Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[N:5]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C(C)=C1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C.[CH2:35]([O:38][N:39]([C@H:52]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:55]([C:65]([OH:67])=O)[C:54]([CH:68]([CH3:70])[CH3:69])=[CH:53]1)[S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50])(=[O:42])=[O:41])[CH:36]=[CH2:37]>>[CH2:35]([O:38][N:39]([C@H:52]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[O:59])[C@H:55]([C:65](=[O:67])[NH2:5])[C:54]([CH:68]([CH3:70])[CH3:69])=[CH:53]1)[S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50])(=[O:41])=[O:42])[CH:36]=[CH2:37]
Reactant: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 43.7 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (0.260 g, 43.7%) was prepared a similar manner as described in Intermediate 83 as a pale yellow oil, using (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 93, 0.595 g, 1.13 mmol) as a starting material.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:29]O>>[CH3:29][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(O)c3)cn2)cc1
Product: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(OC)c3)cn2)cc1

Procedure:
5-(3-Hydroxyphenyl)-2-(4-octyloxyphenyl)pyrimidine is reacted with methanol analogously to Example 1 to give 5-(3-methoxyphenyl)-2-(4-octyloxyphenyl)pyrimidine. ##STR37## The compound has the phase sequence: X98 I
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[ClH:15]>CS(C)=O>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: COc1ccc(Br)c2c1CCC(=O)N2
Reactant: Cl
Solvent: CS(C)=O
Product: COc1ccc(Cl)c2c1CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
22.7 grams of 8-bromo-5-methoxy-3,4-dihydrocarbostyril and 25 g of cuprous chloride are mixed with 100 ml of dimethyl sulfoxide and heated at 135°-140° C. for 4 hours under stirring conditions. After the reaction is completed, the reaction mixture is mixed with 200 g of ice and 50 ml of concentrated hydrochloric acid and stirred at a room temperature for 1 hour. The crystals thus precipitated are separated by filtration, washed first with diluted hydrochloric acid and then with water and dried. The crude crystals thus obtained are recrystallized from ligroin-benzene to obtain 13 g of 8-chloro-5-methoxy-3,4-dihydrocarbostyril in the form of pale organic needle-like crystals with a melting point of 165° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2cc[nH]c(=O)c2n1
Product: Cc1ccc2ccnc(Cl)c2n1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A suspension of 2-Methyl-7H-[1,7]naphthyridin-8-one (820 mg, 5.12 mmol) and phosphorus oxychloride (7 ml, 76.8 mmol) was stirred at 90° C. for 4 hours. The reaction mixture was evaporated to dryness, poured on ice and set alkaline with aqueous ammonia. A red solution resulted. The aqueous layer was extracted with dichloromethane (three times). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 0:100->20:80 gradient). The desired compound was obtained as a white solid (810 mg, 89%), MS: m/e=(M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:22]3[N:21]=[C:20]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[NH:29]C(=O)OC(C)(C)C)[N:19]=[CH:18][C:17]=3[N:16]([CH3:37])[C:15](=[O:38])[C@H:14]2[CH2:39][CH3:40])[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:20]1[N:19]=[CH:18][C:17]2[N:16]([CH3:37])[C:15](=[O:38])[C@@H:14]([CH2:39][CH3:40])[N:13]([CH:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:22]=2[N:21]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(=O)OC(C)(C)C)nc2N1C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Three mL of TFA was added to a solution of (R)-tert-butyl 4-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)pyridin-3-ylcarbamate (Example 92, 760 mg) in 3 mL of DCM. The mixture was stirred for 4 h at rt, and the solvent was removed under reduced pressure. Aqueous Na2CO3 was added and extracted with EtOAc. The organic layer was dried with Na2SO4, concentrated and the residue was purified by silica column to give the title compound. LCMS (0.05% TFA): 353.0 m/z (M+H)+; 1H-NMR (CDCl3, 500 MHz): δ: 8.17 (s, 1H), 8.08 (d, 1H, J=5 Hz), 7.99 (d, 1H, J=5 Hz), 7.94 (s, 1H), 6.23 (s, 2H), 4.48 (m, 1H), 4.32 (m, 1H), 3.39 (s, 3H), 2.0-1.69 (m, 10H), 0.88 (t, 3H, J=7.5 Hz).
