Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.OS(O)(=O)=O.[N+:19]([O-])([O-:21])=[O:20].[K+]>C1C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([N+:19]([O-:21])=[O:20])=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: c1ccccc1
Product: O=C1Nc2c([N+](=O)[O-])cc(Cl)c(Cl)c2C1=O

Procedure:
To a solution of 4,5-dichloroisatin (13f, 430 mg, 2.0 mmol) in cone H2SO4 (5 mL) was added powdered KNO3 (300 mg, 2.5 mmol) at 0° C. in portions with stirring. The mixture was stirred at 22° C. for 16 h, poured into ice-H2O (50 mL). The precipitate was filtered, washed with H2O (5×10 mL) and dried to give 295 mg (54%) of 13 h as a yellow powder. The analytical sample was obtained by crystallization from benzene, mp 204°-5° C. IR 1776, 1768, 1749, 1614, 1473, 1340, 1227 cm-1 ; 1H NMR δ 11.932 (s, 1H), 8.535 (s, 1H). HRMS Calcd for C8H2Cl2N2O4 : 259.9391; Found: 259.9389.
Reaction SMILES: C([O:9][C@@H:10]([C@@H:12]1[C@@H:15]([S:16][CH3:17])[N:14]([C:18]([C:22]([O:24][CH3:25])=[O:23])=[C:19]([CH3:21])[CH3:20])[C:13]1=[O:26])[CH3:11])(=O)C1C=CC=CC=1.[Na].C(O)(=O)C>CO.C(OCC)(=O)C>[OH:9][C@@H:10]([C@@H:12]1[C@@H:15]([S:16][CH3:17])[N:14]([C:18]([C:22]([O:24][CH3:25])=[O:23])=[C:19]([CH3:20])[CH3:21])[C:13]1=[O:26])[CH3:11]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)c2ccccc2)[C@H]1SC
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)O)[C@H]1SC
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
91 mg (0.24 mmole) of (3S, 4R)-3-[(R)-1-benzoyloxyethyl]-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-methylthioazetidin-2-one were dissolved in 1 ml of methanol. To the resulting solution was added a solution of 7.17 mg (0.31 mmole) of sodium in 0.65 ml of methanol at 0° C., and then the mixture was stirred at room temperature (18°-20° C.) for 5 hours. After completion of the reaction, the mixture was made slightly acidic by the addition of acetic acid, diluted with 20 ml of ethyl acetate and washed with water. After drying the mixture, the solvent was distilled off. The resulting residue was subjected to preparative thin layer chromatography on silica gel developed with a 2:1 by volume mixture of benzene and ethyl acetate to give 50 mg (yield 74.4%) of the pure product as an oil, which was proved by nuclear magnetic resonance spectroscopy to be an approximately 4:1 mixture of the 1'R- and 1'S-isomers.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][N:19]([CH3:25])[C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>CN(C)C=O>[CH3:18][N:19]([CH3:25])[C@H:20]1[CH2:24][CH2:23][N:22]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH2:21]1
Reactant: Nc1ccnc(Cl)n1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(c2nccc(N)n2)C1
Temperature: 220 °C
Yield: 64.1 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (539 μl, 3.09 mmol) and (3S)—N,N-dimethyl-3-pyrrolidinamine (294 μl, 2.316 mmol) in N,N-dimethylformamide (DMF) (2 ml) was heated to 220° C. via a microwave reactor for 30 min. The reaction mixture was purified by RP-HPLC to yield 2-[(3S)-3-(dimethylamino)-1-pyrrolidinyl]-4-pyrimidinamine (205 mg, 0.989 mmol, 64% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:35]=[N:34][CH:33]=[N:32][CH:31]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]([C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)=[O:22]
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cncnc1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(-c4cncnc4)nc(N4CCOCC4)c3s2)CC1
Yield: 31.1 %

