Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([OH:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].[C:15](=O)([O-])[O-].[K+].[K+].ICI.Cl>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:14][CH2:15][O:13][C:12]=12)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Reaction time: 24 h

Procedure:
Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.93 g, 4.6 mmol) and potassium carbonate (3.2 g, 23.4 mmol) in acetone (25 mL) and dimethylformamide (25 mL). Add diiodomethane (6.3 g, 23.3 mmol). Heat to reflux. After 24 hours, cool in an ice bath, acidify with a 1 M aqueous hydrochloric acid solution (35 mL), and extract twice with ethyl acetate. Combine the organic layers and extract with brine. Dry over MgSO4, filter, and concentrate in vacuo to give methyl 3-methoxy-4,5-methylenedioxybenzoate.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:19]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:33]>ClCCl.C(OCC)C>[ClH:33].[N:19]1([C:12]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([NH:9][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH:11]=2)[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(Nc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(Nc1cc(N2CCCNCC2)ccc1[N+](=O)[O-])c1ccccc1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of t-butyl 4-(3-(1-phenylethylamino)-4-nitrophenyl)-1,4-diazepane-1-carboxylate (0.1 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 2 h. The solvent was removed by rotary evaporation to afford the title compound (68%). 1H NMR (400 MHz, CD3OD): δ 7.99 (d, 1H), 7.52 (m, 5H), 6.36 (d, 1H), 5.86 (s, 1H), 4.75 (m, 1H), 3.52 (m, 2H), 3.45 (m, 2H), 3.17 (m, 4H), 1.81 (m, 2H), 1.60 (d, 3H); MS (ESI) m/z: Calculated: 376.8; Observed: 341.5 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23]Br>>[Br:21][CH2:22][CH2:23][O:13][C:10]1[CH:11]=[CH:12][C:4]2[O:3][C:2]([CH3:14])([CH3:1])[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=1
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)NC(=O)c2cc(OCCBr)ccc2O1

Procedure:
A mixture of 48.2 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 70 g of potassium carbonate and 250 ml of 1,2-dibromoethane is refluxed for 4 hours whilst stirring. The semi-liquid reaction mixture is extracted 3 to 4 times whilst hot with 1 liter of methanol each time; the combined methanol extracts are concentrated by evaporation and the residue is recrystallised from methanol. 6-(2-Bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one having a melting point of 190°-195° is obtained.
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.Br[C:19]1[CH:20]=[C:21]([CH3:26])[C:22]([Cl:25])=[N:23][CH:24]=1>>[Cl:25][C:22]1[N:23]=[CH:24][C:19]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)=[CH:20][C:21]=1[CH3:26]
Reactant: Cc1cc(Br)cnc1Cl
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Product: Cc1cc(N2C[C@H]3CN(C(=O)OCc4ccccc4)C[C@H]32)cnc1Cl
Yield: 11 %

Procedure:
The product of Example 52D (1.30 g, 5.60 mmol) and 5-bromo-2-chloro-3-methylpyridine (1.73 g, 8.39 mmol) were processed according to the procedure described in Example 1E. The crude product was purified by chromatography (SiO2, ethyl acetate:hexane, 1:1) to provide the title compound (0.22 g, 11% yield) which was used directly in the next step without further purification. MS (DCI/NH3) m/z 358, 360 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)N)=[CH:5][CH:4]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O.S(=O)(=O)(O)O>O1CCOCC1>[CH3:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=3[C:25]3[CH2:24][NH:23][CH2:28][CH2:27][C:26]2=3)=[CH:5][CH:4]=1
Reactant: O=C1CCCCN1
Reactant: COC(=O)c1ccc(N(N)CCc2ccc(C)nc2)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc(CCn2c3c(c4cc(C(=O)O)ccc42)CNCC3)cn1
Reaction time: 2 h

