Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4C=CN=[C:24]4[CH3:28])=[CH:19][CH:18]=3)[CH:11]=2)[CH2:8][CH2:7][O:6][CH:5](C)[CH2:4]1)#[N:2].[CH3:29][C:30]1[CH:34]=C(C)N(C2C=CC(I)=CC=2)[N:31]=1.C(C1(C2C=CC=C(S[Si](C(C)C)(C(C)C)C(C)C)C=2)CCOCC1)#N.C(C1(C2C=CC=C(S[Si](C(C)C)(C(C)C)C(C)C)C=2)CCOC(C)C1)#N>>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:24]([CH3:28])=[CH:29][C:30]([CH3:34])=[N:31]4)=[CH:19][CH:18]=3)[CH:11]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOC(C)C3)c2)cc1
Reactant: Cc1cc(C)n(-c2ccc(I)cc2)n1
Agent: CC(C)[Si](Sc1cccc(C2(C#N)CCOCC2)c1)(C(C)C)C(C)C
Agent: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Product: Cc1cc(C)n(-c2ccc(Sc3cccc(C4(C#N)CCOCC4)c3)cc2)n1

Procedure:
The titled compound was prepared according to the procedure described in example 29E for the preparation of (2SR,4RS)-4-cyano-2-methyl-4-[3-[4-(2-methylimidazol-1-yl) phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran using 4-(3,5-dimethylpyrazol-1-yl)phenyl iodide and 4-cyano-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran in place of 4-(2-methylimidazol-1-yl)phenyl iodide and (2SR,4RS)-4-cyano-2-methyl-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran, respectively.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[C:16]([Cl:18])[CH:15]=[N:14]2)=[C:9]([Cl:19])[CH:8]=1)[CH3:6])C.O.[NH2:22][NH2:23].C(Cl)Cl>CN(C)C=O>[Cl:19][C:9]1[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([NH:22][NH2:23])=[O:3])[CH:12]=[CH:11][C:10]=1[N:13]1[CH:17]=[C:16]([Cl:18])[CH:15]=[N:14]1
Reactant: NN
Reactant: CCOC(=O)C(C)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)NN)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 2 h

Procedure:
To a solution of 3.13 g (10 mmoles) of 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic acid ethyl ester in 20 ml of dimethyl formamide there are added dropwise, at room temperature, 15 ml of hydrazine hydrate. Stirring is continued for a further 2 hours at room temperature, followed by pouring on to ice, extraction with methylene chloride, drying of the organic phase and concentration. 2-[3-chloro-4-(4-chloropyrazol-1-yl)phenyl]propionic hydrazide is obtained.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6](=O)[CH2:7][CH2:8][CH3:9])C.[C:12]1([NH:18][C:19]([NH:21][C:22]([NH2:24])=[NH:23])=[NH:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[O:11]=[C:4]1[NH:24][C:22]([NH:21][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[NH:20])=[N:23][C:6]([CH2:7][CH2:8][CH3:9])=[CH:5]1
Reactant: N=C(N)NC(=N)Nc1ccccc1
Reactant: CCCC(=O)CC(=O)OCC
Solvent: CCO
Product: CCCc1cc(=O)[nH]c(NC(=N)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxohexanoic acid ethyl ester (3.2 grams, 0.020 mol, obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added at room temperature to a solution of 1-phenylbiguanide (3.5 grams, 0.020 mol, prepared as described in Part D of Example I) in anhydrous ethanol (15 milliliters). The mixture was heated at reflux and stirred for 4 hours. After a few minutes, all the components dissolved. Cooling the resulting yellow solution mixture to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with water, then with cold ethanol (0° C.), and finally with acetone. The solid was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(6-oxo-4-propyl-1,6-dihydropyrimidin-2-yl)-N′-phenylguanidine as a colorless solid (3.90 grams, 72 percent yield): mp=196° C.; Exact mass calculated for C14H17N5O=271.1433. Measured High Resolution Mass Spectrum (MAB/HR/N2)=271.1431. Anal. Calcd for C14H17N5O: C, 61.98; H, 6.32; N, 25.81. Found: C, 62.32; H, 6.44; N, 25.68.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([NH:29][CH2:30][C@H:31]([NH:35][C:36](=[O:38])[CH3:37])[C:32]([OH:34])=[O:33])=[O:28])[CH2:22]2)=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.[Pd]>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([NH:29][CH2:30][C@H:31]([NH:35][C:36](=[O:38])[CH3:37])[C:32]([OH:34])=[O:33])=[O:28])[CH2:22]2)=[O:20])[CH2:13][CH2:12]1
Reactant: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1)C(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1)C(=O)O
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of N-[(R)-1-[3-(1-benzyloxycarbonyl-4-piperidyl)propanoyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine (0.5 g) 1N HCl (0.94 ml) and 10% Pd—C (0.1 g) in tetrahydrofuran (5 ml) was hydrogenated at atmospheric pressure for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was resolved in water, and neutralized with saturated aqueous NaHCO3, desalted by using the resin of HP-20 eluting with isopropanol:H2O=(1:1), then freeze-dried to give N-[(R)-1-[3-(4-piperidyl)propanoyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine (0.34 g, 91.0%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: BrCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cc2)CCCC1
Reaction time: 2 h

