Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:39])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:23]3=[O:36])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.Cl>O1CCOCC1>[OH:1][C:2]1[C:3]([CH3:39])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]3=[O:36])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)N(CC(=O)O)C3=O)cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of t-butyl α-{5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl ]-2,4-dioxothiazolidin-3-yl}acetate (prepared as described in Example 46) and 10 ml of a 4N dioxane solution of hydrogen chloride was allowed to stand at room temperature overnight. At the end of this time, the solvent was distilled off and the residue was washed with water to give the title compound as a pale yellow powder, softening at 85°-90° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([N:23]=[N+]=[N-])[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O.S>C(O)(=O)C>[NH2:23][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17]
Reactant: [N-]=[N+]=NC(COCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: S
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: NC(COCc1ccccc1)CN1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 20 %

Procedure:
Into a stirred solution of 2-benzyloxymethyl-2-azido-1-phthalimido-ethane (500 mg, 1.5 mmol) in 4:1 pyridine/water (25 ml) was bubbled hydrogen sulphide, and the reaction was monitored by TLC. After 4 hours, the gas flow was stopped, and the reaction flask sealed. The intense green reaction mixture was stirred for another 17 hours. TLC indicated full conversion of the starting material. Glacial acetic acid was added to pH 7, and the reaction mixture was evaporated to dryness in vacuo. After evaporation from ethanol (3×25 ml), the resulting brown solid was purified by chromatography. Yield=20%. The structure was confirmed by NMR and IR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([O:30]C)=O)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:37][NH2:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([NH:38][CH3:37])=[O:30])=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1
Reactant: CN
Product: CNC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1

Procedure:
The title compound was prepared methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate following a procedure analogous to that described in Example 444 Step 3 using methylamine in place of ammonia. LC-MS Method 2 tR=1.055 min, m/z=491.12; 1H NMR (CD3OD) 1.18 (m, 1H), 1.48 (d, 3H), 1.51 (m, 1H), 1.85 (m, 2H), 2.13 (m, 1H), 2.25 (m, 1H), 2.48 (m, 1H), 2.88 (s, 3H), 3.09 (m, 1H), 3.38 (m, 2H), 5.51 (m, 1H), 6.98-7.07 (m, 4H), 7.22 (m, 2H), 7.42 (m, 2H), 8.28 (m, 1H), 8.75 (s, 1H), 8.82 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:36]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:28][CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:36][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:7][CH:8]=1)[C:14]([N:16]([CH2:28][CH:29]([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)=[O:15]
Reactant: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 120.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (S)-(9H-fluoren-9-yl)methyl 3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-3) (740 mg, 1.0 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (596.1 mg, 100%).
Reaction SMILES: [N:1]1[C:11]2[C:10](=O)[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][NH2:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C([O-])(=O)C.[Na+].[K+].[Br-]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][N:24]=[C:10]2[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:11]2=3)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C1CCC(=O)c2ncccc2N1
Reactant: NNc1cc(Cl)cc(Cl)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Br-]
Product: O=C1CCC(=NNc2cc(Cl)cc(Cl)c2)c2ncccc2N1

