Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:17][S:18]([C:21]1[S:25][C:24]2[S:26](=[O:34])(=[O:33])[CH:27]([C:29]([O:31]C)=[O:30])[CH2:28][C:23]=2[CH:22]=1)(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14].CI>C1COCC1.CCCCCC>[C:13]([NH:17][S:18]([C:21]1[S:25][C:24]2[S:26](=[O:33])(=[O:34])[C:27]([CH3:1])([C:29]([OH:31])=[O:30])[CH2:28][C:23]=2[CH:22]=1)(=[O:19])=[O:20])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C1Cc2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(C)(C(=O)O)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 118.1 %

Procedure:
A stirred solution of diisopropylamine (4.44 mL, 31.7 mmol) in THF (200 mL) was cooled to -78° C. under an N2 atmosphere. A solution of n-butyllithium in hexane (12.3 mL, 2.58M) was added via syringe and the mixture stirred for 10 min at -78° C. and 15 min at 0° C. The mixture was cooled to -78° C. and product from Step B (5.3 g, 14.4 mmol) in THF (50 mL) was added dropwise. The reaction was stirred for 30 min and then methyl iodide (0.94 mL, 15.1 mmol) was added. The reaction was allowed to warm to room temperature overnight, and then quenched with water and 10% aqueous NaOH for 1 h. The DMF was removed in vacuo and water added. The aqueous solution was acidified with 6N HCl and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over MgSO4. The solution was filtered and the filtrate freed of solvent to give the title compound (6.25 g, crude product). 1H NMR (300 MHz,DMSO-d6) 1.20(s,9H), 1.70(s,3H), 3.17(d,1H), 3.80(d,1H), 7.60(s,1H), 8.20(s,1H,exch.).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)[CH:3]([CH3:6])[C:4]#[N:5].[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:22][NH:13][C:9]2[CH:8]=[C:7]([CH:2]([OH:1])[CH:3]([CH3:6])[C:4]#[N:5])[CH:12]=[CH:11][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CC1CCCCC1
Reactant: CC(C#N)C(O)c1cccc([N+](=O)[O-])c1
Product: CC(C#N)C(O)c1cccc(NCC2CCCCC2)c1

Procedure:
Hydrogenation of the mixture of 3-hydroxy-2-methyl-3-(3-nitrophenyl)propanenitrile and aldehyde 29 following the method used in Example 11 gives 3-(3-(cyclohexylmethylamino)phenyl)-3-hydroxy-2-methylpropanenitrile.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.C(O[C:13]([C:15]1[N:20]2[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[N:23]=[C:19]2[CH:18]=[C:17]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:16]=1)=[O:14])C.[Na].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>O1CCCC1.CCCCCCC.C(OCC)(=O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13]([C:15]1[N:20]2[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])[N:23]=[C:19]2[CH:18]=[C:17]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:16]=1)=[O:14])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OCC)n2n1
Reactant: CCNCC
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)N(CC)CC)n2n1

Procedure:
Diethylamine (0.400 mL) was suspended in tetrahydrofuran (2.00 mL) and cooled in an ice bath. This solution was charged with trimethylaluminum (0.500 mL of a 2 M solution in heptane). After 20 minutes the reaction was charged with the 2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester, prepared as in Example 16, Step 1, (0.255 g, 0.720 mmol) and shaken. After 18 hours the reaction was diluted with 1 volume of ethyl acetate and treated with an equal amount saturated aqueous sodium/potassium tartrate. After 6 hours the organic layer was isolated, dried over magnesium sulfate and concentrated to afford the desired product 2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid diethylamide, MS (APCI+): m/z 382.1 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5]1.Cl.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C.C(O)CO>CO>[ClH:1].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][O:5]2)[CH2:25][CH2:24]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: ClCCC1OCCc2ccccc21
Agent: Cl
Solvent: CO
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1

Procedure:
A mixture of 1-(2-chloroethyl)isochroman (LXIV, PREPARATION 2, 0.497 g, 2.53 mmol), 1-(2-chlorophenyl)piperazine dihydrochloride (XI, 0.952 g, 3.79 mmol), diisopropylethylamine (1.76 ml, 10.1 mmol) and ethylene glycol (5 ml) is heated at 100° for 16 hr. After cooling, the mixture is partitioned between ethyl acetate and saline. The organic phase is dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with methanol/dichloromethane (2/98) to give a material which is taken up in several mls of methanol. Methanol saturated with hydrochloric gas (6 ml) is added. After standing for several minutes, the mixture is concentrated under reduced pressure. Several mls of methanol are added back, followed by ether. The resulting solid is collected, washed with ether, and dried under vacuum to give the title compound; mp 197°-198°; MS ((m/z)) 356; IR (mineral oil) 1093, 1481, 743, 2436 and 2426 cm-1.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[C:9]1([S:8][C:4]2[N:3]([O:2][C:17](=[O:18])[N:16]([CH3:15])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: On1ccnc1Sc1ccccc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Product: CN(C(=O)On1ccnc1Sc1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-phenylsulfanylimidazole hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (61%, oil).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22]>ClC1C=CC=CC=1>[CH:21]([C@H:20]1[CH2:24][O:25][C:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(CCc1ccccc1)OCc1ccccc1
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(CCc2ccccc2)=N1
Yield: 74 %