Reaction SMILES: O[CH:2]([CH2:15][O:16][CH3:17])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18]1(=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[NH:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:28]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[CH:2]([CH2:15][O:16][CH3:17])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COCC(O)CNC(=O)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCC(CNC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
12.10 g (38.4 mmol, 76%) rac-benzyl (2-hydroxy-3-methoxypropyl)carbamate (Example 132A), 6.79 g (46.1 mmol) of 1H-isoindole-1,3(2H)-dione and 15.12 g (57.7 mmol) triphenylphosphine were initially charged in THF (158 ml). 11.4 ml (57.7 mmol) of diisopropyl azodicarboxylate were added dropwise, and the mixture was then stirred at RT for 10 min. The mixture was then concentrated and the residue purified by silica gel chromatography (cyclohexane/ethyl acetate gradient: from 3:0 to 2:1). The product fractions were concentrated. This gave 14.84 g (97% of theory, purity 93%) of the target compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][N:14]3[C:18](=[O:19])[CH2:17][S:16][C:15]3=[O:20])[C:5]=12.[CH:21](=O)[CH2:22][CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:21](=[C:17]1[S:16][C:15](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:18]1=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCOc1cccn2ccnc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.17 g (4.0 mmol) of 3-[3-(imidazo[1,2-a]pyridin-8-yloxy)propyl]thiazolidine-2,4-dione and 0.36 ml (4.0 mmol) of n-butyraldehyde in 15 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 1.07 g (77.5%, light orange oily substance) of the desired product.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[NH:10][C:11](=[O:13])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.O>CN(C)C=O>[CH:19]1([CH2:22][O:13][C:11]2[N:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[N:10]=2)[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2nc(OCC3CC3)nc3sccc23)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 500 mg of 4-phenyl-1,2 -dihydrothieno[2,3-d]pyrimidin-2-one in 10 ml of dimethylformamide is added 100 mg of 63 % sodium hydride. After stirring at 60°C for 1 hour, 590 mg of cyclopropylmethyl bromide is added dropwise thereto. The mixture is heated at 120°C for 4 hours, then cooled to room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-(cyclopropylmethoxy)-4-phenylthieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 86.5°- 87.5°C. From the second fraction 1-cyclopropylmethyl-4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 191° - 191.5°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2([NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[C:12]2=[O:17])[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)NC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To 1 g (3.7 mmol) of 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester were added successively 554 μL (4.08 mmol) of 4-methoxybenzyl chloride, 565 mg (4.08 mmol) of potassium carbonate and 37 mL of anhydrous DMF. The reaction mixture was stirred overnight at room temperature. Then 250 mL of water were added and a white precipitated solid was collected by filtration. This crude material was back washed with diethyl ether and dried under reduced pressure yielding 1.15 g (79%) of 3-(4-methoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=O)=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26]C(=O)CCl)=[CH:21][CH:20]=1)[CH3:18].Cl.[CH2:32]([OH:34])[CH3:33]>>[ClH:11].[CH2:32]([O:34][C:15](=[O:17])[CH2:14][O:13][C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([Cl:11])[C:8]=1[Cl:12])[C:2](=[O:1])[C:3]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[CH:23][CH:24]=1)([CH3:18])[CH2:4]2)[CH3:33]
Reactant: CC1(c2ccc(CNC(=O)CCl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(CN)cc1)C2
Temperature: 5 °C

Procedure:
{1-Oxo-2-[4-(2-chloroacetamidomethyl)phenyl]-2-methyl-6,7-dichloro-5-indanyloxy}acetic acid (2.0 g., 0.004 mole), absolute ethanol (20 ml.) and 12N hydrochloric acid (7 ml.) are combined and heated at reflux for 3 hours. On cooling to 5° C. 1.14 g. of ethyl[1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride precipitates and melts at 211°-213° C. after crystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][CH:31]([OH:33])[CH3:32]>C1COCC1.C(OCC)(=O)C>[CH:31]([O:33][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[NH2:1])([CH3:32])[CH3:30]
Reactant: CC(C)O
Reactant: COc1cc(N)cc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(N)cc(OC(C)C)c1
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a solution of 3-amino-5-methoxyphenol (Example 20, step i, 140 mg, 1.0 mmol), triphenylphosphine (390 mg, 1.5 mmol) and propan-2-ol (90 ul, 1.2 mmol) in THF (3 ml) was added portion wise di-tert-butyl diazocarboxylate (345 mg, 1.5 mmol) at room temperature. After stirring for 3 hours the reaction mixture was diluted with ethyl acetate and extracted with a 1N aqueous solution of HCl. The combined aqueous phases were brought to pH=10 with a aqueous solution of 1N NaOH and then extracted with ethyl acetate. The combined organics were filtered through a hydrophobic frit and the solvents were removed under reduced pressure to give 3-isopropoxy-5-methoxyaniline as a light brown oil (169 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([NH2:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[O:17]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:12][NH:18][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: NCc1ccco1
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)O)c(NCc2ccco2)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
2-Chloro-6-methylnicotinic acid (1.72 g) and furfurylamine (1.94 g) were dissolved in 1-methylpyrrolidin-2-one (25 ml), and the mixture was stirred at 150° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure, and the precipitate was collected by filtration to give the object compound (838 mg) as a powder.
Reaction SMILES: C([O:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])([OH:20])[CH2:16][CH2:15]2)[CH:9]=[N:8][CH:7]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[OH:20][C:17]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:10]2[NH:11][C:6](=[O:5])[CH:7]=[N:8][CH:9]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)Oc1cncc(CCN2CCC(O)(COc3ccccc3F)CC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1cncc(CCN2CCC(O)(COc3ccccc3F)CC2)[nH]1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
After dissolving 274 mg of 1-[2-(6-tert-butoxypyrazin-2-yl)ethyl]-4-(2-fluorophenoxymethyl)piperidin-4-ol in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was all owed to stand at room temperature for 2 hours. Aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (186 mg, 79% yield).
Reaction SMILES: [N:1]#[N:2].[C:3]([C@@H:5]([NH:14][C@H:15]([C:27]([OH:29])=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:4].Cl.[OH-:31].[Na+]>>[N:1]#[N:2].[C:3]([C@@H:5]([NH:14][C@H:15]([C:27]([OH:29])=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:31])[NH2:4]
Reactant: N#C[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: N#N
Agent: [Na+]
Product: NC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Temperature: 0 °C

Procedure:
After stirring a mixture of 12 g of N2 -(1(S)-cyano-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysine and 40 ml of concentrated hydrochloric acid for 5 hours at room temperature, 200 ml of ice-water was added thereto and after adjusting the pH thereof to about 4.5 with an aqueous sodium hydroxide solution with stirring, the mixture was stirred for 30 minutes at 0° C. The crystals thus deposited were washed with water, recovered by filtration, and dried in vacuo at 45° C. to provide 8.3 g of N2 -(1(S)-carbamyl-3-phenylpropyl)-N6 -trifluoroacetyl-L-lysine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14].[C:19]1([C:25]([CH:27](Br)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([O:15][CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14]
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: COc1cccc(CN2CCCCC2C(=O)O)c1
Product: COc1cccc(CN2CCCCC2C(=O)OC(C(=O)c2ccccc2)c2ccccc2)c1

Procedure:
2-Oxo-1,2-diphenylethyl 1-(3-methoxybenzyl)-2-piperidinecarboxylate was prepared from 1-(3-methoxybenzyl)-2-piperidinecarboxylic acid and desyl bromide in a similar manner to that of Preparation 65. (+) APCI-MS (m/z): 444 (M+ +1) IR (Film): 1730, 1690, 1260 cm-1