Procedure:
A mixture of Methyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate hydrochloride (0.15 gm, 0.447 mol), piperidone (0.13 gm, 1.34 mol) and 7% sulfuric acid in dioxane (5 mL) was heated at 100 deg C. for 2 h. Reaction mass was cooled and concentrated under reduced pressure to give crude 2,3,4,5-tetrahydro-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole-8-carboxylic acid (LCMS; 44% of desired peak) as a brown colored oil which is submitted for purification by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCC1CCN(c2ccc(Br)cc2)CC1
Yield: 19.8 %

Procedure:
6.19 g (21.90 mmol) of 1-bromo-4-iodobenzene, 5.00 g (21.90 mmol) of tert-butyl (2-piperidin-4-ylethyl)carbamate, 9.98 g (60.66 mmol) of caesium carbonate and 0.54 g (0.88 mmol) of BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) suspended in 100 mL of toluene are placed under an inert atmosphere. 0.098 g (0.44 mmol) of palladium diacetate is then added. The reaction mixture is then refluxed for 6 hours. 0.045 g (0.20 mmol) of palladium diacetate and 0.25 g (0.40 mmol) of BINAP are added and the mixture is left to stir at reflux for 12 hours. The reaction medium is allowed to cool, and ethyl acetate and water are added. The aqueous phase is separated out and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia to give 1.66 g of expected product in the form of a white solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>>[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: Fc1cccc(CBr)c1F
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1cccc(F)c1F
Yield: 77.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 580 mg of indole-4-carbaldehyde and 911 mg of 2,3-difluorobenzyl bromide in place of the benzyl bromide used in Example 1 to give 841 mg of 1-(2,3-difluorobenzyl)indole-4-carbaldehyde as pale brown crystals. The yield thereof was found to be 76%.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)C.Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1.C(O)(=O)C.[OH-].[Na+]>O.O1CCOCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:6]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[N:5][CH:4]=[N:2]2)=[CH:18][CH:17]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)C=NC(=O)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-n2ncnc2-c2ccncc2)cc1
Reaction time: 8 h

Procedure:
A 6.0 g. portion of N-(dimethylaminomethylene)isonicotinamide is added to a mixture prepared by adding 6.05 g. of p-fluorophenylhydrazine hydrochloride to 80 ml. of 30% aqueous acetic acid, 40 ml. of p-dioxane and 7.5 ml. of 5 N sodium hydroxide. The mixture is heated to reflux for 1.5 hours, poured into water and allowed to stand overnight. Extraction with ether gives a dark solid which is recrystallized from acetone-hexane giving 1.7 g. of the desired product, mp. 114°-115° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([OH:33])=O)[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:37]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19][C@H:18]2[C:31]([NH2:37])=[O:33])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(=O)O)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A 3 L round bottom flask was charged with (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC.HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol), and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled into the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; this ammonia addition was repeated and the reaction was stirred for an additional 10 min. Water was added. The organic phase was washed with sat. NaHCO3, NaH2PO4, and brine before being concentrated in vacuo. The residue was slurried with acetonitrile (0.5 L) and then concentrated in to give (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxamide as a white solid (75.9 g, ˜100%), which was used in the next step without further purification. LC/MS for primary peak: [M-Boc+H]+=375.3; [M+H]+=475.4; [M-tBu+H]+=419.3. 1H-NMR (400 MHz, d-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H), 3.70 (m, 1H), 3.6 (m,1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9-2.05 (m, 2H), 1.65-1.9 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:22][CH:21]=2)[CH2:10][CH2:9][CH2:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CC1CCCN(C(=O)c2ccc(C3CCCCC3)cc2)c2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CCCN(C(=O)c2ccc(C3CCCCC3)cc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 5-ethoxycarbonylmethyl-7-chloro-1-(4-cyclohexyl-benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (2 g) in ethanol (20 ml) is added a 5N aqueous sodium hydroxide solution (5 ml), and the mixture is stirred at room temperature overnight. The reaction solution is acidified with hydrochloric acid, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated to remove the solvent to give 5-carboxymethyl-7-chloro-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) in colorless amorphous.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:15])=[CH:6][C:5]=1[CH2:27][OH:28].O.Cl>C1COCC1>[CH:3]([C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[O:15])=[CH:6][C:5]=1[CH2:27][OH:28])=[O:2]
Reactant: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nc2c(cc1CO)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 0.25 h