Procedure:
Under an argon atmosphere, a mixture of benzyl 3-phenylpropionate (1.5 mmol), (L)-valinol (1.8 mmol), Zn4(OCOCF3)6O (0.15 mmol) and chlorobenzene (2.5 mL) was heated under reflux for 18 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography to give (S)-4-isopropyl-2-(2-phenylethyl)-1,3-oxazoline in 74% yield. The compound was identified by comparison with physical property data of the known compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: [O-][n+]1ccc(Br)cc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2cc[n+]([O-])cc2)cc(OC)c1OC

Procedure:
3,4,5-Trimethoxyphenylboronic acid (2.49 g) and 4-bromopyridine-N-oxide (2.25 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([CH2:15][CH2:16][CH2:17]O)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[BrH:19]>>[BrH:19].[Br:19][CH2:17][CH2:16][CH2:15][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[N:8][CH:7]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: COc1ccc(C2(CCCO)CCCNC2)cn1
Agent: Br
Product: Oc1ccc(C2(CCCBr)CCCNC2)cn1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
0.100 g (0.4 mmol) of 3-[3-(6-methoxypyridin-3-yl)piperidin-3-yl]propan-1-ol obtained in stage 1.3, in solution in 5 ml of aqueous hydrobromic acid (48% by weight solution), is introduced into a sealed tube. The reaction medium is stirred at 110° C. for 12 hours. This solution is then brought back to ambient temperature and concentrated under reduced pressure. The resulting residue is dissolved in methanol and evaporated twice under reduced pressure, and triturated from diethyl ether, to result, after filtration, in 0.150 g of the desired compound in the form of a brown powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16]>>[CH3:24][O:23][C:19]1[CH:18]=[C:14]([CH:13]=[C:12]([O:11][CH3:10])[C:20]=1[O:21][CH3:22])[C:15]([C:5]1[S:1][C:2]([CH2:6][C:7]([OH:9])=[O:8])=[CH:3][CH:4]=1)=[O:16]
Reactant: O=C(O)Cc1cccs1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)c2ccc(CC(=O)O)s2)cc(OC)c1OC

Procedure:
Using the procedure of Example 1, thiophene-2-acetic acid and 3,4,5-trimethoxybenzoyl-chloride were reacted to obtain 5-(3',4',5'-trimethoxybenzoyl)-thiophene-2-acetic acid melting at 124° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][C@@H:24]1[C@H:25]([OH:27])[CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
5-Bromo-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 71.1, 60 mg, 0.13 mmol), pyrimidin-5-ylboronic acid (32.2 mg, 0.26 mmol), Pd(PPh3)2Cl2 (9.11 mg, 0.013 mmol) and Na2CO3 (55.0 mg, 0.519 mmol) were added to a MW vial and treated with a mixture of DME (551 μL), water (157 μL) and EtOH (79 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 10 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 54.1 mg, 0.078 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column DEAP, isocratic 25% in 9 min.) to yield the title compound as a white amorphous solid. UPLC-MS (Condition 3) tR=0.83 min, m/z=462.1 [M+H]+, m/z=460.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.05 (dd, J=10.76, 4.16 Hz, 2H) 3.26 (dd, J=10.51, 4.89 Hz, 2H) 3.98 (t, J=3.91 Hz, 2H) 4.89 (br. s, 2H) 7.35 (d, J=8.56 Hz, 2H) 7.79-7.90 (m, 2H) 8.10 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.17 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([CH:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([Cl:20])[C:15]=2[Cl:19])[C:10]1=[O:23])[CH3:8].[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].C1([I+]C2C=CC=CC=2)C=CC=CC=1>C(O)(C)(C)C.O>[CH2:7]([C:9]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([Cl:20])[C:15]=2[Cl:19])[C:10]1=[O:23])[CH3:8]
Reactant: CCC1C(=O)c2cc(OC)c(Cl)c(Cl)c2C1=O
Reactant: c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCC1(c2ccccc2)C(=O)c2cc(OC)c(Cl)c(Cl)c2C1=O
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (8.4 g.) dissolved in tert-butanol (300 ml.) is added to a refluxing solution of 2-ethyl-4,5-dichloro-6-methoxyindan-1,3-dione (1.3 g) in tert-butanol (400 ml.)-benzene (200 ml.) and refluxing is continued for 15 min., then diphenyliodonium chloride (19.0 g.) is added and refluxing is continued for an additional 2 hours. The reaction mixture is cooled to 25°, 300 ml. water added, and the mixture concentrated to dryness in vacuo to give 2-ethyl-2-phenyl-4,5-dichloro-6-methoxyindan-1,3-dione.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)([OH:3])=[O:2].[H][H].[OH-].[Na+:22]>[Pd]>[Na+:22].[Na+:22].[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH:14]([CH3:18])[C:15]([O-:17])=[O:16])=[CH:6][C:5]=1[CH2:4][C:1]([OH:3])=[O:2].[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH:14]([CH3:18])[C:15]([O-:17])=[O:16])=[CH:6][C:5]=1[CH2:4][C:1]([OH:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])c(CC(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)[O-])c1ccc(N)c(CC(=O)O)c1