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (61 mg) was reacted with 29 mg of pyrimidin-5-yl-5-boronic acid via General Procedure A to give 20.9 mg of 211. MS (Q1) 470.3 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[CH3:46][C:47]1[C:51](B(O)O)=[C:50]([CH3:55])[O:49][N:48]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:51]2[C:47]([CH3:46])=[N:48][O:49][C:50]=2[CH3:55])=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2c(C)noc2C)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (95.1 mg, 0.139 mmol), 3,5-dimethylisoxazole-4-boronic acid (98.5 mg, 0.699 mmol), Pd(PPh)3Cl2 (4.84 mg, 0.0069 mmol), 2 M Na2CO3 (aq., 0.210 mL, 0.419 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (35 min gradient of 20-90% CH3CN in 0.05% aqueous formic acid) afforded the product (30.2 mg, 31%) as a white solid.
Reaction SMILES: C[Al](C)C.Cl.Cl.[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]=[CH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1.[CH:20]1([C:25]([OH:37])([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)[C:26](OCC)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.Cl.C(=O)(O)[O-].[Na+]>CCCCCC.C1(C)C=CC=CC=1>[CH3:18][C:17]([CH3:19])=[CH:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:26](=[O:27])[C:25]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)([OH:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)C(O)(c1ccncn1)C1CCCC1
Reactant: CC(C)CC=CN1CCC(N)CC1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccncn2)C2CCCC2)CC1
Reaction time: 2 h
Yield: 13.4 %

Procedure:
0.65 ml of a 1M trimethylaluminum solution in hexane was added to a solution of 85 mg of 4-amino-1-(4-methyl-pentenyl)piperidine dihydrochloride in 5 ml of toluene under cooling with ice, and this mixture was stirred at the same temperature for 2 hours. A solution of 29 mg of ethyl 2-cyclopentyl-2-hydroxy-2-(4-pyrimidinyl)acetate in 3 ml of toluene was added to the reaction mixture. The resulting mixture was stirred at 100° C. for 18 hours, mixed with 1N hydrochloric acid under cooling with ice, made alkaline with a saturated aqueous solution of sodium bicarbonate, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Art 5744 (manufactured by E. 35 Merck); developing solvent: chloroform/methanol=9/1] to obtain 6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8]Cl)[C:5]([C:10]([O:12]C)=O)=[CH:4][CH:3]=1.[CH3:14][NH2:15].O1CCCC1>O>[Cl:1][C:2]1[N:7]=[C:6]2[CH2:8][N:15]([CH3:14])[C:10](=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1CCl
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2nc(Cl)ccc2C1=O

Procedure:
Methyl 6-chloro-2-(chloromethyl)pyridine-3-carboxylate (1.5 g, 6.82 mmol) was stirred in a solution of methylamine in tetrahydrofuran (35 mL, 70.0 mmol) at room temperature overnight. Water was added and the products extracted into ethyl acetate (2×). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in diethyl ether to give a first batch of product. The mother liquor was concentrated in vacuo and the residue purified by flash chromatography (silica, 40-100% ethyl acetate/hexanes) and combined with the first batch to afford the title compound as a white solid. LRMS (APCI) calcd for C8H8ClN2O [M+H]+ 183.0, found 183.0.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]([O:22]CC)=[O:21])[CH:15]=1>Cl.C(O)(=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=1
Reactant: CCOC(=O)c1cc(CCN2C(=O)c3ccccc3C2=O)n(C)n1
Agent: Cl
Solvent: CC(=O)O
Product: Cn1nc(C(=O)O)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
A solution of ethyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylate (75.2 g, 230 mmol) in 1 M aqueous hydrochloric acid (450 mL) and acetic acid (450 mL) was heated at 100° C. (internal temperature) for 5.2 hours, cooled to ambient temperature, and stirred for about 12 hours. A white solid was isolated by filtration, washed with water, and dried to provide 52.6 g of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:14][O:15][C:16]([C:18]12[CH2:23][CH:22]1[CH2:21][CH2:20][C:19]2=[O:24])=[O:17]>C(O)(C)(C)C>[CH3:14][O:15][C:16]([C:18]1[C:19](=[O:24])[CH2:20][CH2:21][C:22]=1[CH2:23][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: Sc1ccccc1
Reactant: COC(=O)C12CC1CCC2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(CSc2ccccc2)CCC1=O
Reaction time: 0.17 h

