Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.ClCO[CH2:13][O:14][CH2:15][O:16][CH2:17]Cl.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23]C=1O.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:17]=1[O:16][CH2:15][O:14][CH3:13]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: ClCOCOCOCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
N,N-diisopropylethylamine (1.24 ml, 7.09 mmol), chloromethoxymethyl ether (0.494 ml, 6.50 mmol) and tetrabutylammonium bromide (218 mg, 0.591 mmol) were added to a solution of 2-methoxy-4-nitrophenol (1.0 g, 5.91 mmol) in dichloromethane (20 ml) at 0° C. After 1 hour, the mixture thus obtained was warmed up to room temperature. After 15 hours, the mixture was poured into water (50 ml) and extracted with chloroform (50 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-methoxy-1-(methoxymethoxy)-4-nitrobenzene (1.26 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:17]([O:14][C:13]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:8]([C:9]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:10])[CH:7]=1)=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCBr
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Product: CCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCC)cc([N+](=O)[O-])c1

Procedure:
Using this procedure the reaction of 5-nitroisophthalic acid with 1-bromodecane gave 5-nitro-1,3-benzenedicarboxylic acid didecyl ester (mp 48°-50°, Anal. Calcd for C28H45NO6 : C, 68.40; H, 9.23; N, 2.85. Found: C, 67.68; H, 9.13; N, 2.86.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:23])([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N>C(Cl)Cl>[N:16]1[CH:15]=[C:14]([C:11]2([OH:23])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[N:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cnc3ccccn23)CC1
Agent: N
Solvent: ClCCl
Product: OC1(c2cnc3ccccn23)CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-hydroxy-4-imidazo[1,2-a]pyridin-3-yl-piperidine-1-carboxylic acid tert-butyl ester (2.0 g 6.26 mmol) in CH2Cl2 (100 ml) trifluoro acetic acid (10 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 24 hrs. At the end, the reaction mixture was basified with methanolic ammonia and concentrated to dryness. The residue was directly chromatographed over silica-gel column and eluted with methanol:10% methanolic ammonia. The product, 4-imidazo[1,2-a]pyridin-3-yl-piperidin-4-ol was obtained as yellow oil; Yield; 620 mg (48%); 218 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH3:21])[C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][C:17]=2[CH3:26])=[CH:12][CH:11]=1>C1COCC1.C(OCC)(=O)C>[Br:1][C:18]1[C:17]([CH3:26])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:20]([CH3:21])[C:19]=1[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: -78 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
A solution of N-bromosuccinimide (4.42 g, 24.83 mmol) in THF (62.5 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)propan-1-one (compound 49a, 6.5 g, 24.83 mmol) in THF (100 ml) at −78° C. The resulting reaction mixture was then stirred at a temperature of −78° C. for 5 hr. The reaction mixture was allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent from the reaction mixture was evaporated under reduced pressure and residue so obtained was mixed in ethyl acetate (200 ml). The resulting mixture was washed with saturated sodium bicarbonate solution (1×100 ml) which was followed by washing with water (1×100 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10% ethyl acetate in hexanes to obtain the title compound (7.58 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:25][C:26]([F:34])([F:33])[CH2:27]OS(C)(=O)=O)(=O)=O>CN(C=O)C.O>[F:33][C:26]1([F:34])[CH2:27][O:13][C:11]2=[CH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][N:10]2[CH2:25]1
Reactant: CS(=O)(=O)OCC(F)(F)COS(C)(=O)=O
Reactant: Oc1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2cc3n(n2)CC(F)(F)CO3)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazol-5-ol (4 g, 22.47 mmol) in DMF (30 mL) was added K2CO3 (12.4 g, 89.88 mmol) and 2,2-difluoropropane-1,3-diyl dimethanesulfonate (9 g, 33.7 mmol) at room temperature and then stirred for 16 h at 60° C. The progress of the reaction was monitored by TLC. Thereafter, the reaction mixture was diluted with cold water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulphate and concentrated to get the crude product. Purification by column chromatography over silica gel (eluent 5-10% ethyl acetate in petrol ether) yielded 6,6-difluoro-2-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (3.2 g, 56%) as an off-white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].[OH-].[Na+]>CN(C)C=O.C(O)C>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13])[CH2:15][CH3:16]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: CCCNCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCN(CCC)C(=O)c1ccc(C(=O)O)cn1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
N,N′-carbonyldiimidazole (145 mg, 0.89 mmol) was added to a solution of 5-(methoxycarbonyl)pyridine-2-carboxylic acid (162 mg, 0.89 mmol) in N,N-dimethylformamide (2.5 mL) at 60° C. The reaction mixture was stirred at 60° C. for 10 min. Dipropylamine (90 mg, 0.89 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at ambient temperature over night. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Half the amount of the crude intermediate (83 mg, 0.31 mmol) was dissolved in ethanol (3 mL) and 1 M sodium hydroxide (3 mL, 3 mmol) and heated to 50° C. for 30 min. The solvents were removed in vacuo and the residue was dissolved in water (3 mL) and cooled on ice. A 6 M hydrochloric acid solution was added dropwise and the solvents were removed in vacuo. The residue was added acetonitrile followed by evaporation in vacuo in order to remove trace of water. The procedure was repeated twice. The material was suspended in N,N-dimethylformamide and filtered. The filtrate was concentrated in vacuo to give 80 mg (64% total yield); MS (APPI/APCI) m/z 251[M+H+].
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][CH:17]4[C:20]([CH3:22])([CH3:21])[CH:13]3[CH2:14][C:15]3[C:26]([O:27]C)=[CH:25][CH:24]=[CH:23][C:16]=34)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1>Br>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][CH:17]4[C:20]([CH3:22])([CH3:21])[CH:13]3[CH2:14][C:15]3[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:16]=34)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: COc1cccc2c1CC1N(C(=O)c3ccc4nc[nH]c4c3)CCC2C1(C)C
Agent: Br
Product: CC1(C)C2CCN(C(=O)c3ccc4nc[nH]c4c3)C1Cc1c(O)cccc12
Temperature: 25 °C