Procedure:
To a solution of 2-(4-bromophenyl)acetonitrile (1.0 g, 5.10 mmol) and 1,4-dibromobutane (0.67 ml, 5.6 mmol) in THF (10 ml) was added potassium bis(trimethylsilyl) amide (2.23 g, 11.2 mmol) and tetra-n-butylammonium bromide (164 mg, 0.51 mmol). The mixture was stirred for 2 h and then quenched with 1N HCl. Ethyl acetate was added, the layers separated and the organic layer was washed with water and brine. Drying, solvent evaporation and flash chromatography (silica gel, 20% EtOAc/hexanes) gave 1-(4-bromophenyl)cyclopentanecarbonitrile.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[CH2:9][N:10]=[N+:11]=[N-:12])=[O:5])C.[OH-]>CO.O>[N:10]([CH2:9][C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:5])=[O:3])=[N+:11]=[N-:12]
Reactant: CCOC(=O)[C@@H]1C[C@H]1CN=[N+]=[N-]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NC[C@@H]1C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A solution of trans-ethyl-2-azidomethyl-1-cyclopropane carboxylate (7.282 g, 37.13 mmol) in a mixture of methanol (20 ml) and water (10 ml) was cooled to 0° C. and treated dropwise with 40.8 ml of 1 M solution hydroxide in water (40.8 mmol). After the addition was completed the bath was removed and the solution was stirred at room temperature for 3 h. The methanol was evaporated under reduced pressure and the aqueous solution was extracted with ether (2×10 ml). After acidification with dilute hydrochloric acid (3 N), the aqueous phase was extracted with dichloromethane (4×25 ml) and the combined organic extracts washed with water (10 ml), brine (10 ml) and dried over anhydrous sodium sulfate. Evaporation of the solvent and distillation (bulb to bulb) of the residue under vacuum gave 4.830 g (92%) of a clear oil; bp 100°-108° C./0.6 mm Hg (air bath temperature); ir (film) νmax : 2095 (N3), 1695 cm-1 (C=O); 1Hmr (CDCl3) δ: 3.25 (2H, d, J=6, CH2N3), 2.0~0.6 (4H, m, cyclopropyl), 12.3 (1H, s, COOH). Anal. calcd for C5H7N3O2 : C 42.55, H 5.00, N 29.77; Found: C 42.55, H 4.89, N 29.75.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:8]=[C:7]([C:18](=[O:22])[NH:19][CH2:20][CH3:21])[CH:6]=1)C.[OH-].[Li+].C1COCC1>O>[CH2:20]([NH:19][C:18]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:8]=1)[C:4]([OH:23])=[O:3])=[O:22])[CH3:21]
Reactant: CCCN(C)C(=O)c1cc(C(=O)NCC)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)NCC)c1
Yield: 72.5 %