Procedure:
A solution of 7-(dimethoxymethyl)-6-(hydroxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 14, 18 mg, 0.042 mmol) in THF (0.8 ml) was treated with water (0.6 ml) and conc. HCl (0.2 ml) and stirred for 15 min. The reaction mixture was quenched by addition of sat. aq. NaHCO3 (gas evolution), extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was triturated with EtOAc/heptanes 10:1, filtered and dried under vacuum to give the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>Cl.O.C(Cl)Cl>[N:7]([C:6]1[CH:8]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[CH3:9])=[N+:14]=[N-:15]
Reactant: Cc1ccc(I)cc1N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(I)cc1N=[N+]=[N-]
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A cold (0° C.) suspension of 5-iodo-2-methylaniline (7.0 g, 0.03M) in HCl (5M, 30 ml) was treated dropwise with a solution of sodium nitrite (2.28 g, 0.033 mmol) in water (3 ml) over 20 minutes. The solution was stirred for 20 minutes before sodium azide was added portionwise over 15 minutes. The mixture was stirred for 30 minutes then poured into water. The mixture was diluted with DCM and the pH adjusted to 7 by the addition of Na2CO3. The phases were separated and the organic layer was dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography (silica, 5% Et2O/hexanes followed by 10% EtOAc/Hexanes) to give the azide (5.1 g, 64%). 1H NMR (500 MHz, CDCl3): δ 2.14 (3H, s), 6.88 (1H, d, J 7.9), 7.35 (1H, d, J 7.9), 7.39 (1H, d, J 1.3).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][N:23]=[C:24]2[O:27]C)=[CH:19][C:18]=1F.Cl>>[NH2:1][CH:2]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:3]1[CH2:4][CH2:5][CH:6]([O:9][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:17]=2[Cl:16])[C:24](=[O:27])[NH:23][CH:22]=[CH:21]3)[CH2:7][CH2:8]1
Reactant: COc1nccc2cc(F)c(Cl)cc12
Reactant: NC(c1ccccc1)C1CCC(O)CC1
Agent: Cl
Product: NC(c1ccccc1)C1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Yield: 11.4 %

