Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 582.9 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([S:5]([CH2:8][CH2:9]Cl)(=[O:7])=[O:6])[CH3:4]>C1(C)C=CC=CC=1>[CH3:1][NH:2][CH2:9][CH2:8][S:5]([CH2:3][CH3:4])(=[O:7])=[O:6]
Reactant: CCS(=O)(=O)CCCl
Reactant: CN
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)CCNC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Gaseous methylamine is passed to saturation (about 30 min) into a solution of 15.7 g of chloroethyl ethyl sulfone in 100 ml of toluene at an internal temperature of 50° C. The mixture is stirred at 50° C. for 3 h, the precipitate is filtered off with suction, and the filtrate is concentrated in a rotary evaporator. The remaining yellow mobile liquid (12.3 g) is reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1OB(O)O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[N:6][CH:7]=1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Reactant: Brc1ccc(C#CCCc2ccc(CN3CCCC3)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#CCCc3ccc(CN4CCCC4)cc3)nc2)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
10 mg (0.01 mmol) tetrakis-triphenylphosphane-palladium are added to a suspension of 60 mg (0.16 mmol) 5-bromo-2-[4-(4-pyrrolidin-1-ylmethyl-phenyl)-but-1-ynyl]-pyridine and 63 mg (0.32 mmol) 2,4-dichlorophenylboric acid in 4 mL 1,4-dioxane and 1 mL 2 M Na2CO3 solution and the reaction mixture is stirred for 1 h at 110° C. The mixture is evaporated down i. vac. and the residue is extracted twice with in each case 15 mL EtOH. The solvent is removed and the residue is purified by HPLC.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:12][N:11]1[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[C:19]([O:18][C:16]([N:14]1[C@H:13]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:12][N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C@@H:10]([CH2:9][OH:8])[CH2:15]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2COCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2CO)cc1
Yield: 99.7 %

Procedure:
Palladium hydroxide on carbon (700 mg) was added to a solution of (2R,5R)-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine (6.4 g) in MeOH (60 ml), and the mixture was hydrogenated in hydrogen at 3.5 atm for 4 hours at ambient temperature. The catalyst was removed by filtration through a celite pad and the filtrate was washed with MeOH. The filtrate and combined washings were concentrated in vacuo to give 5.3 g of (2R,5R)-4-(tert-butoxycarbonyl)-2-hydroxymethyl-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:15]=[N:16][NH:17][CH:18]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Br)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)Cl>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:15]=[N:16][N:17]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:18]=2)=[CH:6][CH:7]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(-c2ccccc2-c2c[nH]nn2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
4'-Methyl-2-(1,2,3-triazol-4-yl)biphenyl (2.61 g, 11 mmol, 1.0 eq), triethylamine (1.69 mL, 12 mmol, 1 eq), tritylbromide (3.88 g, 12 mmol, 1 eq) and methylene chloride (30 mL) were mixed and stirred at 0° C. and then allowed to warm to room temperature. After 1 hour, ethyl acetate was added (200 mL) and the organic phase was washed with water (3×200 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo to yield 5.15 g of a yellow solid. This product was recrystallized from methylcyclohexane to give 3.26 g of off-white crystals; m.p. 181.0°-182.5°. NMR (200 MHz, CDCl3) δ 8.18 (d, 1H, J=7Hz); 7.50-7.16 (m, 12H); 7.05-6.89 (m, 10 Hz); 6.47 (s, 1H); 2.54 (s, 3H). Anal. Calcd. for C34H27N3 : C, 85.50; H, 5.70; N, 8.80. Found: C, 86.60; H, 5.80; N, 8.94.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11]O)=[CH:7][CH:6]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.O>C(OCC)C>[Cl:1][C:2]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH:10]([CH3:13])[CH2:11][Cl:29])=[CH:7][CH:6]=1
Reactant: CC(CO)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(CCl)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Yield: 78.7 %

