCl3 (20 mL). The aqueous phase was extracted with 25% IPA/CHCl3 (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: acetone in DCM 20%-70%) to afford an off white solid (0.0286 g) as the desired product. MS (ESI pos. ion) m/z calcd for C20H15ClN4O2S: 410.1; found 410.9 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.85 (s, 1 H) 9.05 (d, J=4.38 Hz, 1 H) 8.86 (d, J=1.75 Hz, 1 H) 8.77 (dd, J=4.82, 1.61 Hz, 1 H) 8.63 (d, J=2.34 Hz, 1 H) 8.24-8.33 (m, 1 H) 8.09-8.24 (m, 3 H) 8.05 (d, J=1.75 Hz, 1 H) 7.59-7.69 (m, 2 H) 3.16 (s, 3 H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:16]C)[CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:18])=[O:5])[CH2:3][CH2:2]1.[B]>ClCCl>[CH:1]1([C:4]([N:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=3[CH2:9][CH2:8][C@@H:7]2[CH3:18])=[O:5])[CH2:2][CH2:3]1
Reactant: COc1cccc2c1CC[C@H](C)N2C(=O)C1CC1
Agent: [B]
Solvent: ClCCl
Product: C[C@H]1CCc2c(O)cccc2N1C(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A 1000-mL round-bottom flask was charged with (2S)-1-cyclopropanecarbonyl-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (15.0 g, 61.2 mmol) and dichloromethane (300 mL). A solution of boron tribomide (1 M in dichloromethane, 308 mL, 308 mmol) was added dropwise at 0° C., and the resulting solution stirred for 1 h at 0° C. The reaction mixture was then poured into 500 mL of water/ice and extracted with dichloromethane (2×500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 0-80% ethyl acetate/petroleum ether) to afford (2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (9.4 g, 66%) as an off-white solid. MS (ES, m/z): 232 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:34]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>O1CCCC1.C(OCC)(=O)C.O>[CH2:42]([N:41]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:11](=[O:12])[CH2:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:14])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(CCC(=O)N(Cc1ccccc1)Cc1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 39.9 %

Procedure:
A solution of 4,4-bis-(4-hydroxyphenyl)pentanoic acid (2.00 g, 6.99 mmol) in 40 mL anhydrous tetrahydrofuran was treated with carbonyl diimidazole (3.76 g, 23.2 mmol) and the resulting solution heated at reflux under a N2 atmosphere for 24 hours. Dibenzylamine (5.38 mL, 28 mmol) was then added, and the reaction refluxed again for 48 hours. The reaction mixture was cooled and treated with 10% aqueous HCl solution (50 mL), followed by water (100 mL) and ethyl acetate (200 mL). The organic phase was collected and washed sequentially with water (100 mL) and brine (100 mL). The organic phase was dried (MgSO4), filtered and concentrate. The residue was purified by chromatography (silica gel, 50% ethyl acetate/hexane) to give the title compound (1.30 g, 40%) as a solid, mp=203-207° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[N:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)=[N:53][C:54]=1[NH2:55]>ClCCl>[NH2:55][C:54]1[C:49]([NH:48][C:10]([C:7]2([C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:50][CH:51]=[C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)[N:53]=1
Reactant: O=C(O)C1(c2cccnn2)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
To a mixture of 1-(pyridazin-3-yl)cyclopropanecarboxylic acid (160 mg, 0.97 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (445 mg, 1.17 mmol) and diisopropylethyl amine (330 mg, 2.4 mmol) in anhydrous dichloromethane (10 mL) was added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (350 mg, 0.98 mmol) dissolved in anhydrous dichloromethane (10 mL) with diisopropylethyl amine (330 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with dichloromethane and washed with water. The organics were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified via column chromatography (100-200 silica gel mesh, 60-80% ethyl acetate in petroleum ether) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridazin-3-yl)cyclopropanecarboxamide (100 mg, 23%). MS (ES+APCI) (M+H) 436.2; LCMS retention time: 3.390 min (Method W1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.[Cl-].[Na+].O>[C:31]1([S:37]([N:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c[nH]c(-c2ccccn2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccn2)n(S(=O)(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution (16 mL) of 5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde (80 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 56 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (307 mg) was added dropwise and the mixture was stirred for 30 min. Benzenesulfonyl chloride (165 mg) was added, and the mixture was further stirred for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1), and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 85 mg, 59%).