Procedure:
Thiophenol (660 mg: 6 mmol) was added to a solution of potassium t-butoxide (650 mg: 6 mmol) in 5 ml of t-butyl alcohol. The mixture was stirred for 10 minutes. A solution of 2-oxo-bicyclo[3.1.0]hexane-1-carboxylic acid methyl ester of Preparation 2(924 mg, 6 mmol) in 2 ml of t-butyl alcohol was added to the mixture. After stirring the mixture at room temperature for about 30 minutes, most of the solvent was distilled off under reduced pressure. Ether was added to the residue and dilute hydrochloric acid was added to acidify the solution, and the ethereal solution was washed with a saturated aqueous solution of sodium chloride and was dried over anhydrous magnesium sulfate and was filtered. The solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from ether and n-hexane to obtain 2-oxo-5-phenylthiomethyl-cyclopentenecarboxylic acid methyl ester as white crystals.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:12]=[C:13]([C:19]2(O[Si](C)(C)C)[CH2:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>ClCCl.O>[Br:10][C:11]1[CH:12]=[C:13]([C:19]2([F:7])[CH2:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(C2(O[Si](C)(C)C)CC2)cc1Br
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2(F)CC2)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Diethylaminosulfur trifluoride (2.4 ml) was added to a solution of [1-(3-bromo-4-methoxyphenyl)cyclopropyloxy]trimethylsilane (3.84 g) in dichloromethane (68 ml). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.88 g).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=O)[CH:21]=1>>[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:17]1[N:18]=[CH:19][N:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH:4][CH2:1][C:2]#[CH:3])=[O:26])[CH:21]=1
Reactant: C#CCN
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)O)cn1
Product: C#CCNC(=O)c1ccccc1-n1cnc(-c2c(-c3ccccc3)noc2C)c1
Yield: 25 %

Procedure:
As described for Example 71, prop-2-ynylamine was converted, using 2-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (28 mg, 25%) which was obtained as an off-white solid. MS: m/e=383.1 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32])(OCC)=O>O>[CH:29]1[CH:28]=[C:25]2[C:26]([N:1]([C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([NH2:6])=[O:7])[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=1)=[O:27]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred solution of L-glutamine (43.8 g, 300 mmoL) and sodium carbonate (33.4 g, 315 mmoL) in 750 mL of water is rapidly added N-carbethoxyphthalimide [65.8 (97% pure, 67.8 g), 300 mmoL] as a solid. After 1 hour, the reaction mixture is filtered to remove unreacted N-carbethoxyphthalimide. The pH of the stirred filtrate is adjusted to 3-4 with 4N hydrochloric acid. The mixture is then seeded with N-phthaloyl-L-glutamine and the pH adjusted to 1-2 with 4N hydrochloric acid. The resulting slurry is stirred for 1 hour. The slurry is filtered and the solid washed with copious amounts of water. The solid is air-dried and then dried in vacuo (60° C., <1 mm) overnight to afford 49.07 g (59%) of N-phthaloyl-L-glutamine, which can be alternatively named as 2-phthalimidoglutaramic acid, as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:27]([CH3:29])[CH3:28]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH:27]([CH3:29])[CH3:28])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)Br
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Product: Cc1nc2c(cc1OC(C)C)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 1 intermediate d), from (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate), sodium hydride and 2-bromopropane.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:34][CH2:35][C:36]([O:38]CC)=[O:37])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CNc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 45a (0.13 g, 0.24 mmol) in THF (3 mL) and water (2 mL) was added LiOH (30 mg, 1.25 mmol). The resulting solution was stirred at rt for 4 h, and concentrated under reduced pressure to remove volatile solvent. The pH of the resulting solution was adjusted to ˜4 with 1N HCl solution. The solids formed were collected by filtration. The crude solid was further purified by flash column chromatography on silica gel (1%-10% MeOH/DCM) to obtain the title compound 17 as a red solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.53 (d, J=8.7 Hz, 1H), 8.31-8.16 (m, 6H), 8.06-8.03 (m, 2H), 7.94-7.78 (m, 3H), 7.65 (t, J=7.5 Hz, 1H), 7.16 (d, J=9.3 Hz, 1H), 6.47 (d, J=5.7 Hz, 1H), 4.19-4.02 (m, 4H), 3.94-3.80 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H25N7O3: 508.2 (M+H). Found: 508.2.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[O:21]=[C:22]1[CH2:27][CH2:26][C:25]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>>[CH3:1][CH:2]([C:6]1[CH:7]=[C:8]([C:16]([F:17])([F:19])[F:18])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[C:3]([NH:34][C:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23][C:22](=[O:21])[CH2:27][CH2:26]1)=[O:4]
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Product: CC(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4) and 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 18) according to the method of Example 1. 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H, m), 5.71 (1H, s), 3.70 (1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60 (1H, m), and 1.52 (3H, d, J 7.0 Hz).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:30]4[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(Br)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)CC2)CC1