Procedure:
3.0 g of β-[4-(2,4-Dichlorophenoxy)phenoxy]propanol and 1.1 g of pyridine were dissolved in 50 ml of anhydrous diethyl ether, and 1.5 g of thionyl chloride was added dropwise to the solution while cooling. The mixture was then heated for 1 hour while refluxing. The reaction mixture was poured into an appropriate amount of water, and the mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The ether was removed by distillation and the residue was distilled under reduced pressure to obtain 2.5 g of the desired product having a boiling point of 192° to 194° C/2mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16])[CH3:13].C([O-])([O-])=O.[Na+].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2cnc(N)c([N+](=O)[O-])c2)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 75.5 %

Procedure:
To a solution of 5-bromo-3-nitropyridin-2-amine (5.00 g, 23.97 mmol) in dioxane (115 mL) was added 3-(ethoxycarbonyl)phenylboronic acid (4.65 g, 23.97 mmol) and 1N Na2CO3 aqueous solution (92.2 mL, 92.2 mmol). The reaction mixture was degassed using Argon gas for 20 min followed by the addition of dichlorobis(triphenylphospine) palladium(II) (971 mg, 1.38 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (881 mg, 2.07 mmol). The reaction flask was put into the preheated oil-bath at 90° C. The reaction mixture was further stirred at 90° C. for a period of 10 h after which it was filtered and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 90:10 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(6-amino-5-nitropyridin-3-yl)benzoate (5.2 g, 78% yield) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCN(CC(=O)N(C)C)CC2
Yield: 60.7 %

Procedure:
Following a procedure analogous to Example 113, 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (47 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (47 mgs) were converted to the title compound (51 mgs) as a white foam. 1H-NMR (CDCl3): δ 10.16 (s, 1H), 8.53 (d, J=7.4 Hz, 1H), 8.06 (s, 2H), 7.85 (d, J=14.4 Hz, 2H), 7.48 (s, 1H), 7.40-7.34 (m, 2H), 7.20 (t, J=7.6 Hz, 1H), 6.65 (s, 1H), 6.52 (s, 1H), 3.88 (s, 3H), 3.30 (s, 2H), 3.17 (s, 3H), 3.00 (s, 3H), 2.90-2.70 (complex m, 7H). LC/MS, found 547.18 (M+H)+; MP:66-67° C.;
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:21]([C:23]1[S:27][C:26](=[N:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39](I)=[CH:38][CH:37]=2)[N:24]=1)[CH3:22].C(OCC)(=O)C>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[C:12]([N:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:39]2[CH:40]=[CH:41][C:36]([CH2:35][N:25]3[N:24]=[C:23]([CH2:21][CH3:22])[S:27][C:26]3=[N:28][C:29](=[O:34])[C:30]([F:31])([F:33])[F:32])=[CH:37][CH:38]=2)=[N:8][N:9]=[N:10]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Reactant: CC(C)(C)n1nnnc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnnn3C(C)(C)C)cc2)c(=NC(=O)C(F)(F)F)s1
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a solution of 5-phenyl-1-tert-butyl-1H-tetrazole (1.0 g) in tetrahydrofuran (20 ml) was added dropwise n-butyl lithium (1.6M hexane solution, 3.5 ml) keeping the temperature below -20° C., followed by stirring at -5° C. for one hour. Zinc chloride (1.0M diethyl ether solution, 6.0 ml) was added dropwise to the reaction mixture keeping the temperature below -30° C., followed by stirring at room temperature for 2 hours. To the resulting mixture were added 5-ethyl-3-(4-iodobenzyl)-2-trifluoroacetylimino-1,3,4-thiadiazoline (1.2 g) and tetrakis(triphenyl-phosphine)palladium (100 mg), and they were heated under reflux overnight. Ethyl acetate (100 ml) was added to the reaction mixture, and the resulting mixture was washed with 10% aqueous citric acid solution and dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was separated by column chromatography on silica gel, whereby 830 mg of the title compound was obtained in the oily form.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:29][C@@:28]2([CH3:30])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:27]2[C:26](=[O:31])[CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:6][C@@H:5]1[OH:33])[CH3:2].[O:34]=[C:35]1[O:41][C@H:40]([C@H:42]([CH2:44][OH:45])[OH:43])[C:38]([OH:39])=[C:36]1[OH:37]>C(O)C>[O:34]=[C:35]1[O:41][C@H:40]([C@H:42]([CH2:44][OH:45])[OH:43])[C:38]([O-:39])=[C:36]1[OH:37].[CH2:1]([O:3][C@H:4]1[CH2:29][C@@:28]2([CH3:30])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:27]2[C:26](=[O:31])[CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:23])[CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:6][C@@H:5]1[OH:33])[CH3:2]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CN5CCOCC5)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Solvent: CCO
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O

