Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[O:15]=[S:16]1(=[O:54])[CH2:21][CH2:20][N:19]([C:22](=[O:53])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:26]=2[C:32]2[CH2:36][C:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[O:34][N:33]=2)[CH2:18][CH2:17]1.N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:31][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:22]([N:19]3[CH2:18][CH2:17][S:16](=[O:15])(=[O:54])[CH2:21][CH2:20]3)=[O:53])=[C:26]([C:32]3[CH2:36][C:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH2:37][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:42])[CH3:43])[O:34][N:33]=3)[CH:27]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)N2CCS(=O)(=O)CC2)=NO1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OC(=O)c3ccc(NC(=N)N)cc3)ccc2CCC(=O)N2CCS(=O)(=O)CC2)=NO1
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (56.4 mg) was added to a mixture of di-tert-butyl 2,2′-(3-(2-(3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropyl)-5-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (140 mg), pyridine (0.2 mL), and NMP (0.2 mL) at 50 C, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (56.4 mg) was further added thereto, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (56.4 mg) was further added thereto, and the obtained mixture was stirred at 50 C for 3 hours. Pyridine (0.2 mL) and NMP (0.2 mL) were further added thereto, 4-carbamimidamidobenzoyl chloride hydrochloride (56.4 mg) was added thereto, and then, the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (56.4 mg) was further added thereto, and the obtained mixture was stirred at 50 C for 30 minutes. 4-carbamimidamidobenzoyl chloride hydrochloride (56.4 mg) was further added thereto, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (49.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2[CH:37]=[CH:38][CH:39]=CC=2N=N1.CN(C=O)C.C1(CN)CC1>C1COCC1>[CH:37]1([CH2:36][NH:32][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:25])[CH2:39][CH2:38]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)NCC3CC3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 22.1 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.080 g, 0.152 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.130 g, 0.406 mmol), TEA (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and 1-cyclopropylmethanamine (0.044 g, 0.406 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 0.220 (q, J=4.5 Hz, 2H), 0.44 (q, J=6.6 Hz, 2H), 1.01 (m, 1H), 1.51 (s, 6H), 3.02 (s, 2H), 3.19 (t, J=6.0 Hz, 2H), 7.22 (s, 1H), 7.77 (s, 1H), 8.43 (s, 2H), 10.99 (s, 1H), 11.40 (s, 1H); MS [M+H]+: 446.27.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH2:9])=[O:8])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1>COC(OC)(OC)CCCC>[CH2:3]([C:2]1[NH:1][C:2]2[N:6]([N:5]=[C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:3]=2)[C:7](=[O:8])[N:9]=1)[CH2:4][CH2:10][CH3:11]
Reactant: NC(=O)n1nc(-c2ccccc2)cc1N
Agent: CCCCC(OC)(OC)OC
Product: CCCCc1nc(=O)n2nc(-c3ccccc3)cc2[nH]1
Temperature: 130 °C
Yield: 150.7 %

Procedure:
A mixture of 4.0 g of the product of Example 2 and 10 ml of trimethylorthovalerate is heated at 130° C. for 1 hour. The reaction mixture is cooled to room temperature and diluted with 400 ml of hexanes. The resulting solid is collected, washed with hexanes and dried to give 4.0 g of the desired product as colorless crystalline solid, m.p. 234° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:19][F:20])[C:3](=[O:18])[CH:4]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=1)[N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[BH4-].[Na+]>CO>[CH3:1][C:2]([CH3:21])([CH2:19][F:20])[CH:3]([OH:18])[CH:4]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=1)[N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: CC(C)(CF)C(=O)C(Oc1cccc(F)n1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CF)C(O)C(Oc1cccc(F)n1)n1cncn1
Yield: 92.4 %

Procedure:
10 g (34 m moles) of 3,3-dimethyl-4-fluoro-1-(6-fluoro-pyridin-2-yl-oxy)-1-(1,2,4-triazol-1-yl)-butan-2-one (obtained as described in Example 1) were dissolved in 100 ml of methanol, and 0.7 g (17 m moles) of sodium borohydride was added. The mixture was stirred under reflux for 10 minutes and concentrated and the residue was partitioned between methylene chloride/water. The organic phase was separated off, washed with water, dried over sodium sulphate and concentrated. 9.3 g (90% of theory) of waxy 3,3-dimethyl-4-fluoro-1-(6-fluoro-pyridin-2-yl-oxy)-1-(1,2,4-triazol-1-yl)-butan-2-ol were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:41])[C@@H:30]([CH3:40])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:39])([CH3:38])[CH:35]=[CH:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:42].[OH2:43].C[N+]([O-])(C)C.C(=O)([O-])O.[Na+].S([O-])(O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O.O>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:41])[C@@H:30]([CH3:40])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:39])([CH3:38])[C@@H:35]([OH:43])[C@@H:36]([OH:42])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: C[C@H]1CC[C@H]2C(C)(C)C=CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Agent: O=C([O-])O
Solvent: CC(C)=O
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.7 %

Procedure:
To a solution of Compound (40a) (Step-2 in Example 44) (40 mg, 0.072 mmol) in 2.0 ml of acetone were added 12 mg (0.108 mmol) of trimethylamine oxide dihydrate and 0.50 ml (0.1 mmol) of 0.2M osmium tetroxide aqueous solution, and the mixture stirred at room temperature for 15 hours. After addition of 8 mg (0.072 mmol) of trimethylamine oxide dihydrate, the mixture was stirred for 5 hours. To the reaction mixture were added 236 mg (2.8 mmol) of sodium hydrogen carbonate and 146 mg (1.4 mmol) of sodium hydrogen sulfite, and the mixture stirred for 1.5 hours. After addition of water, the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; n-hexane:ethyl acetate=2:1) to give 28 mg (66%) of Compound (48a).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][O-:11].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:11][CH3:10])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: C[O-]
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (10 g, 0.052 mol) in dry DMF (300 mL) cooled to 0-5° C. was added sodium methoxide (5.60 g, 0.1036 mol) and the reaction mixture was stirred at RT for 24 h. The reaction mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (7.5 g, 71%).
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][CH:9]1[CH2:13][NH:12][CH2:11][CH:10]1[NH:14][C:15]([CH:17]([NH:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[CH2:18][S:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:20])=[O:16].C([O-])(O)=O.[Na+].[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCOCC1>[C:43]([N:12]1[CH2:13][CH:9]([OH:8])[CH:10]([NH:14][C:15]([CH:17]([NH:29][C:30]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:31])[CH2:18][S:19]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:21])=[O:20])=[O:16])[CH2:11]1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(NC1CNCC1O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CN(C(=O)c2ccccc2)CC1O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
Morpholine-4-carboxylic acid [1-(4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide TFA salt (215 mg, 0.39 mmol) was dissolved in 1,4-dioxane (20 mL). Saturated aqueous NaHCO3 solution (10 mL) was added followed by benzoyl chloride (0.2 mL, 1.72 mmol). The mixture was stirred at ambient temperature for 1 hour and then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel (Eluent: 5% methanol in ethyl acetate to 20% methanol in ethyl acetate) to yield morpholine-4-carboxylic acid [1-(1-benzoyl-4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethane-sulfonyl-ethyl]-amide (92mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[N:18]1([CH2:22][CH2:23][N:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)[N:26]=[C:25]2[CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:21]C[CH2:19]1.C(N(CC)CC)C>CC#N>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:43]2[CH2:44][CH2:45][CH:40]([C:25]3[N:24]([CH2:23][CH2:22][N:18]([CH3:21])[CH3:19])[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:30]=4)[N:26]=3)[CH2:41][CH2:42]2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc(Cl)c1C=O
Reactant: Fc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
The reaction mixture of 4-Amino-6-chloro-pyrimidine-5-carbaldehyde (150.00 mg; 0.95 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate (2) (594.52 mg; 0.95 mmol; 1.00 eq.) and Triethyl-amine (0.80 ml; 5.71 mmol; 6.00 eq.) in MeCN 4 ml were stirred at RT for 2 hr, lc-ms showed desired as major. Filtrate, collected white solid as 4-amino-6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbaldehyde, 277 mg, yield 56.2%. LC-MS: (M+1=506, obsd.=506).