Procedure:
A solution of (3H-benzoimidazol-5-yl)-(10-methoxy-11,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone (0.10 g) in hydrobromic acid (2 mL, 48% in water) is stirred at 80° C. for 24 h. After cooling to ambient temperature, the solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH3).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10])[C:5](=[O:14])[CH2:4]1.[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:14]=[C:5]1[CH2:4][CH:3]([CH2:2][O:1][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][N:6]1[C@@H:8]([CH2:12][CH3:13])[C:9]([NH2:11])=[O:10]
Reactant: Oc1ccccc1
Reactant: CC[C@@H](C(N)=O)N1CC(CO)CC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H](C(N)=O)N1CC(COc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 ml three necked flask fitted with magnetic stirrer and dropping funnel under inert atmosphere, 1 g (5 mmoles, 1 eq) of (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanamide 6 is dissolved in 20 ml of THF and cooled down to 0° C. 517 mg of phenol, 0.87 ml (960 mg) of diethyl azodicarboxylate and 1.44 g of triphenylphosphine (5.5 mmoles, 1.1 eq each) are successively added and the mixture stirred for 2 hours. The mixture is concentrated to dryness and purified by Prep LC (500 kg SiO2, CH2Cl2/EtOH, 97.5:2.5) to give 1.1 g of pure 18, 80%, crystallised from ethyl acetate.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][CH:6]([CH3:15])[CH2:7][CH2:8][CH2:9][C:10]([O:13][OH:14])([CH3:12])[CH3:11].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>O.CCCCC>[C:16]([O:14][O:13][C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]([CH3:15])[CH2:5][CH2:4][OH:3])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(CCO)CCCC(C)(C)OO
Reactant: CC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCC
Solvent: O
Product: CC(CCO)CCCC(C)(C)OOC(=O)C(C)(C)C
Temperature: 30 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A jacketed reactor equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 9.3 g (0.075 mole) of 45% KOH, 4.7 g of water and 11.3 g (0.058 mole) of 97.3% 7-hydroxy-1,1,5-trimethylheptyl hydroperoxide. To this vigorously stirred solution at 30° C. was slowly added 6.4 g (0.050 mole) of 94.3% pivaloyl chloride over a period of 20 minutes. The resulting mixture was then vigorously stirred for one hour at 30° C. after which it was cooled to 15° C. and 100 ml of pentane and 25 ml of water were added. After separating and discarding the aqueous phase the product solution was washed at 10° to 15° C. with 20 g of buffered sodium sulfite solution (consisting of 0.8 g of acetic acid, 1.2 g of sodium acetate, 2.0 g of sodium sulfite and 16 g of water), with 15 ml of water and then with 20 g of 7.7% sodium hydrogen carbonate solution. The resulting pentane solution was then dried over anhydrous MgSO4 and after separation of the spent desiccant by filtration the pentane was removed in vacuo at 0° to 10° C. leaving 8.2 g of liquid product. The assay of the product according to peroxyester active oxygen was 69.6% and the corrected yield was 41.7%. An infrared spectrum of the product showed a strong, broad OH band centered at 3400 to 3500 cm-1.
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>C(O)C.O1CCCC1>[C:21]([C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:25])=[O:3])=[CH:8][CH:9]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)/C=C/c1ccc(C#Cc2cccc(C(C)(C)C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C#Cc2ccc(/C=C/C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of (E)-3-[4-(3-tert-butyl-phenylethynyl)-phenyl]-acrylic acid ethyl ester (Intermediate 103, 0.015 g, 0.047 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 10% aqueous hydrochloric acid and evaporated in vacuo to a solid that was washed with water and hexane and dried to afford the title product as a white solid (0.012 g, 85%). 1H NMR (300 MHz, CDCl3): δ 7.78 (d, 1H, J=16.2 Hz), 7.59-7.26 (m, 8H), 6.47 (d, 1H, J=16.2 Hz), 1.34 (s, 9H).
Reaction SMILES: [CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.[Cl:11][C:12]1[S:13][C:14]([CH2:17]Cl)=[CH:15][CH:16]=1>C(Cl)(Cl)Cl>[Cl:11][C:12]1[S:13][C:14]([CH2:17][CH:1]2[N:6]3[CH2:5][N:4]4[CH2:10][N:8]([CH2:9][N:2]2[CH2:3]4)[CH2:7]3)=[CH:15][CH:16]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClCc1ccc(Cl)s1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(CC2N3CN4CN(C3)CN2C4)s1
Yield: 99.5 %

