Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C@@H:8]2[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:8]2[CH2:9][C:7]2([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CC[C@H]1CC1(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC[C@H]1CC1(c1ccccc1)c1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
As in Example 111, (S)-2,2-diphenylcyclopropanepropanoic acid (6.38 g) and 4-nitrophenol (4 g) in dichloromethane (100 mL) was treated with 1,3-dicyclohexylcarbodiimide (4.95 g) and the mixture was stirred at 25° C. for 1 hour. The crude ester, isolated in the usual way, was crystallized from 2-propanol to give 4.8 g of (S)-2,2-diphenylcyclopropanepropanoic acid 4-nitrophenyl ester. The analytical sample was obtained from the same solvent, mp 76°-77° C.; [α]D25 -93.53° (c, 1.0, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14](C=O)[N:13]=[CH:12]1.[CH:18](OC)([O:21][CH3:22])[O:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O.S([O-])(O)(=O)=O.[Na+]>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([CH:18]([O:21][CH3:22])[O:19][CH3:20])[N:13]=[CH:12]1
Reactant: O=Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Reactant: COC(OC)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
1-(2-Fluoro-4-nitrophenyl)-1H-imidazole-4-carboxaldehyde (Intermediate 30) (361.7 g, 1.538 mol) was suspended in dry methanol (1700 ml). Trimethyl orthoformate (340 g, 2 mol) and sodium hydrogen sulfate (8 g) were added and the mixture was heated to reflux for 3.5 hours. It was cooled to room temperature, a solution of sodium carbonate in water (10%, 200 ml) was added and it was stirred for 1 hour. It was diluted with water (4 L) and left for 2 hours. The precipitate was collected by filtration, washed with water and dried to give the title compound (402.4 g) as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.P(=O)(O)(O)O.[C:15]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:21]1[CH2:22][CH2:23][N:18]([C:15](=[O:17])[CH3:16])[CH2:19][CH:20]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CC=C(c2cc3ccccc3[nH]2)CC1

Procedure:
A starting compound of the formula II may also be obtained by reacting an indole of the formula IV in a mixture of glacial acetic acid and phosphoric acid with the equivalent quantity of N-acetyl-4-piperidone, preferably at room temperature. The corresponding 4-indolyl-1-acetyl-1,2,5,6-tetrahydropyridine is thus obtained, which is then hydrogenated in conventional manner in the presence of palladium/coal at room temperature and atmospheric pressure to form the corresponding piperidine derivative; the latter is subsequently hydrolized in a mixture of a lower alkanol and aqueous 50% potassium hydroxide.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27](OCC)[O:28]CC)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
To a solution of diethyl 2-methyl-4-(3-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (462.5 mg) in acetone (4 ml) was added 6N-hydrochloride acid (0.4 ml) and stirred at room temperature for an hour. After the reaction, the solvent was removed from the resultant solution. To the residue was added water, and the residue was pulverized. The powder was collected by filtration, washed with water and dried to give diethyl 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (360 mg), m.p. 130° to 133° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[O:14]1[CH:16]([CH2:17][CH3:18])[CH2:15]1>C(O)C>[OH:14][CH:16]([CH2:17][CH3:18])[CH2:15][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1]
Reactant: CCC1CO1
Reactant: CC1CC(C)(C)NC2CCCCC12
Solvent: CCO
Product: CCC(O)CN1C2CCCCC2C(C)CC1(C)C

Procedure:
Following the procedures given above, 2,2,4-trimethyl decahydroquinoline of about 76% cis structure was reacted with 1,2-epoxybutane in the presence of ethanol to yield 58 grams of 1-(2'-hydroxybutyl)-2,2,4-trimethyl decahydroquinoline, which had a boiling point of 110°-112° C. at 0.50 mm Hg. Calculated contents for the formula C16H31NO were 75.83% carbon, 12.33% hydrogen, and 5.53% nitrogen and the measured values were 76.55% carbon, 13.13% hydrogen, and 5.49% nitrogen.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([N:13]2[C:17]3([CH2:21][CH2:20][CH2:19][CH2:18]3)[C:16](=[O:22])[NH:15][C:14]2=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:25][C:26]([NH:28][C:29]1[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[CH:38]([CH3:40])[CH3:39])=[O:27].O>CN(C)C=O>[CH:38]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH:35]([CH3:36])[CH3:37])[C:29]=1[NH:28][C:26](=[O:27])[CH2:25][N:15]1[C:16](=[O:22])[C:17]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:14]1=[O:23])([CH3:39])[CH3:40]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reactant: O=C1NC(=O)C2(CCCC2)N1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1C(=O)N(c2ccccc2)C2(CCCC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