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26](I)[CH:27]=5)[N:22]=[CH:21][N:20]=4)=[CH:14][C:13]=3[CH3:30])=[CH:7][C:6]=12.[CH3:31][C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([NH:37][C:34]6[S:35][CH:36]=[C:32]([CH3:31])[N:33]=6)[CH:27]=5)[N:22]=[CH:21][N:20]=4)=[CH:14][C:13]=3[CH3:30])=[CH:7][C:6]=12
Reactant: Cc1cc(Nc2ncnc3ccc(I)cc23)ccc1Oc1ccn2ccnc2c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc(Nc2ccc3ncnc(Nc4ccc(Oc5ccn6ccnc6c5)c(C)c4)c3c2)n1
Temperature: 100 °C

Procedure:
A solution of N-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-iodoquinazolin-4-amine hydrochloride (0.20 g, 0.378 mmol) and 4-methylthiazol-2-amine (0.086 g, 0.755 mmol) and sodium 2-methylpropan-2-olate (0.145 g, 1.51 mmol), Xanthphos (0.016 g, 0.028 mmol), Pd2 dba3 (0.017 g, 0.018 mmol) in toluene (3.6 mL) was degassed and sealed. After heating to 100° C. for 16 hours, the mixture was diluted with water and ethyl acetate. The resulting solid was filtered to provide the product as brown solid. MS APCI (+) m/z 480 (M+1) detected; 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.86 (s, 1H), 8.63 (s, 1H), 8.55 (d, 1H), 7.79 (m, 5H), 7.44 (s, 1H), 7.14 (d, 1H), 6.80 (dd, 1H), 6.55 (d, 1H), 2.50 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.O1CCCC1>[CH:1]1([CH:6]([C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCC2)oc2c(F)cc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(O)C2CCCC2)oc2c(F)cc(F)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methanone (1.24 g) synthesized above was dissolved in methanol (4 mL)-tetrahydrofuran (20 mL), and sodium tetrahydroborate (90%)(355 mg) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (1.18 g, 100%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][CH:3]=1.CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C>[CH3:15][CH:10]1[N:9]2[C:14]3[C:5](=[CH:4][CH:3]=[C:2]([N:1]4[CH:22]=[CH:26][CH:25]=[CH:24]4)[C:13]=3[CH2:12][CH2:11]1)[C:6](=[O:19])[C:7]([C:16]([OH:18])=[O:17])=[CH:8]2
Reactant: CC1CCc2c(N)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC1CCc2c(-n3cccc3)ccc3c(=O)c(C(=O)O)cn1c23

Procedure:
To a suspension of 3.0 g of 8-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 30 ml of glacial acetic acid was added 3.0 g of 2,5-dimethoxytetrahydrofuran and the mixture was heated on a steam bath for 1.5 hours. Cooling produced a solid which was separated by filtration to provide 6,7-dihydro-5-methyl-1-oxo-8-(1-pyrryl)-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 303°-305° C. Analysis: Calculated for C18H16N2O3 : %C, 70.1; %H, 5.2; %N, 9.1; Found: %C, 69.5; %H, 5.1; %N, 9.2. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:20])[C@@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:6]([CH3:8])[CH3:7].[C:21]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:26]=[CH:25][C:24]([CH2:27][C@@H:28]([NH:37]C(OC(C)(C)C)=O)[CH2:29][C@:30]([CH2:35][OH:36])([CH3:34])[C:31]([OH:33])=[O:32])=[CH:23][CH:22]=1.CCN(CC)CC.Cl.O1CCOCC1>CC(C)=O.CC#N>[CH2:13]([O:12][C:10]([NH:9][C@@H:5]([CH:6]([CH3:8])[CH3:7])[C:4]([O:3][CH2:2][O:33][C:31](=[O:32])[C@@:30]([CH2:35][OH:36])([CH3:34])[CH2:29][C@H:28]([NH2:37])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:22][CH:23]=1)=[O:20])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