Procedure:
To a suspension of hexamethylenetetramine (HMTA) (3.12 g, 22.2 mmol) in CHCl3 (35 mL) was added 2-chloro-5-chloromethylthiophene (1.02 mL, 8.46 mmol). The reaction mixture was heated at reflux for 4 hr, cooled, and filtered to give white solid 5-chloro-2-[(1,3,5,7-tetraazatricyclo-[3.3.1.1(3,7)]decyl) methyl]thiophene (2.28 g, 88%). ES-MS (M)+=271, 273 (Cl). 1H-NMR (DMSO-d6): δ 4.27 (s, 2H), 4.39-4.57 (ABq, 6H), 5.06 (s, 6H), 7.21-7.24 (ABq, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH2:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[N:30][N:29]=[N:28]4)=[CH:23][N:22]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-n2cnnn2)cn1
Reactant: NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3ccc(-n4cnnn4)cn3)CC2)nc1
Temperature: 70 °C

Procedure:
2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanamine (50 mg, 0.18 mmol) from Example 5 step 3 and 2-fluoro-5-(1H-tetrazol-1-yl)pyridine (35.6 mg, 0.20 mmol) from step 1 were added in NMP (0.89 mL), then potassium carbonate (73.8 mg, 0.53 mmol) was added and the reaction was heated to 70° C. 6.5 hours. The reaction was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (20 mL), second wash with brine (10 mL). The organic phase was dried by magnesium sulfate, filtered and concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 40% ethyl acetate/hexane to give the title compound as a white-solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9]1.[CH3:23][C:24]([C:27]([OH:29])=[O:28])([CH3:26])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:27]([C:24]([NH:25][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9]1)([CH3:26])[CH3:23])([OH:29])=[O:28]
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1ccccc1C1Nc2ccc(C(=O)O)cc2CC1(C)C)C(=O)O
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
A mixture of 2-(2-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.42 mmol), copper(I) iodide (24 mg, 0.13 mmol), 2-methylalanine (170 mg, 1.7 mmol), and potassium carbonate (174 mg, 1.26 mmol) in dimethyl sulfoxide (3 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (128 mg, 80%) as a white solid: LC/MS m/e calcd for C22H26N2O4 (M+H)+: 383.46, observed: 383.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]2[CH3:20])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:20][N:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:28][C:29]([OH:31])=[O:30])[CH:2]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN1C(=O)c2ccccc2C1c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2C1c1cn(CC(=O)O)c2ccccc12
Temperature: 100 °C

Procedure:
The product from example 20, step b) (450 mg, 1.72 mmol) was dissolved in DMF and treated with K2CO3 (284 mg, 2.06 mmol) followed by t-butyl bromoacetate (255 μL, 1.72 mmol). The reaction was heated to 100° C. for 5 h. The reaction was cooled, diluted with EtOAc, washed 3 times with water, and concentrated. The crude product was treated with TFA (neat) at room temperature for 45 minutes. The reaction was then concentrated to dryness and purified by preparative LCMS to give the title compound. 1H NMR (CD3OD) δ 7.74-7.78 (m, 1H), 7.43 (t, J=3.7 Hz, 1H), 7.41 (t, J=3.6 Hz, 1H), 7.36 (s, 1H), 7.28-7.31 (m, 1H), 7.20 (d, J=8.1 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.67 (t, J=7.2 Hz, 1H), 6.48 (d, J=7.8 Hz, 1H), 4.62 (s, 2H), 2.78 (s, 3H); MS: ESI (negative): 319 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](Cl)(=[O:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1.[NH3:15]>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9]([NH2:15])(=[O:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2s1
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-chloro-benzo[b]thiophene-2-sulfonyl chloride (Komoriya, Satoshi; Haginoya, Noriyasu, Bioorganic & Medicinal Chemistry (2005), 13(12), 3927-3954; 0.57 g, 2.1 mmol) in THF (8.0 mL) was added ammonia gas until saturation at ca. 10° C., then the flask was stoppered, and the reaction mixture was stirred at rt for 4 h. The reaction mixture was then quenched with water; the organic solvent was slowly evaporated under vacuum. The precipitate formed was filtered off, washed with water and dried over P2O5 under high vacuum to obtain the desired compound (0.52 g) as a white solid.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([CH2:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]2)[O:3]C1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O.CCCCCC.C(OCC)(=O)C>[O:3]=[C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:6][CH2:5]1
Reactant: O=C(CC1CCC2(CC1)OCCO2)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(CC(=O)OCc2ccccc2)CC1
Temperature: 55 °C
Reaction time: 10 h
Yield: 86.3 %

