Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O.[Br:19][C:20]1[C:21]([CH3:34])=[C:22]([CH3:33])[C:23]2[O:27][C:26]([CH2:29]I)([CH3:28])[CH2:25][C:24]=2[C:31]=1[CH3:32]>C(OCC)(=O)C.O>[Br:19][C:20]1[C:21]([CH3:34])=[C:22]([CH3:33])[C:23]2[O:27][C:26]([CH2:28][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([CH3:29])[CH2:25][C:24]=2[C:31]=1[CH3:32]
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CI)O2
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(CN1CCCCC1)O2
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Piperidine (323 mg, 3.80 mmol) and potassium carbonate (525 mg, 3.80 mmol) were added to a solution of DMA (3 mL) containing 5-bromo-2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (300 mg, 0.759 mmol) synthesized in Reference Example 133, and the mixture was stirred under microwave irradiation at 150° C. for 10 minutes. The reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with water and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-85:15) to give 170 mg of the title compound (yield: 64%).
Reaction SMILES: [NH2:1][C:2]1([CH2:14][F:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[F:15][CH2:14][C:2]1([NH:1][C:25](=[O:26])[CH2:24][NH:23][C:21](=[O:22])[C:20]2[CH:28]=[CH:29][CH:30]=[C:18]([C:17]([F:16])([F:32])[F:31])[CH:19]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(CF)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CF)(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
337 mg (1.52 mmol) of tert-butyl 3-amino-3-(fluoromethyl)pyrrolidine-1-carboxylate, 457 mg (1.85 mmol) of {[3-(trifluoromethyl)benzoyl]amino}acetic acid, BOP reagent (817 mg, 1.85 mmol) and 0.64 mL (4.6 mmol) of triethylamine were dissolved in 15 mL of DMF at room temperature. The reaction mixture was stirred at r.t. overnight. Direct chromatography on silica gel (flash chromatography grade) with 50% ethyl acetate-hexane gave 578 mg (1.29 mmol, 84%) of tert-butyl 3-(fluoromethyl)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate: 1H NMR (400 MHz, CDCl3) δ 8.15-8.12 (1H, m), 8.05-7.98 (1H, m), 7.81-7.77 (1H, m), 7.63-7.58 (1H, m), 6.64-6.62 (1H, m), 4.20-4.16 (2H, m), 3.61-3.57 (2H, m), 3.55-3.42 (1H, m), 2.98-2.94 (2H, m), 2.90-2.86 (2H, m), 1.62-1.60 (2H, m), 1.45 (9H, s); MS (m/e): 448 (M+1)+.
Reaction SMILES: [CH2:1]([S:7][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:9]([O:11]C)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[OH-].[Li+]>O1CCCC1.O.CO>[CH2:1]([S:7][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSC(C(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCSC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a stirred solution of methyl α-hexylthio-3,4-dichloro-phenylacetate (0.197 g) in tetrahydrofuran (10 ml) were added a solution of lithium hydroxide monohydrate (0.123 g) in water (10 ml) and methanol (10 ml), and the mixture was continued to stir for 2 hours at room temperature. At the end of the stirring it was evaporated to remove the organic solvents and the residue was partitioned between methylene chloride and 1N HCl. The organic layer was separated, washed with brine, dried (sodium sulfate) and evaporated to give an oily residue of α-hexylthio-3,4-dichloro-phenylacetic acid (0.179 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.Cl.[CH:44]1([C:47]([NH2:50])([CH3:49])[CH3:48])[CH2:46][CH2:45]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH:44]1([C:47]([NH:50][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:22])([CH3:49])[CH3:48])[CH2:46][CH2:45]1
Reactant: CC(C)(N)C1CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C5CC5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 9.4 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (130 mg, 0.68 mmol), DMAP (83 mg, 0.68 mmol) and DIEA (88 mg, 0.68 mmol) in 6 mL of DMF was added 2-cyclopropylpropan-2-amine hydrochloride (92 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 75% acetonitrile/25% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(2-cyclopropylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (12 mg, 9.4%) as a yellow solid. MS: (M+H)+=375; 1H NMR (300 MHz, DMSO): δ 13.38 (s, 1H), 12.80 (s, 1H), 9.16 (s, 1H), 8.41-8.35 (m, 2H), 7.95 (s, 1H), 7.41 (s, 1H), 7.06 (d, 1H, J=8.4 Hz), 2.57 (s, 3H), 1.67-1.54 (m, 1H), 1.59 (s, 6H), 0.48-0.44 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C)C(=O)C.[CH2:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[S:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:36](=[S:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6]1
Reactant: CCCCCCCCCCCCCCCCCCCCC(=S)Cl
Reactant: NCCN1CCOCC1
Solvent: c1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCCCCCC(=S)NCCN1CCOCC1

Procedure:
2.6 Grams of N-(2-aminoethyl)morpholine and 30 ml of N,N-dimethylacetamide were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 7.5 g of 11-decylthioundecanoic acid chloride. After completion of the addition, the temperature of the solution was returned to room temperature, followed by further stirring for 2 hours. The reaction mixture was diluted with 300 ml of benzene, and washed with 5% aqueous sodium bicarbonate solution, pure water and saturated aqueous sodium chloride solution in succession. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain a crystal. The crystal was recrystallized from n-hexane to obtain 7.3 g of the desired product. m.p. 80° C.