(S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid chloromethyl ester (232 mg, 774 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (0.2 g, 484 μmol) and Et3N (71 μL, 508 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified (Interchim reverse phase chromatography column) the solvent was removed under vacuum. MeCN (2 mL) and 4 M HCl in 1,4-dioxane (2 mL, 8 mmol) was added and the resulting mixture was stirred for 30 minutes. The solvent was evaporated under vacuum and the product was azeotroped with toluene (1×) to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (S)-2-benzyloxycarbonylamino-3-methyl-butyryloxymethyl ester.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20](OC)=[O:21].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([CH3:19])=[N:4][C:3]=1[C:20]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21]
Reactant: COC(=O)c1nc(C)c2cccc(Oc3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Oc3ccccc3)cccc12
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 1e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 1e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-(4-hydroxy-1-methyl-5-phenoxyisoquinoline-3-carboxamido)acetic acid.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[C:12]([O:15][CH:16]([C:25]([CH3:32])([CH3:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:18])(=[O:14])[CH3:13].[CH:33]1[C:38]([NH2:39])=[CH:37][CH:36]=[C:35]([OH:40])[CH:34]=1>C(Cl)Cl>[C:12]([O:15][CH:16]([C:25]([CH3:32])([CH3:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:17]([NH:19][CH2:20][CH2:21][C:22]([NH:39][C:38]1[CH:33]=[CH:34][C:35]([OH:40])=[CH:36][CH:37]=1)=[O:24])=[O:18])(=[O:14])[CH3:13]
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)Nc1ccc(O)cc1
Yield: 48.7 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.30 g) was added to a solution of 3.03 g of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid and 2.18 g of p-aminophenol in 50 ml of methylene chloride, and the mixture was stirred for one night. After completion of the reaction, the reaction mixture was washed with water, and dried over anhydrous sodium sulfate. After removing the solvent by evaporation, the residue obtained was purified by silica gel column chromatography to obtain 1.92 g of the objective compound was obtained as a residue (yield: 50%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2([CH2:22][CH2:23][CH2:24][N:25]([CH3:35])CCC3C=CC(C)=CC=3)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][S:13]2(=[O:21])=[O:20])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>CC(C)=O.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2([CH2:22][CH2:23][CH2:24][NH:25][CH2:35][CH2:23][CH2:22][CH2:12][C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)[S:13](=[O:20])(=[O:21])[CH2:14][CH2:15][CH2:16][S:17]2(=[O:19])=[O:18])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2(CCCN(C)CCc3ccc(C)cc3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCCCNCCCC2(c3ccc(OC)c(OC)c3)S(=O)(=O)CCCS2(=O)=O)cc1OC

Procedure:
2-(3,4-dimethoxyphenyl)-N-methyl-N-(p-methylphenethyl)-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride of melting point 169°-171° C (from acetone/ethyl acetate).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3cc(Br)cc(Cl)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.06 g, 3.00 mmol), 4-methoxy-benzylamine (0.521 mL, 4.0 mmol), and K2CO3 (0.967 g, 7.0 mmol) in toluene (7 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.365 g, 33%). GC-MS: m/z 367 (M)+, 336 (M−31)+. 1H NMR (300 MHz, CDCl3): δ (ppm) 3.79 (S, 3H), 4.20 (s, 2H), 4.70 (s, 2H), 6.85 (d, 2H) 7.27 (d, 2H), 7.42 (s, 1H), 7.57 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:25]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:26])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (37%, white crystals). HPLC-MS m/z=369.1 (M+1), Rt: 4.3 min.