Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([F:40])=[C:24]([NH:28][CH2:29][C:30]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:31]=4[C:32]([OH:34])=O)[CH:25]=[CH:26][CH:27]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[F:40][C:23]1[C:24]([N:28]2[CH2:29][C:30]3[C:31](=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:32]2=[O:34])=[CH:25][CH:26]=[CH:27][C:22]=1[C:7]1[C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NCc4ccc(C)cc4C(=O)O)c3F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N4Cc5ccc(C)cc5C4=O)c3F)c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 7.4 %

Procedure:
A homogeneous, orange solution of 2-((3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-fluorophenylamino)methyl)-5-methylbenzoic acid (0.105 g, 0.194 mmol), BOP (0.257 g, 0.582 mmol), DIPEA (0.119 mL, 0.679 mmol) and N-methylmorpholine (0.192 mL, 1.746 mmol) in DMF (1.940 mL) under nitrogen was heated at 45° C. After 45 min, the reaction was cooled to room temperature, dissolved in EtOAc (75 mL) and washed with water (4×30 mL) and brine (30 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo. It was diluted with DMF (0.3 mL) and MeOH (2 mL) and purified by reverse phase HPLC. The appropriate fractions were combined, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined extract was dried over MgSO4, and concentrated in vacuo to give the desired product (0.00758 g, 0.0144 mmol, 7.4%) as a light tan solid. LC/MS (M+H)=525.30; 1H NMR (500 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 7.89 (dd, J1=7.6, J2=1.7 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.61-7.66 (m, 2H), 7.54-7.59 (m, 2H), 7.50-7.54 (m, 2H), 7.47 (dd, J1=8.7 Hz, J2=1.8 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 6.77 (dd, J1=8.9 Hz, J2=2.2 Hz, 1 H), 5.03 (d, J=16.1 Hz, 1H), 4.95 (d, J=16.6 Hz, 1H), 4.15-4.19 (m, 2H), 3.69-3.74 (m, 2H), 3.33 (s, 3H), 2.44 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:11]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1nc(C(F)(F)F)cs1
Solvent: CC#N
Product: Nc1nc(C(F)(F)F)c(Cl)s1

Procedure:
2-Amino-4-trifluoromethylthiazole (10 g) was dissolved in acetonitrile (80 ml) and N-chlorosuccinimide (8.8 g) was added at room temperature with stirring. The mixture was refluxed for 9 hr and the solvent was removed under reduced pressure. The residue was dissolved in chloroform and washed with cold diluted aqueous sodium hydroxide. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to give crude 2-Amino-5-chloro-4-trifuloromethylthiazole (12 g). It was recrystallized from n-hexane-benzene (1:1 mixture) as colorless needles (6.8 g), m. p. 107-108° C.
Reaction SMILES: [NH3:1].CN.[Cl:4][C:5]1([Cl:14])[CH2:10][CH2:9][CH2:8][C:7]([Cl:12])([Cl:11])[C:6]1=O>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:4][C:5]1([Cl:14])[CH2:10][CH2:9][CH2:8][C:7]([Cl:12])([Cl:11])[C:6]1=[NH:1]
Reactant: N
Reactant: O=C1C(Cl)(Cl)CCCC1(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN
Solvent: Cc1ccccc1
Product: N=C1C(Cl)(Cl)CCCC1(Cl)Cl

Procedure:
The procedure of Example 1 was repeated except that 1.56 moles of each amine and ammonia shown in Table 1 was used instead of aniline to give oily 2,2,6,6-tetrachlorocyclohexaneimine derivative. In Examples 4 and 5, gaseous ammonia and methylamine were introduced into the mixture of 2,2,6,6-tetrachlorocyclohexanone, toluene and titanium tetrachloride, respectively. The structural formulae, yields and results of IR analysis of the obtained 2,2,6,6-tetrachlorocyclohexaneimine derivatives (I) are shown in Table 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: CC(C)CCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OCCC(C)C)c1
Yield: 83.8 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.646 ml (5.181 mmol) of isopentyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate., The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 1908 mg (0.4342 mmol, 84%) of 2-isopentyloxy-2'-hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.86 (6H, d, 2CH3), 1.0-2.2 (7 H, m, CH, 3CH2), 2.35 (4H, t, 2CH2), 2.64 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 4.04 (2H, t, CH2), 6.58 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 455 (M-H)-
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]([O:19][CH3:20])[CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH:11]([O:19][CH3:20])[CH2:10]1
Reactant: [H][H]
Reactant: COC(=O)C1CCC(NCc2ccccc2)CC1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CCC(N)CC1OC
Reaction time: 24 h