Procedure:
A solution of 0.05 m of 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(p-bromophenyl)ethane (DE 3317597) and 0.05 m of p-trifluoromethylphenylboric acid (prepared from p-bromotriflurotoluene by consecutive reaction with n-BuLi/B(OCH3)3 and H+ /H2O) in 100 ml of toluene and 50 ml of ethanol is refluxed for 4 hours after 0.0001 m of Pd(Ph3)4 and 50 ml of Na2CO3 solution (2M) have been added, Conventional extractive work-up and subsequent purification by chromatography and crystallization give 1-[trans-4-(trans-4-n-propylcyclohexyl)-cyclohexyl]-2-(4-trifluoromethylbiphenyl-4'-yl)ethane,
Reaction SMILES: [C:1]([NH:4][C:5]([N:7]([CH3:9])[CH3:8])=[S:6])(=O)[CH3:2].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](=[O:18])[CH2:16]Br)=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>C(O)(C)C>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([C:16]2[S:6][C:5]([N:7]([CH3:9])[CH3:8])=[N:4][C:1]=2[CH3:2])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)NC(=S)N(C)C
Solvent: CC(C)O
Product: Cc1nc(N(C)C)sc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
The starting material is prepared as follows: A mixture of 3.7 g of N-acetyl-N',N'-dimethyl-thiourea and 7 g of 4-chloro-3-nitro-phenacyl bromide in 100 ml of isopropanol is refluxed for 2 hours, cooled and filtered. The residue is rendered basic and extracted with methylene chloride. The extract is dried and evaporated and the residue is recrystallised from a mixture of ethyl acetate and hexane, yielding 4-chloro-3-nitro-1-(4-methyl-2-dimethylamino-5-thiazoloyl)-benzene, which melts at 165°-169°.
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12]([C:18]([O:21][C:22]([C:28](F)=[O:29])([C:24]([F:27])([F:26])[F:25])[F:23])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[OH:31][CH2:32][CH2:33][CH2:34][O:35][CH:36]([CH2:38][OH:39])[CH3:37]>C([O-])(O)=O.[Na+]>[C:1]([C:5]([C:8]([O:11][C:12]([C:18]([O:21][C:22]([C:28]([O:39][CH2:38][CH:36]([O:35][CH2:34][CH2:33][CH2:32][O:31][C:28]([C:22]([O:21][C:18]([C:12]([O:11][C:8]([C:5]([C:1]([F:2])([F:3])[F:4])([F:6])[F:7])([F:9])[F:10])([C:14]([F:15])([F:17])[F:16])[F:13])([F:20])[F:19])([C:24]([F:27])([F:26])[F:25])[F:23])=[O:29])[CH3:37])=[O:29])([C:24]([F:25])([F:26])[F:27])[F:23])([F:19])[F:20])([C:14]([F:17])([F:16])[F:15])[F:13])([F:9])[F:10])([F:6])[F:7])([F:4])([F:2])[F:3]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: CC(CO)OCCCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(COC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)OCCCOC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
CF3(CF2)2OCF(CF3)CF2OCF(CF3)COF (120.69 g) was loaded into an autoclave and stirred under a nitrogen stream, and HO(CH2)3OCH(CH3)CH2OH (15.1 g) prepared in Example 2-3 was fed over 2 hours, while the temperature in the autoclave was maintained at 30° C. or below. Then, the reaction solution was stirred at room temperature under a nitrogen stream overnight and poured onto saturated aqueous NaHCO3 (500 mL) with ice.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 80 °C

Procedure:
A suspension of Example 4C (13.0 g, 29.9 mmol) and LiOH monohydrate (3.78 g, 90.0 mmol) in dioxane (250 mL) and water (100 mL) was heated at 95° C. for 16 hours, concentrated to dryness, treated with water (600 mL), heated to 80° C., and filtered. The filtrate was treated with 1M HCl (90 mL) and the resulting precipitate was collected by filtration and dried to give the desired product.