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:26]([CH3:27])=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20](I)[CH:19]=1>>[F:17][C:18]1[C:26]([CH3:27])=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[CH:19]=1
Reactant: Cc1cc(C(=O)O)c(I)cc1F
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Product: Cc1cc(C(=O)O)c(-n2nccn2)cc1F

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 4-fluoro-2-iodo-5-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:14](Cl)[C:15](=[CH2:17])[CH3:16].C1(C)C=CC=CC=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[C:1]([C:4]1([CH2:16][C:15](=[CH2:14])[CH3:17])[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C(C)CCl
Agent: CC(=O)C1CCCC(C)(C)C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)CC1(C(C)=O)CCCC(C)(C)C1

Procedure:
A slurry of 1-acetyl-3,3-dimethylcyclohexane (624 grams, 4 moles), granular sodium hydroxide (240 grams, 6 moles), Aliquot® 336 (tricaprylmethylammonium chloride [35 grams]), methallyl chloride (432 grams, 4.8 moles), and 400 ml of toluene is heated at reflux for 4 1/4 hours. At the end of this time, one liter of water is added to the cooled reaction mass. The aqueous layer is discarded, and the organic layer is distilled rapidly through a short column to afford 203 grams of recovered 1-acetyl-3,3,-dimethylcyclohexane, 500 grams of 1-acetyl-3,3-dimethyl-1-methallyl cyclohexane, and 73 grams of 3,3-dimethyl-1-(2-methyllyl-5-methyl-4-pentenoyl)cyclohexane) (1°-4°, 3.0 mm Hg) containing 5% of 3,3-dimethyl-1-(4-methyl-4-pentenoyl). A portion of the latter compound is isolated by GLC chromatography (1'×1/4" 80% SE-30 packed column; 200° C. isothermal) and exhibits the following odor and flavor properties:
Reaction SMILES: N[C:2]1[N:18]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9](CN3CCNC(=O)C3)[N:4]2N=1.FC(F)(F)C(O)=O.C(OC([N:33]([C:51](OC(C)(C)C)=O)[C:34]1[N:50]=[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([CH2:42][N:43]3[CH2:48][CH2:47][NH:46][C:45](=[O:49])[CH2:44]3)[N:36]2[N:35]=1)=O)(C)(C)C>ClCCl>[NH:4]1[C:5]2=[N:18][CH:2]=[C:51]([NH:33][C:34]3[N:50]=[C:37]4[CH:38]=[CH:39][CH:40]=[C:41]([CH2:42][N:43]5[CH2:48][CH2:47][NH:46][C:45](=[O:49])[CH2:44]5)[N:36]4[N:35]=3)[CH:6]=[C:7]2[CH:8]=[CH:9]1
Reactant: Nc1nc2cccc(CN3CCNC(=O)C3)n2n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2cccc(CN3CCNC(=O)C3)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(Cc2cccc3nc(Nc4cnc5[nH]ccc5c4)nn23)CCN1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97 %

Procedure:
4-((2-Amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazin-2-one. Trifluoroacetic acid (2.55 mL, 33.1 mmol) was added to a stirred solution of N,N-di-tert-butoxycarbonyl-5-((3-oxopiperazinyl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.740 g, 1.657 mmol) in dichloromethane (18.5 mL). The resulting solution was capped and stirred at room temperature for 23 h. Most of the solvent was removed on a rotary evaporator. The residue was loaded onto two 5 g Strata X—C ion exchange columns from Phenomenex. The columns were washed successively with acetonitrile, water, acetonitrile, methanol, and then 10% ammonium hydroxide in methanol. The product came off with the 10% ammonium hydroxide in methanol eluent. The 10% ammonium hydroxide in methanol eluent from both runs was concentrated on a rotary evaporator and dried under high vacuum at 40° C. to give the desired product (0.406 g, 1.649 mmol, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.82 (br s, 1H), 7.43 (dd, J=7.42, 8.59 Hz, 1H), 7.28 (d, J=8.59 Hz, 1H), 6.92 (d, J=7.03 Hz, 1H), 6.03 (s, 2H), 3.94 (s, 2H), 3.21 (br s, 2H), 3.12 (s, 2H), 2.71 (t, 2H); MS (ESI) m/z 247.3 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NN1CCOCC1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NN3CCOCC3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture is microwave at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][OH:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:24])=[CH:4][N:3]=1.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27].CCCCCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([OH:23])[C:25](=[O:28])[CH:26]=[CH2:27])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:24])=[CH:4][N:3]=1