80 mg (0.57 mmol) of potassium carbonate are added to a solution of 120 mg (0.52 mmol) of 1-phenyl-1,3-diazaspiro[4.4]nonane-2,4-dione and 145 mg (0.57 mmol) of 2-chloro-N-(2,6-diisopropylphenyl)acetamide in 20 ml of dimethylformamide. The reaction medium is stirred at room temperature for 24 hours. It is then poured into water and extracted with ethyl acetate. The organic phases are collected, washed with water and dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane and then heptane/ethyl acetate 80/20, v/v). 120 mg of N-(2,6-diisopropylphenyl)-2-(2,4-dioxo-1-phenyl-1,3-diazaspiro[4.4]non-3-yl)acetamide are obtained in the form of a white solid. Yield=51%, m.p.=275-7° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:34]=[CH:33][C:12]([CH2:13][O:14][C:15]3[C:24]4[C:19](=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:29]([F:32])([F:31])[F:30])[CH:16]=3)=[CH:11][CH:10]=2)O1.[CH3:36][O:37][C:38](=[O:54])[CH:39]([NH:43][S:44]([C:47]1[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=1)(=[O:46])=[O:45])[CH:40]([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:36][O:37][C:38](=[O:54])[CH:39]([NH:43][S:44]([C:47]1[CH:48]=[CH:49][C:50]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]3[C:24]4[C:19](=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:29]([F:30])([F:31])[F:32])[CH:16]=3)=[CH:33][CH:34]=2)=[CH:51][CH:52]=1)(=[O:46])=[O:45])[CH:40]([CH3:42])[CH3:41]
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Reactant: CC1(C)OB(c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)OC1(C)C
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: [K+]
Solvent: COCCOC
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Step 2B [Intermediate 5, G9591-162]: To 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-2,8-bis-trifluoromethyl-quinoline (1.5 g, 3.0 mmol, 1 equiv.) in 45 mL of ethylene glycol dimethyl ether was added 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (1.06 g, 3.0 mmol, 1.0 equiv.) and Pd(PPh3)4 (174 mg, 0.15 mmol, 0.05 equiv.) under N2. The reaction mixture was stirred for 0.5 hr, then an aqueous solution of K2CO3 (834 mg, 6.0 mmol, 2 equiv.) was added. The mixture was heat to reflux overnight. After cooling to room temperature, solvent was removed under vacuum. The residue was diluted with EtOAc (100 mL) and washed with brine solution. The organic layer was dried over anhydrous MgSO4, solvent evaporated under vacuum, and the crude product was purified on silica gel column (30% EtOAc/Hexane) to give 1.026 g of 2-[4′-(2,8-Bis-trifluoromethyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester in 53% yield.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[Na].C(OCC)(=O)C>CN(C)C=O>[OH:1][C:3]1([CH2:2][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2ccnc2)CC1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 87.9 %

Procedure:
4.25 g of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate was dissolved in 30 ml dimethylformamide, 5.38 g of sodium imidazole was added thereto, and the mixture was stirred at 60° C. for 3 hr and 40 min. After cooling, ethyl acetate was added to the reaction solution, and it was washed with water for 3 times and then with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated and subjected to silica gel column chromatography to give 4.93 g of tert-butyl 4-hydroxy-4-(1H-1-imidazolylmethyl)-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>>[CH3:18][C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:10]1[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=2)=[CH:12][N:11]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(4-chlorobenzyl)-2-methylthio-4-pyrimidone (17.7 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (11.4 g) was heated at 145°-150° for 5 hours. After cooling, the reaction mixture was triturated with water to give the free base, which was separated by decantation and recrystallised from methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone m.p. 204.5°-206°.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.O.Cl>CO>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