Procedure:
Stir a solution of 3-ethylcarbamoyl-5-(methyl-propylcarbamoyl)-benzoic acid ethyl ester (157 mg, 0.5 mmol), 1 N aqueous lithium hydroxide (2.45 mL, 2.45 mmol) and THF (2.45 mL) at room temperature overnight. Dilute the reaction with water and extract with dichloromethane. Acidify the aqueous with 5 N HCl, extract the aqueous with dichloromethane and dry (magnesium sulfate) and concentrate to give the title compound (106 mg, 74%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]=1[NH:17][C:18](=[O:36])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[NH:17][C:18](=[O:36])[CH2:19][CH:20]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Yield: 71.3 %

Procedure:
3.5 ml (7.0 mmol) of a 2 N aqueous solution of sodium hydroxide were added to a solution of 1.64 g (3.48 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 6) in 30 ml of methanol, and the resulting mixture was heated under reflux for 2 hours, after which the solvent was removed by distillation under reduced pressure. The residue was acidified with 2 N aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of ethyl acetate and hexane to give 1.13 g (yield 71%) of the title compound, melting at 153-154° C.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][CH2:25][CH2:26][CH3:27])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[BH4-].[Na+].CO.C(O)(=O)C>COC(C)(C)C.O1CCCC1.O>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][OH:2])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCOc1ccccc1C[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CO
Product: CCCCOc1ccccc1CC(CO)NC(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
3.9 g (11 mmol) of N-benzyloxycarbonyl-3-[2-butoxyphenyl]-alanine-methyl ester (Example a) is dissolved in 30 ml of tert-butyl methyl ether and mixed with 0.55 g (15 mmol) of sodium borohydride. At 3° C., 8 ml of methanol is added, and it is stirred for five hours at constant temperature. Then, 0.8 ml of acetic acid, dissolved in 3 ml of tetrahydrofuran, is added, mixed with 5 ml of water and stirred for ten minutes at room temperature. The organic phase is separated, washed with water and dried on sodium sulfate. The drying agent is suctioned off, the filtrate is concentrated by evaporation and the residue is chromatographed for purification on silica gel.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Cl:21])[NH:10][C:9]=2[C:8]([O:22]C)=[CH:7][CH:6]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
2-(2-chloro-4-fluoro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (3 g, 8.98 mmol) obtained in step 2 was dissolved in toluene and aluminum chloride (5.99 g, 44.90 mmol) was added thereto, refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (1.87 g, 6.11 mmol) in a yield of 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=O)[CH2:7]2.N1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:29]([NH2:33])(=[O:32])[CH:30]=[CH2:31]>C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[CH2:4][CH2:5][C:6]3[NH:33][C:29](=[O:32])[CH2:30][CH2:31][C:7]=3[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: C=CC(N)=O
Reactant: O=C1CCc2c(Cl)cccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Solvent: c1ccccc1
Product: O=C1CCC2=C(CCc3c(Cl)cccc32)N1