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH2:17][C@H:16]2[CH3:31])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:33][OH:34]>CO.CO.C(#N)C>[OH:34][NH:33][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:24]=[CH:23][N:22]=2)[CH2:17][C@H:16]1[CH3:31])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Reactant: NO
Solvent: CO
Solvent: CC#N
Product: CC(C)C[C@H](C(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 29.8 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-[(1S)-3-methyl-1-({(2R)-2-methyl-4-[4-(trifluoro methyl)pyridin-2-yl]piperazin-1-yl}carbonyl)butyl]-1,3-dioxolan-4-one (142 mg; 0.31 mmol; 1.0 eq.) in MeOH (5.0 mL) was added an aqueous solution of hydroxylamine (50%; 0.046 mL; 1.55 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 4.5 h. Evaporation of the solvents gave an oil. This residue was taken up in MeOH/ACN (2 mL/1 mL) and purified by reverse-phase chromatography to give the title product (3) as a white powder (40 mg; 29.8%) as a single diastereoisomer. M−(ESI): 431.0; M+(ESI): 433.6. HPLC (condition C): Rt: 10.8 min (HPLC purity: 98.7%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8].Cl[CH2:21][CH:22]=[CH:23][CH3:24]>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH2:21]([N:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:9]([CH:7]=[O:8])=[C:10]1[C:16]([O:18][CH3:19])=[O:17])[CH:22]=[CH:23][CH3:24]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: CC=CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=CCn1c(C)c(C)c(C=O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.5 %

Procedure:
2.21 g (0.0199 mole) of potassium tert-butoxide were added to a solution of 3.60 g (0.0199 mole) of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 0.36 g (0.0014 mole) of 18-crown-6 in 220 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 45 minutes. 3.60 g (0.0398 mole) of 1-chloro-2-butene (a mixture of cis and trans isomers) was added to the mixture and heated under reflux for 7 hours. 1.80 g (0.0199 mole) of 1-chloro-2-butene were then added thereto and heated under reflux for 22 hours. The reaction mixture was allowed to cool to room temperature, subsequently ice-water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel using a 95:5 mixture of toluene and ethyl acetate as an eluent to give 4.50 g (0.0192 mole) of methyl 1-(2-butenyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate (cis/trans =24/76) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]1=[O:20].C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([N:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]2=[O:20])=[C:2]([CH3:1])[CH:7]=1
Reactant: COc1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccn(-c2c(C)cc(N)cc2C)c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2.05 g (7.47 mmol) of the compound from Example 69A are dissolved in 70 ml of ethyl acetate and 70 ml of ethanol, 2.35 g (37.4 mmol) of ammonium formate and 0.39 g (0.37 mmol) of palladium/carbon (10%) are added and the mixture is stirred at 80° C. for 2 h. For work-up, the reaction solution is brought to room temperature and passed through a silica gel frit. The filter cake is washed with ethanol and the filtrate is concentrated under reduced pressure. The reaction product (1.65 g) is reacted without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14](=N)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Product: O=C(O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
Hydrochloride of methyl ester of L-phenylalanine (5.95 g) and benzophenoneimine (5.00 g) were added to methylene chloride (100 ml), and they were stirred at room temperature overnight. A solid thus formed was filtered out of the reaction mixture. The filtrate was concentrated under reduced pressure. Diethyl ether (100 ml) was added to the residue. A solid thus formed was again filtered out of the reaction mixture. The ether layer was washed with water (100 ml) and then dried over anhydrous magnesium sulfate. Magnesium sulfate was removed, and the solution in ether was concentrated to obtain the intended methyl ester of N-(diphenylmethylene)-L-phenylalanine (9.44 g) in a yield of 99.6%.