Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=[O:10]>CCO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH2:9][OH:10])[CH:11]=1
Reactant: COc1ccc(F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(F)cc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add Sodium borohydride (540 mg, 13.95 mmol) in portions to a solution of 5-Fluoro-2-methoxy-benzaldehyde (2.15 g, 13.94 mmol) in absolute EtOH (20 ml) and stir at room temperature. After 1 h, evaporate the solvent, dilute the residue in CH2Cl2 and treat with aqueous 3M HCl. Separate the phases, wash the organic one twice with H2O, dry over Na2SO4 and concentrate at vacuum to obtain pure (5-Fluoro-2-methoxy-phenyl)-methanol as white solid. Add aqueous concentrated HBr (15 ml) to a solution of (5-Fluoro-2-methoxy-phenyl)-methanol (1.9 g, 12.17 mmol) in CHCl3 (10 ml) and stir at room temperature. After 1 h, separate the phases, wash the aqueous one with CH2Cl2, combine organic phases, wash with H2O, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane to afford 2-Bromomethyl-4-fluoro-1-methoxy-benzene as white solid. 1H-NMR (CDCl3, 200 Mz): δ 7.06 (dd, J=3.0 and 8.6 Hz, 1H), 6.98 (m, 1H), 6.81 (dd, J=4.4 and 9.0 Hz, 1H), 4.50 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Product: CCCCCC(CC(=O)Nc1cc(CNS(C)(=O)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 11, but using N-[2-t-butyl-5-(aminomethyl)phenyl]-3-(2,4-dimethoxy-phenyl)octanamide (prepared as described in Preparation 26A) and methanesulfonyl chloride in similar relative proportions, the title compound was obtained as a foam-like substance.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[C:6]=1[C:7](=[O:9])[NH2:8].[H][H]>[Pd].CO>[NH2:1][C:2]1[N:3]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:4]=[C:5]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[C:6]=1[C:7](=[O:9])[NH2:8]
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc([N+](=O)[O-])cc2)c(C(N)=O)c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(-c2ccc(N)cc2)c(C(N)=O)c1N
Yield: 105.4 %

Procedure:
0.075 g (0.216 mmol) of tert-butyl 2-amino-3-carbamoyl-4-(4-nitrophenyl)-pyrrole-1-carboxylate is added at a temperature in the region of 25° C. to a suspension of 0.008 g (0.0076 mmol) of 10% palladium on carbon in 12 cm3 of methanol. After hydrogenating for 17 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.072 g of tert-butyl 2-amino-4-(4-aminophenyl)-3-carbamoylpyrrole-1-carboxylate, in the form of a yellow solid; 1H NMR (400 MHz, (CD3)2SO, —δ in ppm); 1.55 (s: 9H); from 4.80 to 5.35 (very broad m: 1H); 5.22 (broad s 2H); 6.32 (s: 1H); from 6.40 to 6.85 (very broad m: 1H); 6.60 (broad d, J=8.5 Hz: 2H); 6.99 (broad d, J=8.5 Hz: 2H); 7.01 (broad s: 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][N:18]=[C:19]([CH3:21])[CH3:20])=[O:5].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][CH:19]([CH3:20])[CH3:21])=[O:5]
Reactant: CC(C)=NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cc(C)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(NC(=O)c2c(Cl)cccc2Cl)c2nccc(NNC(C)C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-6-methyl-4-(2-isopropylidenehydrazino)quinoline (159 mg) in methanol (5 ml) was added sodium cyanoborohydride (25 mg) and acetic acid (50 mg), and the mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated to dryness and the residue was triturated with water (5 ml) and filtered. The solid was treated with hot water (5 ml), allowed to cool to ambient temperature, filtered and washed with water to give 8-(2,6-dichlorobenzoylamino)-6-methyl-4-(2-isopropylhydrazino)quinoline (117 mg) as pale yellow powder.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([NH2:28])[C:20]=2[N:19]=[C:18]1[CH2:29][O:30][CH2:31][CH3:32]>>[NH2:28][C:21]1[C:20]2[N:19]=[C:18]([CH2:29][O:30][CH2:31][CH3:32])[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:11]([NH:10][C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:12])[C:25]=2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)N[C@@H]1C[C@H]1c1ccccc1

Procedure:
Using the method of Examples 94-105, trans-2-phenylcyclopropyl isocyanate was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 437.2674.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:16][C:10]=2[C:9]=1O.CI>CC(C)=O>[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:22])[C:18]([F:19])([F:21])[F:20])[CH2:15][CH2:16][C:10]=2[C:9]=1[O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(N1CCc2ccc(Br)c(O)c2CC1)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Br)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