Procedure:
Methyl 4-(benzylamino)-2-methoxycyclohexanecarboxylate (1.84 g, 6.63 mmol, racemic mixture of diastereomers) and palladium hydroxide on carbon (20 weight %, 0.233 g, 0.332 mmol) in methanol (35 mL) were combined, and the atmosphere was exchanged for hydrogen (balloon) via four vacuum hydrogen flush cycles. After 24 hours, additional palladium hydroxide on carbon (20 weight %, 0.233 g, 0.332 mmol) was added, and the reaction mixture was again placed under a hydrogen atmosphere. Following another 24 hours, the reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give methyl 4-amino-2-methoxycyclohexanecarboxylate as a racemic mixture of three diastereomers, which was carried forward without further purification. MS ESI calcd. for C9H18NO3 [M+H]+ 188. found 188.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1B(O)O.[F-].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:34]4[C:33]([Cl:32])=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:39])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1c(Cl)cccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4c(Cl)cccc4Cl)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2,6-dichlorophenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 μmol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 μmol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.50 in 1:4 ethyl acetate:hexanes; MS (EI) 554.2 (M+H)+.
Reaction SMILES: C(O[CH2:9][C:10]1[C:11](OC)=[N:12][CH:13]=[CH:14][C:15]=1[C@@:16]([OH:23])([CH2:21][CH3:22])[CH2:17][C:18](O)=[O:19])C1C=CC=CC=1.Br>COCCOC>[CH2:21]([C@:16]1([OH:23])[C:15]2[CH:14]=[CH:13][NH:12][CH2:11][C:10]=2[CH2:9][O:19][CH2:18][CH2:17]1)[CH3:22]
Reactant: CC[C@@](O)(CC(=O)O)c1ccnc(OC)c1COCc1ccccc1
Agent: Br
Solvent: COCCOC
Product: CC[C@@]1(O)CCOCC2=C1C=CNC2
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 53.6 %