Procedure:
Prepared according to general procedure A from 338.5 mg (1.92 mmol) 5H-pyrido[3,2-b]azepine-6,9(7H,8H)-dione, 452 mg (2.11 mmol) (3,5-dichlorophenyl)hydrazine hydrochloride, and 169 mg (2.11 mmol) sodium acetate. Recrystallization from ethanol afforded a beige powder. Yield: 213 mg (33%); m.p. 270° C. (dec.); IR (KBr): 3281 cm−1 (NH), 3067/3029 cm−1 (CH-arom.), 2892 cm−1 (CH-aliph.), 1671 cm−1 (C═O); 1H-NMR (DMSO-d6, 400 MHz): δ (ppm)=2.57-2.60 (m, 2H, azepine-CH2, part of AA′XX′-system), 3.02-3.05 (m, 2H, azepine-CH2, part of AA′XX′-system), 6.91-6.92 (m, 1H, arom. H), 7.16 (d, 2H, 1.9 Hz, arom. H), 7.37-7.44 (m, 2H, arom. H), 8.44 (dd, 1H, 4.2/1.8 Hz, arom. H), 9.72 (s, 1H, NH), 9.81 (s, 1H, NH); C15H12Cl2N4O (335.20).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18](S(C(F)(F)F)(=O)=O)[N:17]=[CH:16][C:15]2=3)[C:10]1=[O:30].ClC1C=C(OS(C(F)(F)F)(=O)=O)C=C(Cl)C=1C[C@@H]1CCN(C2CCCC3C2=CN(S(C(F)(F)F)(=O)=O)N=3)C1=O.[F:79][C:80]([F:91])([F:90])[C:81]1[CH:86]=[CH:85][C:84](B(O)O)=[CH:83][CH:82]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.[Li+].[OH-].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:1][C:2]1[CH:3]=[C:4]([C:84]2[CH:85]=[CH:86][C:81]([C:80]([F:91])([F:90])[F:79])=[CH:82][CH:83]=2)[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:22][CH2:21][CH2:20][C:19]3[NH:18][N:17]=[CH:16][C:15]2=3)[C:10]1=[O:30]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCc2c1cnn2S(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCc2nn(S(=O)(=O)C(F)(F)F)cc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)CCN1C1CCCc2[nH]ncc21
Temperature: 80 °C

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(1-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-pyrrolidin-3-ylmethyl]phenyl ester and trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.5 g, 0.78 mmol), 4-trifluoromethylphenylboronic acid (0.18 g, 0.93 mmol), sodium carbonate (0.25 g, 2.3 mmol) in THF (15 mL) and water (5 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.04 g, 0.03 mmol). Raise the reaction temperature to 80° C. and stir the reaction for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford crude product (0.48 g). Dissolve in THF (5 mL) and stir in LiOH (2 N, 3 mL) at room temperature for 1.5 hour. Quench the reaction with HCl (1N, 8 mL), dilute with ethyl acetate, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and then purify on silica gel column with 100% dichloromethane to 10% methanol in dichloromethane to afford 0.35 g of the title product. MS (m/z): 508 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].[NH:16]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]1=2.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]2=3)=[O:13])=[CH:14][CH:15]=1
Reactant: c1ccc2c(c1)CCCCN2
Reactant: COC(=O)/C=C/c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C(=O)N2CCCCc3ccccc32)cc1
Yield: 48 %