Add potassium carbonate (10.214 g, 73.9 mmol) to a solution of 7-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.0 g, 14.8 mmol) in acetone (50 mL) and stir for 10 min. Add methyl iodide (4.2 g, 1.5 mL, 29.6 mmol) and stir the mixture overnight at room temperature. Remove the solvent in vacuo and partition the residue between water and DCM. Extract the aqueous phase twice with DCM. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a solid (5.15 g, 99%). MS (ES+) m/z: 352 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:22]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: OC1CCCNC1
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCCC(O)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (±)-3-hydroxypiperidine hydrochloride by the method described in Example 41. Colorless solid (101 mg, 85%). 1H NMR (CD3OD) 1.51-1.71 (m, 2H), 1.84-2.05 (m, 2H), 2.39 (q, JH-F=1.5, 3H), 3.34-3.65 (m, 2H), 3.68-3.85 (m, 2H), 3.86-4.14 (m, 1H), 7.49 (d, br, J=3.9, 1H), 7.60 (d, br, J=3.9, 1H). 13C NMR 8.0, 23.6 (br), 33.5, 45.1 (br), 55.1 (br), 67.0, 116.7 (q, J=2), 120.3 (q, J=270), 129.8, 130.9, 132.4, 141.1, 155.8 (q, J=40), 159.4, 165.0. 19F NMR −64.8. LC/MS 6.00 min, [M+1]+ 361.
Reaction SMILES: [H-].[Na+].C(OC(N1CCC(O)CC1)=O)(C)(C)C.[Cl:17]C1N=CC=CN=1.C(OC([N:31]1[CH2:36][CH2:35][CH:34]([O:37][C:38]2[N:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH2:33][CH2:32]1)=O)(C)(C)C.Cl>CS(C)=O.O1CCCC1>[N:39]1[CH:40]=[CH:41][CH:42]=[N:43][C:38]=1[O:37][CH:34]1[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]1.[ClH:17]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncccn2)CC1
Reactant: Clc1ncccn1
Agent: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1cnc(OC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
60% Sodium hydride (0.232 g) was gradually added to a tetrahydrofuran (4.5 ml) solution containing 1-tert-butoxycarbonyl-4-hydroxypiperidine (0.900 g) and 2-chloropyrimidine (0.666 g), and 2 hours later, dimethyl sulfoxide (1.0 ml) was added thereto, and the mixture was stirred at room temperature for 1 day to undergo reaction, thereby obtaining 1-tert-butoxycarbonyl-4-(2-pyrimidinyloxy)piperidine. This compound was acid-treated with hydrochloric acid to obtain 4-(2-pyrimidinyloxy)piperidine•hydrochloride.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:17][C:16]1[C:11]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
1.72 kg (10.75 mol) of the raw 3-trifluoromethylpyrazole obtained in step a), 1.75 kg (11.83 mol) of 2,3-dichloropyridine and 4.73 kg of dimethyl formamide were charged to a reaction vessel. 2.97 kg (21.50 mol) of potassium carbonate were added, the mixture was heated to 120° C. with stirring and kept at 120-125° C. for further 3 h. The reaction mixtures was cooled to 25° C. and poured into 20 l of water. The thus obtained mixture was extracted twice with 5 L of tert.-butylmethyl ether. The combined organic phases were washed with 4 l of water and then evaporated to dryness. Toluene was added and the mixture was again evaporated to dryness. Thereby, the 2.7 kg of the title compound was obtained (purity >75% as determined by GC; yield 81.5%). The product can be purified by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1Cc1ccccc1
Yield: 73 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (2.69 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 24 mg of lithium hydride and 507 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 746 mg of 3-benzyl-2-[(4-chlorophenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one (65%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 163 mg of 2-[N-benzyl-N-(4-chlorophenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (14%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:26])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Solvent: C1CCOC1