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N(c1cccc(NO)c1)c1nc(Cl)ncc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: C=CC(=O)N(O)c1cccc(N(C(=O)OC(C)(C)C)c2nc(Cl)ncc2F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
In a 25 ml 3-neck RBF was equipped with a magnetic stirrer and CaCl2 guard tube was added tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(hydroxyamino)phenyl)carbamate (0.409 g in 5 ml DCM). The reaction was cooled to −40° C. and acryloyl chloride (0.114 g in 3 ml DCM) was slowly added. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 min. The reaction was monitored on TLC using hexane:ethyl acetate (7:3) as mobile phase. The reaction was complete after 30 min and was poured in water (100 ml) and basified using sodium bicarbonate solution. The reaction mixture was extracted with DCM (2×25 ml) and the combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated completely under reduced pressure at 40° C. Crude material was purified by using column chromatography. Product was eluted with 14% ethyl acetate in hexane to give, after concentration, 0.250 g of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([N:22]([CH:32]2[CH2:34][CH2:33]2)CC2C=CC(OC)=CC=2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1.CCN(C(C)C)C(C)C.Cl[C:50](Cl)([O:52]C(=O)OC(Cl)(Cl)Cl)Cl.C(O)(C(F)(F)F)=O>ClC(Cl)C.C1(OC)C=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][O:12][C:50]2=[O:52])=[CH:6][C:5]([C:13]#[N:14])=[CH:4][C:3]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][CH:32]2[CH2:33][CH2:34]2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(NCCCO)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: COc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
To a solution of 2-((2-chloro-5-cyano-3-((3-hydroxypropyl)amino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (15 mg, 0.028 mmol) in dichloroethane (1 mL) was added Hunig's Base (0.048 mL, 0.276 mmol) followed by triphosgene (40.9 mg, 0.138 mmol). After stirring at room temperature for 1 h, LC-MS indicated the desired peak. After concentration, purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave 15 mg of the PMB protected product. This was dissolved in 1 mL of dichloroethane and then 1 drop of anisole was added followed by 0.5 mL of TFA. The solution was heated at 60° C. for 1 h. LC-MS indicated completion, and then it was cooled and concentrated. The crude was dissolved in methanol and neutralized with 7N ammonia in methanol. After stirring for 10 min it was concentrated, purification via preparative HPLC gave the title compound as a yellow solid (4.2 mg).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH:8]1([NH:12][C:13]2[N:14]=[C:15]3[CH2:38][CH2:37][NH:36][CH2:35][C:16]3=[N:17][C:18]=2[N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[F:34])[CH2:21][CH2:20]2)[CH2:11][CH2:10][CH2:9]1.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42].C(N(CC)CC)C>C(Cl)Cl>[CH:8]1([NH:12][C:13]2[N:14]=[C:15]3[CH2:38][CH2:37][N:36]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH2:35][C:16]3=[N:17][C:18]=2[N:19]2[CH2:20][CH2:21][CH:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[F:34])[CH2:23][CH2:24]2)[CH2:11][CH2:10][CH2:9]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCNC4)CC2)c(F)c1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CCC3)CCN(C(=O)N(C)C)C4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-cyclobutyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10.6 mg, 0.020 mmol), dimethylcarbamic chloride (4.2 mg, 0.039 mmol) and triethylamine (5.9 mg, 0.059 mmol) in DCM (200 μL) was stirred at room temperature for 30 min. The mixture was purified by HPLC Method A to give the title compound as a TFA salt (7.1 mg, 59.2%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.77-1.87 (m, 2H), 1.90-2.00 (m, 2H), 2.03-2.15 (m, 4H), 2.39-2.49 (m, 2H), 2.81-2.87 (m, 2H), 2.90 (s, 6H), 2.98-3.08 (m, 2H), 3.38-3.47 (m, 2H), 3.54 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 4.26 (s, 2H), 4.33-4.47 (m, 2H), 6.67 (dd, J=9.1, 1.5 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 499.4.