Procedure:
11.07 g of 5-chloro-2-tetralone were boiled at reflux for 2 hours in 200 ml of benzene and 10.1 ml of pyrrolidine in the presence of 0.3 g of p-toluenesulphonic acid. The crude 1-(5-chloro-3,4-dihydro-2-naphthyl)pyrrolidine obtained was treated, without purification, with 9.0 g of acrylamide and 0.5 g of p-toluenesulphonic acid. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. 250 ml of ethyl acetate and 50 ml of water were added to the reaction mixture, whereupon the insoluble constituents were filtered off, washed with ethyl acetate and water, dried and recrystallized from ethyl acetate. There was obtained 7-chloro-1,2,5,6-tetrahydrobenzo[f]quinolin-3(4H)-one of melting point 252°-253°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[C:10](OC)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[CH3:9][S:8][C:4]1[N:3]=[C:2]([CH2:1][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:17])[CH:7]=[CH:6][N:5]=1
Reactant: COC(=O)c1ccccc1
Reactant: CSc1nccc(C)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
A mixture of 4-methyl-2-methylthio-pyrimidine (30 g, 0.21 mol) and methyl benzoate (30 g, 0.21 mol) is added to a solution of potassium tert-butoxide (54 g, 0.48 mol) in tetrahydrofuran (350 ml) with cooling in such a way that the reaction temperature does not exceed +20° C. After stirring the mixture for additional 20 minutes the solution is poured onto crushed ice. The resulting solution is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Drying of the organic phase, filtering and evaporation of the solvent under reduced pressure gives the 2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethanone in form of a mixture of tautomers.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>ClCCCl>[Cl:9][CH2:10][C:11]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=1)=[O:12]
Reactant: Cc1nccc(N)n1
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Product: Cc1nccc(NC(=O)CCl)n1
Temperature: 80 °C
Yield: 7.5 %

Procedure:
2-Methyl-pyrimidin-4-yl amine (545 mg) was suspended in DCE (5 mL) and chloroacetylchloride (0.4 mL) was added dropwise. The reaction was heated in a microwave at 80° C. for 5 mins. The reaction mixture was cooled to give a solid that was filtered, washed with dichloromethane then suspended in dichloromethane and sat. NaHCO3 (aq) was added. The organic phase was collected and the aqueous layer extracted with dichloromethane (×2). The combined organic layer was dried over sodium sulphate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the sub-titled compound as a yellow solid (70 mg, 7.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH2:8][Br:32])[CH:7]=1
Reactant: COc1c(C)cc(Br)cc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C)cc(Br)cc1CBr
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(5-Bromo-2-methoxy-3-methylphenyl)methanol (2.0 g, 8.7 mmol) and triphenylphosphine (4.5 g, 17.4 mmol) were combined in tetrahydrofuran (30 mL) and cooled to 0° C. N-Bromosuccinimide (3.2 g, 17.4 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (hexanes) gave 1.87 g (73%) as a white powder. 1H-NMR (CDCl3, 300 MHz) δ 7.32-7.33 (m, 1H), 7.23-7.24 (m, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:20]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.08 (s, 1H), 7.85 (dd, J=7.1, 2.2 Hz, 1H), 7.65 (m, 2H), 7.57 (dd, J=5.0, 1.0 Hz, 1H), 7.52 (m, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.01 (m, 2H), 4.11 (d, J=15.4 Hz, 1H), 3.95 (d, J=15.4 Hz, 1H), 2.41 (m, 2H), 0.78 (t, J=7.0 Hz, 3H); MS (ES) m/z 400 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([C:12]([F:15])([F:14])[F:13])=[CH2:11])[CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([CH3:11])[C:12]([F:13])([F:14])[F:15])[CH:3]=1
Reactant: C=C(c1cc(F)ccc1OC)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: COc1ccc(F)cc1C(C)C(F)(F)F

Procedure:
4-Fluoro-1-methoxy-2-(3,3,3-trifluoroprop-1-en-2-yl)benzene (C42) (82 g, 370 mmol) was split into four batches; each batch was dissolved in methanol (200 mL), treated with 10% palladium on carbon (1 g, 10 mmol) and hydrogenated at 50 psi for 15 minutes. After careful filtration through Celite and rinsing of the filter pad with methanol, the four filtrates were combined and concentrated in vacuo, keeping the bath temperature at <25° C. The residue was dissolved in dichloromethane, filtered through Celite, and concentrated under reduced pressure, providing the product as a light yellow oil. Yield: 71.0 g, 320 mmol, 86%. 1H NMR (400 MHz, CDCl3) δ 1.42 (d, J=7.2 Hz, 3H), 3.83 (s, 3H), 4.06-4.19 (m, 1H), 6.84 (dd, J=9.0. 4.5 Hz, 1H), 6.98 (ddd, J=9.0, 7.8, 3.1 Hz, 1H), 7.06-7.11 (m, 1H).
Reaction SMILES: [OH-].[NH4+].O.[CH3:4][N:5]([CH3:25])[CH2:6][CH2:7][C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])[O:9]1.N>[Zn].C(O)C>[CH3:25][N:5]([CH3:4])[CH2:6][CH2:7][CH:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:18][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:10]([OH:11])=[O:9]
Reactant: CN(C)CCC1(c2ccccc2)Cc2ccccc2C(=O)O1
Agent: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)CCC(Cc1ccccc1C(=O)O)c1ccccc1