Procedure:
A solution of 2β-Ethoxy-3α-hydroxy-21-morpholino-5α-pregnane-11,20-dione (116 mg; 0.25 mmole) in ethanol (2 ml.) was treated with an 0.1N aqueous solution of ascorbic acid (2.5 ml; 0.25 mmole) and the resulting solution was evaporated under vacuum. The residue was dissolved in water (ca. 5 ml.) and clarified by filtration. The filtrate was diluted to 11.6 ml. with distilled water, thereby giving a 1% aqueous solution of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:6][CH3:7].CN(C)[CH2:18][CH2:19][CH2:20]N=C=NCC.CN([CH:30]=[O:31])C>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:6]([C:30](=[O:31])[C:5]1[CH:8]=[C:9]([CH3:10])[CH:20]=[C:19]([CH3:18])[CH:4]=1)[CH3:7]
Reactant: CN[C@H](Cc1ccccc1)C(=O)OC
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of N-BOC-N-methyl-(D)-phenylalanine (3 g, 10.5 mmol) in methylenchoride (25 ml) is treated at 0° C. with slight excess of diazomethane in ether (25 ml). The reaction mixture is stirred at 0° C. and concentrated in vacuo to give N-BOC-N-methyl-(D)-phenylalanine methyl ester as a colorless oil. The above crude material is dissolved in a mixture of trifluoroacetic acid (8 ml) and ethanedithiol (2 ml) and stirred under nitrogen at r.t. for 1 hour. A 4M solution of hydrogen chloride in dioxane (3.6 ml) is added. The hydrochloride is precipitated by addition of ether (400 ml) and hexane (300 ml), filtered and washed with ether to give N-methyl-(D)-phenylalanine methyl ester hydrochloride (2.4 g) as a white powder. A solution of the above N-methyl-(D)-phenylalanine methyl ester hydrochloride (2.4 g, 10 mmol) and, 5-dimethylbenzoic acid (1.8 g, 11 mmol) in DMF (15 ml) at 0° C. is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.2 ml, 11 mmol). The reaction mixture is slowly warmed to r.t. and stirring continued overnight. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 1:2 to give N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine methyl ester as a colorless oil. [a]D =+111° (c=0.94, ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([C:23]([F:26])([F:25])[F:24])([CH:21]=C)[C:6]=2[CH:27]=1.[O:28]=[O+][O-].[BH4-].[Na+].CC(C)=O>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:21][OH:28])([C:23]([F:26])([F:24])[F:25])[C:6]=2[CH:27]=1
Reactant: O=[O+][O-]
Reactant: C=CC1(C(F)(F)F)OC(=O)N(Cc2ccc(OC)cc2)c2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)OC(CO)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (71.5 g, 0.161 mol) was dissolved in dichloromethane (200 mL) and methanol (200 mL), and the solution was cooled to 0° C. and stirred in an ozone atmospher for 2 hours. After the ozone atmospher was replaced by a nitrogen atmospher, sodium borohydride (12.2 g, 0.323 mol) was slowly added thereto at 0° C. After the reaction solution was stirred at 0° C. for 10 minutes, excess acetone was added thereto. After the solvent was evaporated under reduced pressure, the resulting residue was diluted with ethyl acetate, and 1 N hydrochloric acid was added until the pH of the aqueous layer reached about 6. The organic layer was separated and washed with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was crystallized from water and ethanol, whereby the objective compound (62.4 g, 87%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[CH:27]=[C:28]([F:44])[C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(C)cc(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)cc(F)c1-c1cccc-3c1
Yield: 100 %