Procedure:
WSCD (1.17 g, 6.16 mmol) was added to a solution of 4-((E)-2-methoxycarbonyl-vinyl)-benzoic acid from Example E65.1 (740 mg, 3.59 mmol), 2,3,4,5-tetrahydro-1H-benzo[b]azepine (445 mg, 3.02 mmol) and DMAP (370 mg, 3.02 mmol) in dichloromethane (40 ml) and triethylamine (0.7 ml, 5.02 mmol). The mixture was heated at reflux for 42 h then solvents were concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M KHSO4 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% pet. ether) to yield the title compound (484 mg, 48%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C[Al](C)C.[NH2:13][C:14]1[C:15]2[N:16]([C:20]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:21][C:22]=2[C:23](OC)=[O:24])[CH:17]=[CH:18][N:19]=1>C1(C)C=CC=CC=1>[NH2:13][C:14]1[C:15]2[N:16]([C:20]([CH:27]3[CH2:28][CH2:29][CH2:30]3)=[N:21][C:22]=2[C:23]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])=[O:24])[CH:17]=[CH:18][N:19]=1
Reactant: COC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Reactant: Nc1ccccc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Nc1ccccc1NC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A suspension of 1,2-phenylenediamine (60 mg, 0.6 mmol) in toluene (2.0 mL) was treated with a 2M solution of trimethylaluminum in toluene (0.5 mL) effecting the formation of a pink solution. After 5 min this solution was treated with solid methyl 8-amino-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxylate (30 mg, 0.1 mmol) and the mixture heated at 120° C. for 30 min then stirred at rt overnight. The mixture was then partitioned between 2M NaOH (10 mL) & EtOAc (10 mL) and stirred for 15 min. The organic layer was separated and the aqueous layer extracted further with EtOAc (3×10 mL). The combined organics were washed with brine, dried and concentrated in vacuo to give ˜85% pure 8-amino-N-(2-aminophenyl)-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxamide which was used without purification.
Reaction SMILES: [CH3:1][NH2:2].O[CH:4]1[NH:10][C:9](=[O:11])[C:8]2[S:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[CH:16][CH:17]=[C:5]12>O>[CH3:1][NH:2][CH:4]1[NH:10][C:9](=[O:11])[C:8]2[S:12][CH:13]=[CH:14][C:7]=2[N:6]2[CH:15]=[CH:16][CH:17]=[C:5]12
Reactant: CN
Reactant: O=C1NC(O)c2cccn2-c2ccsc21
Solvent: O
Product: CNC1NC(=O)c2sccc2-n2cccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
3 ml of 35% aqueous solution of methylamine are added in a single portion to a suspension of 1.1 g (0.005 mol) of 6-hydroxy-5,6-dihydro-4-oxo-4H-pyrrolo -[1,2-a]thieno[2,3-f][1,4]diazepine in 20 ml of water, and the reaction mixture is then stirred for 4 hours at room temperature The product is gradually solubilized and then reprecipitates The precipitate is drained, washed with water, dried and recrystallized. 0.7 g of 6-methylamino-5,6-dihydro-4-oxo-4H -pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine is obtained in the form of white crystals, melting point 146° C. (ethyl ether).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[C:18]([CH2:19][OH:20])=[CH:22][CH:23]=[C:24]([O:26][CH3:27])[N:25]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)c(Nc2cccc(CNC(=O)OC(C)(C)C)c2)n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CO)c(Nc2cccc(CNC(=O)OC(C)(C)C)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
To a mixture of the compound (300 mg) obtained in Example 452, triethylamine (101 mg) and tetrahydrofuran (8 ml), a tetrahydrofuran solution (1 ml) of ethyl chlorocarbonate (109 mg) was added under ice cooling and the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was filtered and a tetrahydrofuran solution (2 M, 0.8 ml) of lithium borohydride was added to the filtrate under ice cooling. The reaction mixture was stirred at 0° C. for 30 min and thereafter a 1 N aqueous sodium hydroxide solution was added under ice cooling. Further, the reaction mixture was stirred at 0° C. for 5 min and then ether and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:methylene chloride=1:10) to give 199 mg of the titled compound (yield, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]1=[O:23].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([OH:20])=[O:19])[C:7]1=[O:23]
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2ccccc21
Yield: 96.2 %

Procedure:
A mixture of ethyl 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (1.2 g) and aqueous 1N sodium hydroxide (3 ml) in methanol (25 ml) was refluxed for 1 hour. After cooling, the solvent was removed under reduced pressure to give a residue, which was acidified with aqueous 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated. Thus obtained product was purified by recrystallization from isopropyl ether to give 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetic acid (1.075 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:4]=1[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([O:7][CH3:21])=[O:6]
Reactant: COc1cc(OC)c(C(=O)O)c(OC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 25 °C