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CCOCC>[O:29]=[C:23]([CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Br:7])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCc1cc(OC)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(Cc1cc(OC)ccc1Br)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Potassium t-butoxide (6.72 g) was suspended in 30 ml of anhydrous ether and cooled to 0° C. A solution of 14.35 g of ethyl 3-(2-bromo-5-methoxyphenyl)propionate and 10.95 g diethyl oxalate in 10 ml ether was added dropwise over 15 min. After 2 h at 25° C., the reaction was poured into 100 ml H2O and the aqueous layer was separated, acidified to pH 1 and extracted with ether. The ether layer was dried (MgSO4) and the solvent was evaporated to yield 17.48 g of the desired product as a colorless oil (90%). NMR (CDCl3) δ 1.20 (t, 3H), 1.35 (t, 3H), 3.32 (dd, 2H), 3.76 (s, 3H), 4.18 (q, 2H), 4.32 (q, 2H), 4.53 (t, 1H), 6.67 (dd, 1H), 6.80 (d, 1H), 7.40 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH2:38][F:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:37][CH2:38][F:39])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: FCCBr
Product: COc1ccc(CC2c3c(OCCF)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-2-fluoro-ethane
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Cl)c(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 70.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-chloro-3-trifluoromethylphenylboronic acid (175 mg, 0.78 mmol), 0.65 mL of 2M aq. sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 188 mg (71%) of the title compound as a white solid. mp 134°-137°. FDMS: m/e=407. α[D]589 =+59.74 (c=1.02, chloroform).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C:16]3[C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]([O:26][CH3:27])=[C:18]([O:28][CH3:29])[C:17]=3[O:30][CH3:31])[C:5]([C:12]([O:14]C)=[O:13])=[CH:6][C:7]=2[O:10][CH3:11])[O:2]1.[OH-].[K+].Cl>O1CCOCC1>[CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C:16]3[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]([O:26][CH3:27])=[C:18]([O:28][CH3:29])[C:17]=3[O:30][CH3:31])[C:5]([C:12]([OH:14])=[O:13])=[CH:6][C:7]=2[O:10][CH3:11])[O:2]1
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1-c1c(C(=O)OC)cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)c(-c2c(C(=O)O)cc(OC)c3c2OCO3)c(OC)c1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
In 50 ml of dioxane was dissolved 1.3 g of dimethyl 2',3'-methylenedioxy-2,3,4,4'-tetramethoxy-1,1'-biphenyl-6,6'-dicarboxylate obtained in Example 2, and 10 mg of potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight. When the pH value of the mixture was adjusted to 1 by 3N hydrochloric acid, crystals were precipitated. The precipitated crystals were recovered by filtration and recrystallized from ethanol to obtain 1.12 g of 2',3'-methylenedioxy-2,3,4,4'-tetramethoxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 92%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCCCCCCCCBr)OCc1ccccc1
Yield: 101.9 %

Procedure:
This compound was prepared from 11-bromoundecanoic acid (2.65 g; 10.0 mmol), benzyl alcohol (1.62 g; 15.0 mmol), and p-toluenesulphonic acid (50 mg) in toluene (100 mL) using Procedure B. 3.62 g product was obtained, which was used in 13b without further purification.