Procedure:
To a stirred solution of 3.00 g (R)-3-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-3-hydroxy-pentanoic acid (8.69 mmol), as obtainable from Example 10, in 11 mL 1,2-dimethoxyethane, were added 2.01 mL aqueous HBr (48%) (17.89 mmol, 2.06 eq). After 15 min at room temperature, the solution was heated to 50° C. After 4 h, the first product crystals appeared. The reaction was monitored by HPLC. After 24 h at 50° C. (<1% area (R)-3-(3-benzyloxymethyl-2-methoxy-pyridin-4-yl)-3-hydroxy-pentanoic acid), the reaction was cooled to room temperature. The mixture was allowed to stir at room temperature for 72 h and was then filtered. The solid was washed twice with 2.24 mL, in total with 4.48 mL TBME, and subsequently with 2.24 mL acetone; twice with 2.24 mL, in total with 4.48 mL water, and finally twice with 2.24 mL, in total with 4.48 mL acetone. After drying in vacuo, the title compound (1.040 g, 4.66 mmol, 54% by weight) was obtained as white crystals, and in an enantiomeric ratio of er=99.95:0.05 as determined by the following Chiral HPLC method:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]COCC.[Mg].CI>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]([CH3:33])([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(=O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CCOCC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCCC(C)(O)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 1.75 g of 1-(3,4-dibenzyloxyphenyl)-3-nonanone in 10 ml of tetrahydrofuran was cooled to 0° to 5° C. and then an ether solution of a Grignard reagent prepared from 0.24 g of metallic magnesium and 1.7 g of methyl iodide was added dropwise to the mixture. Thereafter, the resultant mixture was stirred for 15 minutes and after adding thereto 50 ml of an aqueous 5% hydrochloric acid solution, the product was extracted with toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide 1.6 g of 1-(3,4-dibenzyloxyphenyl)-3-methyl-3-nonanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:22][C:23]([F:41])([F:40])[C:24]([N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([CH2:37][CH2:38]I)=[CH:36][C:29]=2[CH2:28][CH2:27]1)=[O:25]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:38][CH2:37][C:35]2[CH:34]=[CH:33][C:30]3[CH2:31][CH2:32][N:26]([C:24](=[O:25])[C:23]([F:22])([F:41])[F:40])[CH2:27][CH2:28][C:29]=3[CH:36]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(N1CCc2ccc(CCI)cc2CC1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(N1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 152 mg (0.76 mmol) 4-benzyloxy-1H-pyridin-2-one in THF at 0° C. is added subsequently 492 mg (1.51 mmol) cesium carbonate, 14 mg (0.08 mmol) tetra-butylammonium-iodide and 300 mg (0.76 mmol) 2,2,2-trifluoro-1-[7-(2-iodo-ethyl)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-ethanone (preparation 6b). The reaction mixture is stirred overnight at RT, diluted with DMF and filtered. The residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 5:95).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:17])[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[S:4][CH:3]=1.O1CCO[CH2:20][CH2:19]1>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:17][C:8]1[N:9]=[C:10]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:4][CH:3]=[C:2]([CH:19]=[CH2:20])[C:6]=2[N:7]=1
Reactant: C1COCCO1
Reactant: Clc1nc(N2CCOCC2)c2scc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1csc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 100 °C
Yield: 39.5 %

Procedure:
4-(7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (3.55 g, 10.6 mmol), (2-Ethenyl)tri-n-butyltin (3.41 mL, 11.7 mmol), Pd(PPh3)4 (613 mg, 0.53 mmol), and 1,4-Dioxane (30 mL, 400 mmol) were combined in a sealed tube and heated at 100° C. 19.5 h. Complete reaction was confirmed by LCMS. Concentrated in vacuo and purified by silica gel chromatography (0 to 50% ethyl acetate/heptanes) on the CombiFlash® Rf system and concentrated in vacuo to give 4-(2-chloro-7-vinylthieno[3,2-d]pyrimidin-4-yl)morpholine (1.18 g, 39.5% yield)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:47])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:47])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2CCCC(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.8 %

Procedure:
Trifluoroacetic acid (1.0 ml, 13.0 mmol) was added dropwise at 25° C. under nitrogen to a solution of 4-(6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)butanoic acid (Preparation 31; 95 mg, 0.167 mmol) in dichloromethane (4.0 ml) and the resulting mixture was stirred at 25° C. for 45 min. The solvent was removed and the residue co-evaporated with toluene followed by trituration with diethyl ether to give the title compound (70 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([OH:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]3[O:41][CH:40]=[CH:39][C:38]=3[CH:42]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].ClCCl>[O:41]1[C:37]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12]([CH2:13][C@@H:14]5[CH2:18][CH2:17][N:16]([C:19]([CH:21]6[CH2:23][CH2:22]6)=[O:20])[CH2:15]5)=[N:11][NH:10][C:9]4=[O:24])=[C:4]([OH:25])[CH:3]=3)=[CH:42][C:38]=2[CH:39]=[CH:40]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2O)C1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2O)C1
Temperature: 100 °C
Yield: 36.8 %