Product: O=C(O)C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To a 50° C. solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline (J Med Chem, 1995:3482) in 10 mL of tetrahydrofuran was added 0.059 g of maleic anhydride. The cold solution stirred for 15 minutes, and then the ice bath was removed. The reaction warmed to room temperature where it continued stirring for 15 hours. The suspension was heated under reflux for 30 minutes and then stirred at room temperature another 15 hours. Another 0.059 g of maleic anhydride and 20 mL of tetrahydrofuran were added, and the reaction was refluxed for an additional 2 hours. After another 15 hours at room temperature, the reaction was refluxed for 15 hours. The reaction was filtered, and the light tan solid was recrystallized first from dimethyl-formamide and then a second time from methanol to afford 0.036 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.[NH2:30][CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:30][CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34])=[O:26])=[CH:27][CH:28]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: NC[C@@H](O)CO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 332, step 2) was coupled with (R)-3-aminopropane-1,2-diol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=483.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li][CH2:28]CCC.IC>O1CCCC1>[CH3:28][C:5]1[N:1]([CH2:6][C:7]23[CH2:14][CH:13]4[CH2:12][CH:11]([CH2:10][C:9]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])([CH2:15]4)[CH2:8]2)[CH2:16]3)[N:2]=[CH:3][CH:4]=1
Reactant: [Li]CCCC
Reactant: OCCOCCOCCOC12CC3CC(CC(Cn4cccn4)(C3)C1)C2
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccnn1CC12CC3CC(C1)CC(OCCOCCOCCO)(C3)C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (−78° C.) solution of EXAMPLE 83A (1.0 g) in tetrahydrofuran (10 mL) was added n-BuLi (5 mL, 2.5 M in hexane). The reaction mixture was stirred for 90 minutes, and iodomethane (1 mL) was added. The reaction mixture was stirred at −78° C. for 90 minutes and quenched by the addition of 1 drop of trifluoroacetic acid. The reaction mixture was warmed to room temperature and concentrated to dryness. The residue was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([C:6]1(C(OCC)=O)[CH2:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]3[O:19][CH2:18][O:17][C:11]=3[CH:12]=2)[CH:7]1[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)([O:3]CC)=[O:2].[OH-].[Na+]>CO.O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([C@@H:7]2[C:8]3[C:13](=[CH:12][C:11]4[O:17][CH2:18][O:19][C:10]=4[CH:9]=3)[C:14](=[O:16])[CH2:15][C@H:6]2[C:1]([OH:3])=[O:2])[CH:21]=[C:22]([O:30][CH3:31])[C:23]=1[O:28][CH3:29]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)c2cc3c(cc2C1c1cc(OC)c(OC)c(OC)c1)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc([C@@H]2c3cc4c(cc3C(=O)C[C@H]2C(=O)O)OCO4)cc(OC)c1OC
Temperature: 110 °C
Yield: 66.7 %

Procedure:
2,2-Dicarbethoxy-1-(3',4',5'-trimethoxyphenyl)-6,7-methylenedioxy-4-tetralone (XV; R2 = ethyl) (45 mg) was suspended in 10 ml of methanol. Aqueous NaOH (10 ml of 5%) was added and the mixture was refluxed for 3.5 hr. Then the mixture was cooled, diluted with water and washed one time with ether. The base layer was acidified to pH 2 with dilute sulfuric acid and extracted four times with chloroform. The organic layer was washed twice with water and once with saturated brine, and was dried over sodium sulfate. Filtration and evaporation gave a white solid which was heated briefly at 110° C. under nitrogen. Recrystallization of the white solid from methanol gave 24 mg (66%) of the title product, m.p. 221°-223° C.
Reaction SMILES: [Br:1]([O-])(=O)=O.[Na+].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].S(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CCOCC>[Br:1][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([F:17])([F:18])[F:19]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of sodium bromate (1109 mg, 7.35 mmol) in H2O (3.3 mL) was added 4-methyl-3-trifluoromethyl-benzoic acid (500 mg, 2.449 mmol) in ethyl acetate (5 mL), followed by a solution of sodium bisulfite (765 mg, 7.35 mmol) in H2O (9 mL) over a period of about 15 min. The mixture was stirred overnight at room temperature and overnight at 50° C. The mixture was poured in ether (50 mL). The aqueous layer was extracted twice with ether and the combined organic layer was washed with anhydrous Na2S2O3 solution, dried, filtered and concentrated in vacuo to give the crude 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid 35 (563 mg, 81%) which was used without further purification. (m/z)=282 and 284 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][CH2:10]Cl>>[CH3:7][O:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COCCCl
Reactant: C1COCCN1
Product: COCCN1CCOCC1
Reaction time: 48 h

Procedure:
In an autoclave of 100 mL, morpholine (45.0 g, 517 mmol) was made reacted with chloroethyl methyl ether (25.0 g, 265 mmol) at 130 deg C. for 48 hours. Solid salt that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 25 cm. Then 1H-NMR measurement of obtained amine is performed, and it was confirmed that chemical shifts, δ (ppm), are 3.53-3.55(m, 4H), 3.33-3.35(m, 2H), 3.17(s, 3H), and 2.36-2.32 (m, 6H), and that N-2-methoxyethylmorpholine was synthesized.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH3:8][C:9]([CH3:14])([CH2:12]O)[CH2:10][OH:11].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH3:6])[O:11][CH2:10][C:9]([CH3:14])([CH3:12])[CH2:8][O:7]1
Reactant: CC(C)(CO)CO
Reactant: CC(=O)CCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(C)(CCCCl)OC1
Temperature: 25 °C

Procedure:
A one liter, round bottom flask is equipped with a magnetic stir bar, a Dean-Stark water separator, a reflux condenser and a nitrogen inlet. This apparatus is dried in an oven overnight at 120° C., assembled hot, and is allowed to cool to room temperature in a stream of nitrogen. The flask is charged with 144.70 grams (1.20 moles) of 5-chloro-2-pentanone, 185.00 grams (1.32 moles) of 2,2-dimethyl-1,3-propandiol, 300 ml of toluene and 0.05 grams of p-toluenesulfonic acid catalyst. The flask is placed in a heating mantle and the reaction mixture is heated to reflux until close to the theoretical amount of water (21.6 ml) is collected in the Dean-Stark trap. The reaction mixture is allowed to cool to room temperature, transferred to a separatory funnel and washed with 200 ml portions of saturated sodium bicarbonate solution, and three times with water. The resulting organic layer is separated, dried over anhydrous potassium carbonate, filtered, and concentrated under reduced pressure on a rotary evaporator. This affords a clear, pale yellow oil, which is employed in the subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:20]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl.C(O)(C)C>[NH2:20][CH:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[CH:16]=[C:15]([C:18]#[N:19])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Tert-butyl 1-benzyl-7-cyano-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (1.1 g, 3.03 mmol) was dissolved in dichloromethane (20 mL) and 5 M hydrochloric acid in isopropanol (2 mL) was added. The reaction mixture was stirred at room temperature for 12 h followed by 4 h at 35° C. The solvent was evaporated in vacuo. Water (30 mL) was added and the pH was adjusted to pH 9 using aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4) and the solvent was evaporated in vacuo. Yield: 790 mg (3.03 mmol, 100%).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16])=[O:4].[CH:19]1[C:31]2[CH:30]([CH2:32][O:33][C:34]([N:36]3[C:47]4[C:39](=[C:40]5[C:44](=[CH:45][CH:46]=4)[NH:43]C(C(O)=O)[CH2:41]5)[CH:38]=[CH:37]3)=[O:35])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[CH:28]1[C:29]2[CH:30]([CH2:32][O:33][C:34]([N:36]3[C:47]4[C:39](=[C:40]5[C:44](=[CH:45][CH:46]=4)[NH:43][CH:2]([C:3]([O:5][C:6]4[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=4[F:16])=[O:4])[CH2:41]5)[CH:38]=[CH:37]3)=[O:35])[C:31]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C1Cc2c(ccc3c2ccn3C(=O)OCC2c3ccccc3-c3ccccc32)N1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C1Cc2c(ccc3c2ccn3C(=O)OCC2c3ccccc3-c3ccccc32)N1

Procedure:
Pentafluorophenyl trifluoroacetate (0.3 mL, 1.75 mmol) was added to a solution of acid 9 (0.3 g, 0.7 mmol) and triethylamine (0.3 mL, 2.1 mmol) in 4 mL of anhydrous DMF. After 1 h DMF was evaporated and the residue chromatographed on silica eluting with 2% acetone in methylene chloride. Concentration of the pure product fraction and drying afforded 0.29 g (70%) of PFP ester 10 as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH:8]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[C:33]=1[S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[C:33]=1[S:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH2:8])=[CH:29][CH:30]=1)(=[O:41])=[O:42]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: c1ccncc1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc(C[C@H](N)C(=O)O)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin (3.0 g, 2.28 mmol) obtained from Example 62 was suspended in pyridine (15 mL), the slurry was cooled to 0° C. and 2,4,6-trimethylphenylsulfonyl chloride (2.49 g, 11.4 mmol) was added. The resulting mixture was agitated for 2 hr. The mixture was filtered and washed with dichloromethane and methanol. The coupling procedure was repeated. The resulting resin was treated with 25% piperidine in N-methylpyrrolidinone (2×15 min) and was washed with dichloromethane and methanol to give 4-[[(2,4,6-trimethylphenyl)sulfonyl]amino]-L-phenylalanine on Wang resin.