Procedure:
To a solution of 4-benzyloxycarbonylmethylcyclohexanone ethylene acetal (7.62 g, 26.2 mmol) in acetone (235 mL)-water (10 mL) was added p-toluenesulfonic acid monohydrate (221 mg, 1.16 mmol), and the mixture was stirred at 55° C. for 10 h. The reaction mixture was adjusted to pH 5 with sodium hydrogen carbonate with stirring under ice cooling, and concentrated under reduced pressure. The residue obtained by azeotropic distillation with the addition of toluene was subjected to silica gel column chromatography (hexane-ethyl acetate 4:1) to give 5.57 g of benzyl 2-(4-oxocyclohexyl)acetate as oil (yield: 86%).
Reaction SMILES: O[C:2]1[N:3]=[N:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:7]=1.OC1N=NC(C(O)=O)=CC=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[N:3]=[N:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc(O)nn1
Agent: O=C(O)c1ccc(O)nn1
Product: CCOC(=O)c1ccc(Cl)nn1

Procedure:
Ethyl 3-hydroxypyridazine-6-carboxylate [22.00 g, 0.13 mol, prepared from 3-hydroxypyridazine-6-carboxylic acid according to the procedure of Libermann, D. and Rouaix, A. (Bull. Soc. Chim . Fr. 1959, 1793-1798)] and phosphorous oxychloride (122 mL, 1.31 mol) were heated at 110° C. (via an oil bath) for 1 h. The mixture was cooled and concentrated under reduced pressure, which removed the excess phosphorous oxychloride. The residue was dissolved into chloroform, cooled, and carefully washed with saturated sodium bicarbonate solution. The chloroform extract was dried (MgSO4) , filtered, concentrated and recrystallized from ethyl acetate-diisopropyl ether to afford ethyl 6-chloro-3-pyridazinecarboxylate as tan needles, mp 145°-150° C.
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH2:17][CH2:18][O:19][C:20]4=O)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH2:17][CH2:18][N:30]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:27]=3[F:26])[C:20]4=[O:19])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCc1ccc(F)cc1F
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c1CCOC2=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c1CCN(Cc1ccc(F)cc1F)C2=O
Temperature: 160 °C
Yield: 36.5 %

Procedure:
A mixture of 2-adamantan-1-yl-N-(1-oxo-isochroman-5-yl)-acetamide (39 mg, 0.115 mmol) and 2,4-difluorobenzylamine (99 mg, 0.689 mmol) was heated at 160° C. for 40 h. The reaction vessel was cooled to room temperature and the solvents removed under reduced pressure. The crude product was purified by prep. HPLC to afford 2-adamantan-1-yl-N-[2-(2,4-difluoro-benzyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yl]-acetamide (19.2 mg, 0.042 mmol, 36%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH3:19])=[O:17].ClCCl>O>[CH3:19][O:18][C:16]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:17]
Reactant: OCC1CCNCC1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1CCC(CO)CC1
Temperature: 5 °C
Yield: 90 %

Procedure:
4-Hydroxymethylpiperidine (47.6 g, 1.0 eq) and water (300 mL) were charged to a flask. The resulting mixture was cooled to 0-10° C. Potassium carbonate (85.7 g, 1.5 eq) dissolved in water (150 mL) and methyl chloroformate (38.4 mL, 1.1 eq) were added while maintaining the temperature at below 10° C. When the addition was complete, the reaction mixture was warmed up to 20-30° C. for 1 hour. After the reaction was complete, dichloromethane (500 mL) was added to the reaction mixture. The organic layer was collected and washed with 1 M phosphoric acid solution (200 mL), saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL). The organic layer was dried over sodium sulfate (50 g, 1 w/w eq) and then distilled under vacuum to produce the title intermediate. (67.0 g, 90% yield)