To a solution of sodium (60 g , 2.6 mol) in 1000 ml of methanol was added 5-fluoroindole (49 g, 0.36 mol) and 4-piperidone.H2O.HCl (170 g, 1.11 mol). The mixture was heated under reflux for 18 h, then concentrated , water was added and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and then concentrated. The resulting solid was dissolved in methanol (about 200 ml) and then diluted with water (about 1000-1500 ml). The precipitate was collected , washed with water and petroleum ether and then dried in a vacuum oven at 60° C. Yield 74 g (95%) of a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH:12]3[CH2:14][CH2:13]3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26]>CN(C=O)C>[CH2:25]([O:1][C:2]1[C:11]2[C:6](=[C:7]([CH:12]3[CH2:14][CH2:13]3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1)[CH3:26]
Reactant: CCI
Reactant: COC(=O)c1cc(O)c2cccc(C3CC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nc2c(C3CC3)cccc12
Reaction time: 12 h

Procedure:
To a stirred solution of 1.04 g (4.28 mmol) of methyl 4-hydroxy-8-cyclopropylquinoline-2-carboxylate in 11 mL of DMF was added 1.18 g of K2CO3 and 0.68 mL of ethyl iodide successively and the mixture was stirred at 60 deg C. for 12 hr. The mixture was partitioned between AcOEt and H2O and the organic layer was washed with H2O and satd. brine, dried over anhydrous Na2SO4, and then concentrated. The residue was purified on SiO2 column chromatography (eluted with n-Hex/AcOEt=19/1) to yield methyl 4-ethoxy-8-cyclopropylquinoline-2-carboxylate as a pale yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[N:15]=[C:14]([S:16]([NH2:19])(=[O:18])=[O:17])[S:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=O>>[N:22]1([CH:20]=[N:19][S:16]([C:14]2[S:13][N:12]=[C:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:15]=2)(=[O:18])=[O:17])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Reactant: O=CN1CCOCC1
Solvent: O=S(Cl)Cl
Product: O=S(=O)(N=CN1CCOCC1)c1nc(-c2ccccc2)ns1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (4.5 ml) was added dropwise to 3.0 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide in 15 ml of dry N-formylmorpholine at -5°. The resulting mixture was stirred at room temperature for 3 hours, poured into ice water and stirred for 15 minutes. The solids were collected, washed with water, dried, triturated with ether, washed with hexane and dried (in vacuo, P2O5). Recrystallization from benzene/hexane gave 1.1. g of solid, m.p. 185°-187°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2cccc(C(C)=O)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccc(C(C)=O)c2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 178 (80 mg, 0.15 mmol) is treated with acid chloride 6 (53 mg, 0.21 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][CH2:11][CH2:12][C:13]1(C#N)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]1=2.O>C1(C)C=CC=CC=1>[CH:24]1[C:15]2[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:13]([CH2:12][CH2:11][CH2:10][O:9][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][O:3]3)[C:14]=2[CH:27]=[CH:26][CH:25]=1
Reactant: N#CC1(CCCOC2CCCCO2)c2ccccc2CCc2ccccc21
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)CCc1ccccc1C2CCCOC1CCCCO1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Under nitrogen, sodium amide (3.5 g, 0.045 mol, 50% suspension in toluene) was added to a 100 ml three-necked roundbottom flask. The above nitrile (4.0 g, 0.011 mol) was dissolved in dry toluene (50 ml) and added. The reaction mixture was heated at reflux temperature for 16 h. After cooling to room temperature, water was added with caution (100 ml). More toluene was added and the organic phase was washed with dilute HCl. After drying (MgSO4), the organic phase was evaporated in vacuo affording 3.0 g (81%) of crude 2-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-propyloxy)tetrahydropyran as an oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([O:21][CH2:20]1)[C@@H:17]([OH:19])[CH3:18]>CN(C)C=O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:21])([C@@H:17]([OH:19])[CH3:18])[CH2:20][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C