Procedure:
To a microwave vial were added 4-(4-bromo-2-hydroxyphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (45 mg, 0.110 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (45 mg, 0.184 mmol), cesium carbonate (130 mg, 0.399 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (6.0 mg, 0.00735 mmol), and the mixture was purged with nitrogen. 1,4-Dioxane (1 mL) and water (0.5 mL) were added to the mixture which was heated overnight at 100° C. Analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH˜6 with 1N aq HCl. The aqueous phase was extracted with ethyl acetate (3×), and the combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the title product as a white solid (18 mg, 37%). MS(ES)+ m/e 445.3 M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:17]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:29].[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:17]=2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1cccc(CCN2CCCC2)c1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 98 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{3-[2-(pyrrolidin-1-yl)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (59 mg, 0.15 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (67 mg, 75%) as a yellow solid: 1H NMR (500 MHz, D2O) δ 9.13 (s, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.1 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 6.79 (s, 1H), 6.66 (br s, 2H), 3.36-3.27 (m, 2H), 2.78 (s, 3H), 2.74-2.64 (m, 2H), 2.62-2.42 (m, 4H), 1.87-1.72 (m, 4H); ESI MS m/z 521 [M+H]+; HPLC 98.9% (AUC), tR=10.34 min.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([Br:11])=[C:7](Br)[CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]=1[CH2:26][NH2:27].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[CH:1]([N:4]1[C:9](=[O:10])[C:8]([Br:11])=[C:7]([NH:27][CH2:26][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[O:15][CH3:14])[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc(Br)c(Br)c1=O
Reactant: COc1ccc2ccccc2c1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ccccc2c1CNc1cnn(C(C)C)c(=O)c1Br
Reaction time: 8 h

Procedure:
A mixture comprising 1.48 g of 2-i-propyl-4,5-dibromo-3(2H)pyridazinone, 1.68 g of 2-methoxy-1-naphthylmethylamine hydrochloride, 1.33 g of sodium carbonate, 30 ml of water and 30 ml of 1,4-dioxane, was refluxed under stirring overnight. Then, the solvent was distilled off under reduced pressure, and water was poured to the residue thus obtained. The mixture was extracted with ethyl acetate. The extract was washed sequentially with a 2 wt% hydrochloric acid aqueous solution, water and a saturated sodium chloride aqueous solution and then dried over sodium sulfate. Then, the solvent was distilled off. The residual solid thus obtained was crystallized from ethyl acetate/n-hexane to obtain 1.18 g of the above identified compound as colorless crystals having a melting point of from 160° to 161° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(C)(C)C.Cl>O1CCOCC1>[ClH:17].[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][CH:8]([NH2:7])[C:18]([N:20]1[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19]
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCN(C(=O)C(N)CCc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 118.1 %

Procedure:
A solution of 1.8 g (4.6 mmol) of tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate in 4.6 mL (18 mmol) of 4 M HCl in 1,4-dioxane is stirred for 2 h, and then concentrated. The residue is stirred in Et2O overnight, and then filtered and washed with Et2O to provide 0.90 g (60%) of 4-(2-chlorophenyl)-1-(4-methyl piperidin-1-yl)-1-oxobutan-2-amine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][C:8]3[NH:9][N:10]=[C:11](C)[C:7]=3[C:4]=2[NH:5][N:6]=1.[CH3:15]O>>[CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][C:8]3[N:9]([CH3:15])[N:10]=[CH:11][C:7]=3[C:4]=2[NH:5][N:6]=1
Reactant: CO
Reactant: Cc1n[nH]c2c1ccc1[nH]nc(C)c12
Product: Cc1n[nH]c2c1ccc1c2cnn1C
Yield: 70 %

Procedure:
1,6-Dihydro-3,8-dimethylbenzo[1,2-c:3,4-c']dipyrazole as a light-lavender powder melting at above 290° C. The product powder (70% yield) was obtained by trituration of the crude product in hot methanol followed by cooling.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[O:23])[C:12]4[N:21]([CH3:22])[N:20]=[CH:19][C:13]=4[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1.O>Br.C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11](=[O:23])[C:12]4[N:21]([CH3:22])[N:20]=[CH:19][C:13]=4[NH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccc3[nH]c4cnn(C)c4c(=O)c23)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cn1ncc2[nH]c3cccc(-c4ccc(O)cc4)c3c(=O)c21
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 8-(4-methoxyphenyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 38, step 3, 41 mg, 0.14 mmol) in a mixture of 48% hydrobromic acid (1 ml) and acetic acid (1 ml) was refluxed for 7 h. After cooling to room temperature, water was added to the mixture. The formed solid was collected by filtration to give 37 mg (94%) of the title compound as a solid.