Procedure:
In 0.5N aqueous sodium hydroxide solution (0.8 mL) was dissolved 2-(3-carboxymethyl-4-nitrophenyl)propionic acid (obtained in Example 1, 50 mg, 0.2 mmol.). The solution was stirred for 18 hours at room temperature in a hydrogen gas atmosphere, after addition of 10% palladium/carbon (10 mg). Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give 55 mg (yield: quantitative amount) of the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[N:6]([C:13]1[C:14]([CH3:35])=[C:15]([CH3:34])[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH:18]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=4)[C:17]=3[C:32]=1[CH3:33])[C:5]2=O>CCCCCC>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[Cl:1])[CH2:5][N:6]([C:13]1[C:14]([CH3:35])=[C:15]([CH3:34])[C:16]3[O:20][C:19]([CH3:21])([CH3:22])[CH:18]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=4)[C:17]=3[C:32]=1[CH3:33])[CH2:7]2
Reactant: Cc1c(C)c(N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Product: Cc1c(C)c(N2Cc3cc(Cl)c(Cl)cc3C2)c(C)c2c1OC(C)(C)C2c1ccc(C(C)C)cc1
Yield: 16 %

Procedure:
By using 5,6-dichloro-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 16%. Melting point: 148-150° C. (Hexane)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39].CC#N.C(Cl)CCl>CC#N.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][C:36]([NH:35][C:32]5[CH:33]=[CH:34][C:29]([Cl:28])=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=5)=[N:27][C:22]=4[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1cc(Oc2ccnc(C(=O)NCCCCN3CCCC3)c2)ccc1O
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc3oc(Nc4ccc(Cl)c(C(F)(F)F)c4)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-Amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Example 253, Step E, 145 mg, 0.4 mmol, 1.0 eq.) was dissolved in CH3CN/DMF (2/1, v/v, 15 ml) and 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (as described in preparation III, 93 mg, 0.4 mmol, 1.0 eq.) as a CH3CN solution was added drop-wise. The reaction was stirred at RT for 16 h. EDC (75 mg, 0.4 mmol, 1.0 eq.) was added and the reaction was heated to 80° C. for 2 h. The mixture was concentrated and the crude product was purified by column chromatography (0-10% MeOH/CH2Cl2/1% NH4OH) to yield 4-[2-(4-chloro-3-trifluoromethyl-phenylamino)-benzoxazol-5-yloxy]-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide. MS m/z=574.2 (M+H)+ Calc'd for C28H27ClF3N5O3: 573.18.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(C(C)C)C(C)C)C.[C:32]([O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])(=[O:34])[CH3:33]>C1C=CC=CC=1>[C:32]([O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:39])(=[O:34])[CH3:33]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCOC(=O)CCCCNc1ccccc1-c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCN(C(=O)c1ccccc1OC(C)=O)c1ccccc1-c1ccccc1
Yield: 73.5 %