Procedure:
2,4,6-trimethoxybenzoic acid (5.61 g, 26.42 mmol) was suspended in 20 mL of methanol. Concentrated sulfuric acid (1 mL) was added to the mixture, and the reaction heated to reflux for 24 hrs. The reaction was cooled to room temperature, and the methanol removed in vacuo. The residues were taken up in 50 mL 5% NaHCO3 and extracted with hexane until all the solids had dissolved. The hexane extract was dried over anhydrous Na2SO4, filtered, and the volatiles were removed in a rotary evaporator to dryness to give the desired product, methyl 2,4,6-trimethoxybenzoate, as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCCCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCCCO)O2
Yield: 23 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 356 mg CDI (2.2 mmol) and 468 mg 6-amino-1-hexanol (4.0 mmol) yielded 161 mg of 6-hydroxy-N-(6-hydroxyhexyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([N+:35]([O-:37])=[O:36])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CI>C(OCC)C.O>[C:8]([O:12][C:13]([N:15]([CH3:3])[C:16]1[CH:17]=[C:18]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:24]([N+:35]([O-:37])=[O:36])[CH:23]=2)[CH:19]=[CH:20][CH:21]=1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)c1cccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 60% sodium hydride (24 mg) was added to an N,N-dimethylformamide (3.0 mL) solution of tert-butyl 4-(3-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate (0.17 g), followed by stirring at the same temperature for 15 minutes and then at room temperature for 20 minutes. Methyl iodide (0.037 mL) was added to the reaction mixture under ice-cooling, followed by stirring at room temperature for 1 hour. Water and diethyl ether was added to the reaction mixture, and the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layer and the extract were combined, and the resulting mixture was washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of sodium chloride sequentially and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 0.17 g of tert-butyl 4-(3-((tert-butoxycarbonyl)(methyl)amino)phenyl)-2-nitrobenzoate as a brown oily substance.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH:21]([CH3:23])[CH3:22])=[N:19][N:20]=2)[CH:17]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH:21]([C:18]1[N:16]2[CH:17]=[C:12]([S:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH2:4][NH2:1])[CH:13]=[CH:14][C:15]2=[N:20][N:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CN=[N+]=[N-])cn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(Sc3ccccc3CN)cn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.8 %

Procedure:
To a solution of 6-(2-Azidomethyl-phenylsulfanyl)-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine (228.0 mg, 0.70 mmol) in THF (2.3 mL) under N2 was added triphenylphosphine (220.0 mg, 0.84 mmol) and water (15.0 μL, 0.84 mmol). The reaction was stirred at ambient temperature under N2 for 12 hours, then warmed to 50° C. for 6 hours. To the reaction mixture was diluted with water, and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (10-100% methanol/ethyl acetate), followed by trituration with ethyl acetate/hexane to give the title compound (127 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[CH2:38]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:41][O:40][C:36](=[O:39])/[CH:37]=[CH:38]/[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2
Reactant: COc1ccc2cccc(Br)c2n1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cccc2ccc(OC)nc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 8-bromo-2-methyloxyquinoline (10.0 g), Pd(OAc)2 (311 mg), P(o-Tol)3 (1.28 g) in DMF (100 mL) was treated with TEA (17.6 mL) and methyl acrylate (18.93 mL). The solution was purged 3 times with nitrogen and stirred at 120° C. for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with ether/EA. The org. layer was washed with water (3×200 mL) and brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by CC (Hept/EA 4:1), affording a pale yellow solid (9.34 g; 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]#[CH:15])=[CH:17]1
Reactant: C#Cc1c[nH]c2ccccc12
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (4.79 g) in dimethylformamide (25 ml) was added 3-ethynylindole (2.9 g) and potassium carbonate (2.84 g), the mixture was heated at 90° C. for 3 hours under an atmosphere of nitrogen and then left to stir overnight at room temperature. The reaction was diluted with water (100 ml) and extracted with hexane (2×100 ml). The organic fractions were separated, combined, evaporated to dryness and purified by column chromatography on silica gel (300 g) eluted with hexane:ethylacetate (97:3) to give the title compound as a white solid (1.3 g), m.p. 120-122° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[C:19]1([C@H:29]([N:31]([CH2:39][C@@H:40]2[C@@H:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:43][NH:42][CH2:41]2)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:34]([O:33][C:32]([N:31]([CH2:39][C@@H:40]1[C@@H:44]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:43][N:42]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:41]1)[C@@H:29]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:30])=[O:38])([CH3:35])([CH3:36])[CH3:37]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CN2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
Potassium carbonate and methyl 4-(bromomethyl)benzoate were added in that order to an acetone solution of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and stirred at room temperature for 20Hours. Thereafter, work-up and purification were carried out in the standard method to obtain methyl 4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin 1-yl]methyl}benzoate. FP: 579.