Yield: 37 %

Procedure:
To an ice cooled suspension of dry NaH (0.216 g, 0.009 mole) in N,N-dimethylformamide (10 ml), 1H-1,2,4-Triazole (0.691, 0.010 mole) was added in small portions under an atmosphere of nitrogen. The mixture was slowly brought to room temperature and a solution of compound 7a, (2S,3R)-3-(2,4-Difluorophenyl)-3,4-epoxy-2-butanol (1.0 g, 0.005 mole) in N,N-dimethylformamide (2 ml) was added. The resulting mixture was heated at 80° C. for 2 hours. The solvent was removed under reduced pressure and 50 g of crushed ice was added to the residue. The so formed mixture was extracted with ethyl acetate (100 ml, 2×50 ml). The combined organic layers were washed with water (20 ml) brine (50 ml) and dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed on silica gel. Elution with methanol in chloroform (0% -3%) gave the title compound 9a as an amorphous solid (0.5 g, 37%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:26])=[C:6]([C:22]([F:25])=[CH:23][CH:24]=1)[O:7][C:8]1[CH2:12][N:11]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14](O)=[O:15])[C:10](=[O:21])[CH:9]=1)[CH3:2].[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH:39][C:14](=[O:15])[C@@H:13]([N:11]3[CH2:12][C:8]([O:7][C:6]4[C:22]([F:25])=[CH:23][CH:24]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=4[F:26])=[CH:9][C:10]3=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[N:35]2)[CH2:30][O:29]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 94.8 %

Procedure:
To a solution of (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.837 g, 2.27 mmol) in N,N-dimethylformamide (50 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.559 g, 2.83 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.505 g, 3.40 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.732 g, 5.66 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 50% to 90% ethyl acetate/hexanes) which afforded (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (1.180 g, 95%) as a pale yellow solid: HR-ES-MS m/z calculated for C27H34F2N4O6 [M+H]+ 549.2519, observed 549.2514, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.38-1.49 (m, 1H), 1.50-1.67 (m, 1H), 1.68-1.84 (m, 1H), 3.73 (dd, J=8.5, 6.0 Hz, 1H), 3.96-4.19 (m, 5H), 4.27 (d, J=18.7 Hz, 1H), 4.31-4.40 (m, 1H), 4.63 (d, J=18.7 Hz, 1H), 4.88 (dd, J=10.7, 4.7 Hz, 1H), 5.06 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.11-7.22 (m, 1H), 7.27 (dt, J=9.7, 1.5 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: COC([C:5]1([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=2[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=O.Cl>C(O)(=O)C>[CH3:26][C:23]([C:14]1[CH:15]=[C:16]([C:19]([CH3:20])([CH3:21])[CH3:22])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])([CH3:24])[CH3:25]
Reactant: COC(=O)C1(CCc2ccc(C(C)(C)C)cc2C(C)(C)C)CCCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CCC2CCCC2=O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 944 mg (2.74 mmoles) of the title product of Example 12 in 20 ml of acetic acid is added 20 ml of concentrated hydrochloric acid. The mixture is stirred at reflux for 6 hours and then cooled to room temperature. After azeotropic distillation of most of the acetic acid with toluene, water is added and the mixture is extracted first with 50/50 diethyl ether/toluene, and then further extracted twice with toluene. The combined organic extracts are washed with aqueous sodium bicarbonate and then brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].[CH3:14][O:15][C:16](Cl)=[O:17]>O>[CH3:14][O:15][C:16]([NH:1][C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@@H](C(=O)O)C(C)C
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a mixture of L-valine (220 mg, 1.9 mmol) and NaHCO3 (482 mg, 5.6 mmol) in H2O (6 mL) at 0° C. is added dropwise methylchloroformate (0.25 mL, 3.25 mmol). The reaction mixture is stirred for 2 hours at 0-5° C. The mixture is diluted with water and washed with Et2O. The aqueous layer is acidified with 1N HCl to pH 3 and the product is extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated in vacuum. The residue is triturated with hexanes-Et2O to give (R)-2-methoxycarbonylamino-3-methyl-butyric acid (248 mg, 75%).