Procedure:
Example 40 was synthesized using the reaction sequence as described for the synthesis of Example 1. 240 mg of 4-(amino-phenyl-methyl)-cyclohexanol (123) and 272 mg of 7-chloro-6-fluoro-1-methoxy-isoquinoline (10) were used to give 51 mg of Example 40 as its hydrochloride. Rt=1.34 min (Method 10). Detected mass: 383.1 (M+H+). 28 mg of the other isomer of 4-(amino-phenyl-methyl)-cyclohexanol (Example 128) were also isolated as its hydrochloride. Rt=1.31 min (Method 10). Detected mass: 383.1 (M+H+). Separation of the two isomers was accomplished by silica gel chromatography after coupling of aminoalcohol 123 and 10. Relative stereochemistry was not assigned.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (232 mg, 0.80 mmol) and 3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K10) (270 mg, 0.82 mmol) according to the general procedure M. Obtained as a yellow foam (287 mg, 66%).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][C:2]1=[O:12].[BrH:13].C(O)(=O)C>O>[Br:13][CH2:4][CH2:5][C:6]1([CH2:1][C:2]([OH:3])=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CC2(CCCCC2)CCO1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC1(CCBr)CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 3-oxaspiro[5.5]undecan-2-one (16.9 g)was added a 30% hydrogen bromide/acetic acid solution (75 mL). The reaction solution was stirred at room temperature for 48 hours. Water was added to the solution, and the crystals thus separated were recovered by filtration and washed with water. The resulting crystals were dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure to give crude crystals. The crude crystals thus obtained were recrystallized from ethyl acetatehexane to give the title compound (20.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.Cl[C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:22])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:6][C:7]=1[O:8][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]
Reactant: O=C(Cl)N1CCCCC1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(=O)N3CCCCC3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with N-chlorocarbonyl-piperidine and sodium hydride in dimethylformamide there is obtained {2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenyl}-1-piperidinecarboxylate, 1 -NMR (CDCl3, 400 MHz): 7.33 ppm (d,1H), 7.25 ppm (d,1H), 6.34 ppm (s,1H), 3.57°-3.69 ppm (m,2H), 3.53 ppm (d,3H), 3.44°-3.56 ppm (m,2H), 1.56°-1.70 ppm (m,6H);
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:14][CH:13]=1
Reactant: Cc1ccc(N)cc1
Reactant: CSc1ccc(C#N)cc1
Product: CSc1ccc(C(=N)Nc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (2.50 g, 16.78 mmol) and 4-methylaniline (1.789 g, 16.78 mmol) by following the procedure described in preparation 1, (2.05 g, 47.6%, purity 79% by HPLC), mp 143-145° C. 1H-NMR (CDCl3):δ 2.33 (s, 3H), 2.52 (s, 3H), 4.75 (bs, 2H, D2O exchangeable), 6.87-6.89 (d, 2H), 7.14-7.16 (d, 2H), 7.27-7.29 (d, 2H), 7.7-7.79 (d, 2H). MS m/z: 257.1(M+).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 56 %

Procedure:
As described for example 344 g, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (120 mg, 56%) which was obtained as a white solid. MS: m/e=372.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[BH4-].[Na+]>O1CCOCC1.C(O)C.O>[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[O:18][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)N=C1c1ccccc1
Reactant: Nc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC1(C)N=C(c2ccccc2)C(c2ccc(N)cc2)O1

Procedure:
48 g of 2,2-dimethyl-3-phenyl-2H-azirine and 18.5 g of p-aminobenzaldehyde were exposed to light for 2 hours in 6 liters of 1,4-dioxane in the manner described in Example 1. The solvent was then removed in a water-jet vacuum and the oily residue was chromatographed on silica gel, the elution was carried out with dichloromethane. The thus-obtained crude product (60 g) was stirred in ethanol for 2 hours at room temperature together with 1.8 g of sodium borohydride. The mixture was then diluted with water and extracted with dichloromethane. The crude product obtained after drying and evaporation of the organic phase was purified by pressure chromatography (6 bar) on silica gel with dichloromethane/ether (3:1), whereby there was obtained a product which, after 2-fold recrystallization from ethanol, yielded 5-(p-aminophenyl)-2,2-dimethyl-4-phenyl-3-oxazoline having a melting point of 162°-163° C. after drying for 4 hours 90° C. and 13 Torr.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].CN(C=O)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[S:20][C:21]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:22][CH:23]=2)=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(-c2cccs2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Sulfuryl chloride (0.32 g, 2.34 mmol) was added dropwise a stirred solution of dry DMF (0.18 ml, 2.34 mmol) at 0° C. under an argon atmosphere resulting in the formation of a white solid. After 15 min, 2-(4-methoxy-phenyl)-thiophene (0.38 g, 2 mmol) was added and the mixture was warmed to 100° C. and the melt was further stirred for 45 min. Crushed ice was added and the reaction mixture was extracted with ethyl acetate (2×) and the combined organic extracts were washed with water, brine, dried (MgSO4.2H2O) filtered and concentrated under reduced pressure. The crude, green solid was purified over silica gel (ethyl acetate/n-heptane 1:9): green solid, 0.13 g (18%).