Procedure:
15.0 g of ethyl 5-(biphenyl-2-yl)aminovalerate is reacted, analogously to Example 47b), with 6.6 g of ethyldiisopropylamine and 10.0 g of o-acetoxybenzoylchloride in 70 ml of benzene to obtain, as reaction product, 17.0 g (73.4% of theory) of ethyl 5-[o-acetoxy-N-(biphenyl-2-yl)-benzamido]valerate as a viscous non-distillable oil. The saponification of this ester yields 9.1 g (63.2% of theory) of 5-[o-hydroxy-N-(biphenyl-2-yl)benzamido]valeric acid, MP 138° to 139°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][C:35](Cl)=[N:34][CH:33]=1.C1N2CCN(CC2)C1>>[CH3:29][O:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:34][CH:33]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, Step 4) was reacted with methyl-4,6-dichloronicotinate and DABCO (5 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.1 [M+H+].
Reaction SMILES: B.CSC.[CH3:5][C:6]([NH:9][C:10](=O)[CH:11]([OH:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)([CH3:8])[CH3:7].CO.Cl>O1CCCC1>[ClH:18].[Cl:18][C:14]1[CH:13]=[C:12]([CH:11]([CH2:10][NH:9][C:6]([CH3:8])([CH3:7])[CH3:5])[OH:19])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)NC(=O)C(O)c1cccc(Cl)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)NCC(O)c1cccc(Cl)c1

Procedure:
Borane-methyl sulphide (2.15g, 2.7ml, 4 equivs.) was added dropwise, under nitrogen, to a stirred solution of N-[1,1-dimethylethyl]-3-chloro-α-hydroxybenzene acetamide (1.71g) in dry tetrahydrofuran. The resulting solution was stirred and heated under reflux for 2h., cooled, and treated with methanol (1ml). The reaction mixture was heated under reflux for 1 h., cooled, treated with methanolic hydrogen chloride, and the solvent evaporated to give 3-chloro-α-[[[1,1-dimethylethyl]amino]methyl]benzenemethanol hydrochloride salt, 1.5g, m.p. 165-175° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:5])=[O:4].[C:14]([O:17][CH2:18][CH2:19]Br)(=[O:16])[CH3:15].Cl>O.CN(C=O)C>[N+:3]([C:6]1([CH2:12][O:13][CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])C1(CO)CCCCC1
Reactant: CC(=O)OCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COCC1([N+](=O)[O-])CCCCC1
Reaction time: 0.33 h

Procedure:
Under the nitrogen gas atmosphere, NaH (2.32 g, 58 mmol) was added in the DMF (70 mL) solution of (1-nitro-cyclohexyl)-methanol (6.96 g, 35 mmol) which had been obtained in 1) while cooling the solution with ice, and the mixture was stirred for 20 minutes while making the temperature rise naturally. Bromoethyl acetate (9.96 g, 58.0 mmol) was dropped, and the mixture was stirred at room temperature over-night. The reaction mixture was diluted with water (200 mL), 2M hydrochloric acid (20 mL, 40 mmol) was added, and the mixture was extracted with ethyl acetate (50 mL) two times. The organic layer was washed with 5% sodium bicarbonate aqueous solution (20 mL) and water (50 mL), and then dried with anhydrous sodium sulfate. The solvents were removed by distillation under reduced pressure, the residue was refined with silica gel column chromatography (Highflash 4L, manufactured by Yamazen Corporation, the mixture of hexane and ethyl acetate of 5:1 in mixing ratio), and pale yellow oily ethyl (1-nitro-cyclohexylmethoxy)-acetate (5.47 g, 57%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([F:24])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:25]([CH:27]1[CH2:30][CH:29]([C:31](Cl)=[O:32])[CH2:28]1)[CH3:26].C(C1CC(C(Cl)=O)C1)CCCCCCC>>[CH2:25]([CH:27]1[CH2:30][CH:29]([C:31]([O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([F:24])[CH:10]=3)=[CH:3][C:2]=2[F:1])=[O:32])[CH2:28]1)[CH3:26]
Reactant: CCC1CC(C(=O)Cl)C1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Agent: CCCCCCCCC1CC(C(=O)Cl)C1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)C3CC(CC)C3)c(F)c2)cc1F
Yield: 70.2 %

Procedure:
Except that 0.60 g of 3,3'-difluoro-4-hydroxy-4'-octyloxybiphenyl obtained in Example 5-(c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.3 g of 3-ethylcyclobutanecarboxylic acid chloride obtained in Example 13-(d) in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=4/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.56 g (yield 30.9%) of 3,3'-difluoro-4-octyloxybiphenyl-4'-yl 3-ethylcyclobutanecarboxylate.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][O:23][CH:24]([C:28]([NH:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26]>>[CH3:22][O:23][CH:24]([C:28]([NH:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:35])[F:36])=[O:29])[C:25]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:26]
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: COCCN1C(=O)[C@@H](NC(=O)C(OC)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (84%). White solid. MS: m/e=530(M+H+).