Procedure:
To a well stirred suspension of 45 g. of zinc dust, 90 ml. of concentrated ammonium hydroxide, 45 ml. of water and 2 ml. of cupric sulfate maintained at 80° C. there is added 14.75 g. (0.05 mole) of 3-(2-dimethylaminoethyl)-3,4-dihydro-3-phenylisocoumarin in 50 ml. ethanol for about 30 minutes. The resulting mixture is heated at 85° C. for 30 hours while a slow stream of ammonia is passed through. The mixture is filtered while under heat and the solids washed throughly with 100 ml. of hot ammonium hydroxide. The combined filtrates are cooled and carefully acidified with concentrated hydrochloric acid to give 2-(β-[-2-dimethylaminoethyl]phenethyl)benzoic acid, m.p. 152° to 154° C.
Reaction SMILES: Cl[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:28]=[C:29]([O:31][C@H:32]2[CH2:36][CH2:35][O:34][CH2:33]2)[CH:30]=1)[C:19]([NH:21][C:22]1[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=1)=[O:20].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:13][N:8]1[C:7](=[O:14])[C:6]2[CH:5]=[CH:4][C:3]([O:15][C:16]3[CH:17]=[C:18]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:19]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)=[O:20])=[CH:2][C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C)n4)c3)c2Cl)C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCOc2cc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C)n4)c3)ccc2C1=O
Yield: 68.5 %

Procedure:
3-[(9-Chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (150 mg, 0.29 mmol) was dissolved in ethanol (5 mL) and ammonium formate (147 mg, 2.33 mmol) was added in one portion. The reaction was blanketed with argon and 10% palladium on charcoal (10 mg) was added. The mixture was heated to 140° C. for a total of 55 minutes in a Smith Creator microwave reactor after which time a further 100 mgs of ammonium formate and 10 mgs of catalyst were added and the suspension heated for a further hour. The catalyst was filtered off and the volatiles removed in vacuo to give the crude product as a colourless oil. This residue was purified by reverse phase preparative HPLC, eluting with 5-95% acetoniltrile in water (+0.2% TFA), to give the title compound as a colourless foam (95 mg). 1H NMR δ (CDCl3): 2.12-2.19 (1H, m), 2.23-2.32 (1H, m), 3.23 (3H, s), 3.59 (2H, t), 3.88-3.91 (4H, m), 4.01 (3H, m), 4.42 (2H, t), 5.15-5.17 (1H, m), 6.61 (5H, d), 6.78-6.79 (1H, m), 6.80 (1H, t), 7.02 (1H, d), 7.33-7.36 (2H, m), 7.38-7.40 (1H, m), 7.85 (1H, d), 10.58 (1H, s); m/z 479 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(Cl)(Cl)[CH:16](O)[OH:17].C(Cl)(Cl)Cl>O>[CH:16]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1ccc(CCN)cc1OC
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(CCNC=O)cc1OC
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
First, 2-(3,4-dimethoxyphenyl)-ethylamine (181.2 g, 1 mol) and chloral hydrate (181 g, 1.1 mol) are mixed together and heated to 120° C., with stirring, for 20 minutes and any volatile components (chloroform and water) are eliminated in a water jet vacuum at an oil bath temperature of 140° C. An oil is left behind which is further processed without any purification.