Procedure:
Prepared in 100% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1):672.35.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[O:12][CH2:13][CH2:14][C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=[O:16].[OH2:20].[OH-:21].[K+]>CO>[OH:20][N:5]1[C:6]2[CH:7]=[C:8]3[CH2:14][CH2:13][O:12][C:9]3=[CH:10][C:11]=2[C:2](=[O:21])[C:3]([C:15]([OH:17])=[O:16])=[CH:4]1
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1Cl)OCC3
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cn(O)c2cc3c(cc2c1=O)OCC3
Yield: 99 %

Procedure:
A mixture containing 12 g of ethyl 8-chloro-2,3-dihydrofuro(2,3-g)quinoline-7-carboxylate, 100 ml of water, 10.9 g of 85% potassium hydroxide and 80 ml of methanol was stirred while refluxing for 2 hours. The methanol was evaporated at atmospheric pressure. The resulting mixture was heated to 90°-95° C and stirred for one further hour. Then, the mixture was acidified to pH 2 by the addition of 6N hydrochloric acid at 80° C. After cooling, the resulting white precipitate was filtered and washed with water to give 10.03 g (99%) of 2,3,5,8-tetrahydro-5-hydroxy-8-oxofuro(2,3-g)-quinoline-7-carboxylic acid as pale yellow prisms having a melting point of 274°-275° C (decomposition). Elementary analysis values for C12H9O5N were as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(C1C=CC([N+]([O-])=O)=CC=1OCCN1CCCCC1)(C)(C)C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[C:8]([CH:9]=1)[O:10][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Agent: CC(C)(C)c1ccc([N+](=O)[O-])cc1OCCN1CCCCC1
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(OCCN2CCCC2)c1

Procedure:
1-[2-(5-Nitro-2-trifluoromethylphenoxy)ethyl]-pyrrolidine was prepared from 5-nitro-2-trifluoromethyl-phenol and 1-(2-chloroethyl)pyrrolidine by a procedure similar to that described for 1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[NH2:13].[C:14]1([C:20]2[N:21]=[C:22]([CH2:31]Br)[O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]1([C:20]2[N:21]=[C:22]([CH2:31][NH:13][CH:8]3[C:9]4[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]3)[O:23][C:24]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COc1cccc2c1CCCC2N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 76.5 %

Procedure:
A solution of 1,2,3,4-tetrahydro-5-methoxy-1-naphthalenamine (0.34 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.50 g) and potassium carbonate (0.60 g) in DMF (7 ml) was stirred for 5 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene (0.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1O.[C:10](=O)([O-])[O-:11].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:11][CH3:10])[CH:3]=1
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(Cl)ccc1C
Yield: 77.5 %

Procedure:
Commercially available 2-chloro-5-methylphenol (19.8 g, 70 mmol) was dissolved in 450 ml acetone. Potassium carbonate (28.9 g, 209 mmol) was added, followed by iodomethane (29.7 g, 209 mmol), and the mixture was refluxed overnight with vigorous stirring. The mixture was then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried with sodium sulfate, and concentrated giving 8.5 g 4-Chloro-2-methoxy-1-methyl-benzene (100%). 1H NMR (300 MHz, CDCl3) •2.28 (s, CH3, 3H), 3.92 (s, —OCH3, 3H), 6.91 (d, Ar, 1H, J=2.0 Hz), 6.95 (dd, Ar, 1H, J=8.0, 2.0 Hz), 7.14 (m, Ar, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6](=[NH:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].Cl[CH2:20][CH:21]=O.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[CH:20]=[CH:21][N:15]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=CCCl
Reactant: COc1cccc(C(=N)Nc2ccccc2C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cccc(-c2nccn2-c2ccccc2C)c1

Procedure:
To a 500 mL round bottom flask was added 3-methoxy-N-(o-tolyl)benzimidamide (6 g, 24.97 mmol), 2-chloroacetaldehyde (6.34 ml, 49.9 mmol), sodium bicarbonate (4.20 g, 49.9 mmol), and 100 mL 2-propanol. The reaction mixture was heated to reflux under nitrogen. The reaction mixture was concentrated, water was added, and the mixture was extracted three times with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 40% ethyl acetate/hexane (5.58 g, 85%).