Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1.[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C.C1(C)C=CC=CC=1>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:32]4[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=4)=[CH:23][C:6]=3[N:7]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1cnn(C)c1)C[C@H]2C
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1cnn(C)c1)C[C@H]2C
Temperature: 115 °C
Yield: 25.9 %

Procedure:
A mixture of (R)-8-bromo-1,4-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (38 mg, 0.1 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (44 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.02 mmol), potassium fluoride (5.8 mg, 0.1 mmol) and potassium carbonate (49 mg, 0.15 mmol) in a mixed solution of toluene (2 mL), ethanol (1 mL) and water (0.2 mL) was heated at 115° C. for 1.5 hours under microwave (pressure: 2.0 bar, equipment power: 150 W). The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane/methanol=8:1) to afford (R)-5-(1,4-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2-amine as a white solid (10 mg, 26%).
Reaction SMILES: [Mg].C([O:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13](Br)[CH2:14][CH2:15]Br)(=O)C.Cl>C1COCC1>[CH:13]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=2[OH:5])[CH2:14][CH2:15]1
Reactant: CC(=O)Oc1c(C)cccc1C(Br)CCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cccc(C2CC2)c1O
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
A 200 ml four-necked round-bottomed flask was equipped with a magnetic stirrer bar, a thermometer and a drying tube. Magnesium (498 mg, 20.5 mmol) and anhydrous THF (7 ml) were added thereto under a nitrogen atmosphere. The mixture was heated in an oil bath of 75° C. for 15 minutes (temperature of the mixture was 62-64° C.). Subsequently, the mixture was heated in an oil bath of 75° C. and a solution of 2-(1,3-dibromopropyl)-6-methylphenyl acetate (6.00 g, 17.1 mmol or less) in THF (21 ml) was added thereto over 20 minutes. The temperature of the mixture was raised to 70° C. After the mixture was stirred in an oil bath of 75° C. for 3 hours, the mixture was cooled and 6M hydrochloric acid (7.13 ml, 42.8 mmol) was added thereto over 5 minutes. After the mixture was stirred at room temperature for 1 hour, it was transferred to a 200 ml round bottom flask and most of THF was distilled off under reduced pressure. Methanol (15 ml) was added to the residue and the obtained mixture was stirred under heating at reflux for 9 hours. The mixture was cooled and methanol was distilled off under reduced pressure. Water (8 ml) was added to the residue and it was extracted with toluene (25 ml and 15 ml). The organic layer was combined and washed with water (20 ml), followed by concentration to obtain 2.69 g of a crude product of 2-cyclopropyl-6-methylphenol.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:25]=[O:26])[C:19]2[O:23][CH:22]=[CH:21][C:20]=2[CH:24]=1>O1CCCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:25]([C:18]2[C:19]3[O:23][CH:22]=[CH:21][C:20]=3[CH:24]=[C:16]([F:15])[CH:17]=2)[OH:26])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=Cc1cc(F)cc2ccoc12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cnc(Cl)nc1Cl)c1cc(F)cc2ccoc12
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 742.5 %

Procedure:
A solution of 5-bromo-2,4-dichloro-pyrimidine (1.0 g, 4.4 mmol, Aldrich) was dissolved in tetrahydrofuran (50 mL), cooled to −30° C., and treated slowly with isopropylmagnesium chloride (2.2 mL, 4.4 mmol, 2M in tetrahydrofuran, Aldrich). After stirring 0.5 hour between −30° C. and −25° C., the reaction was treated with a solution of 5-fluoro-benzofuran-7-carbaldehyde (0.65 g, 0.40 mmol, Step C) in tetrahydrofuran (10 mL). The temperature was slowly raised to −10° C. and then the reaction was quenched with aqueous 20% ammonium chloride. After 0.5 hours of stirring at ambient temperature, the mixture was diluted with hexane (100 mL), washed with water and dried (Na2SO4). Removal of solvent afforded crude (2,4-dichloro-pyrimidin-5-yl)-(5-fluoro-benzofuran-7-yl)-methanol as an oil. Purification was by silica gel chromatography (50% ethyl acetate/hexane) to give 930 mg of oil (˜70%). HRMS, observed: 311.9863; Calcd for (M+H)+: 311.9869
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[O:14][C:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]2)[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[C:21]([C:25]1[O:29][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[N:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22].[F-].[Cs+].O1CCOCC1>ClCCl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[C:21]([C:25]1[O:29][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:2]3[CH:7]=[CH:6][C:5]([C:8]45[O:14][C:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:12][CH2:13]4)[CH2:10][CH2:9]5)=[CH:4][CH:3]=3)=[CH:33][CH:32]=2)=[N:27][N:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1nnc(Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)o1
Reactant: COC(=O)CCC12CCC(c3ccc(Br)cc3)(CC1)O2
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)CCC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)O2
Temperature: 90 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a flask charged with methyl 3-(4-(4-bromophenyl)-7-oxabicyclo[2.2.1]heptan-1-yl)propanoate (103 mg, 0.30 mmol), 5-(tert-butyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadiazol-2-amine (109 mg, 0.32 mmol), Pd(amphos)Cl2 (21 mg, 0.030 mmol) and CsF (138 mg, 0.91 mmol) under N2 was added 1,4-dioxane (2.7 mL) and water (0.30 mL). The mixture was sparged with N2 for 10 min and stirred in a 90° C. oil bath for 2 h. The resulting reaction mixture was diluted with dichloromethane and washed with a saturated aqueous NaHCO3 solution. The organic layer was warmed and filtered (no product evident in filtercake). The filtrate was concentrated to afford 200 mg of crude orange solid. The crude material was washed with triturated with acetonitrile and filtered to afford 106 mg of pale orange solid which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.36 (s, 9H), 1.56-1.83 (m, 6H), 2.04-2.20 (m, 4H), 3.62 (s, 3H), 7.42 (d, J=8.6 Hz, 2H), 7.55-7.69 (m, 6H), 10.51 (s, 1H) (additional 2H signal likely hidden under DMSO solvent peak). ESI-MS m/z: 476.0 [M+H]+, retention time 1.55 min (condition E).
Reaction SMILES: O[CH2:2][C:3](=O)[CH2:4][CH3:5].[CH3:7][C:8]1([CH3:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]1=[O:15]>>[CH2:4]([C:3]1[C:10]2[C:11](=[O:14])[CH2:12][CH2:13][C:8]([CH3:16])([CH3:7])[C:9]=2[O:15][CH:2]=1)[CH3:5]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: CCC(=O)CO
Product: CCc1coc2c1C(=O)CCC2(C)C

Procedure:
The subtitle compound was prepared according to the procedure of example 2 using 1-hydroxy-2-butanone instead of acetol and 4,4-dimethyl-1,3-cyclohexanedione instead of 1,3-cyclohexanedione in step 1.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:25])[CH2:21][CH2:22][CH2:23]O)=[O:19])[N:9]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][S:34]([CH3:33])(=[O:36])=[O:35])=[O:19])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCCO)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCS(C)(=O)=O)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 0 °C
Yield: 69.9 %

Procedure:
To a solution of 1-(2-iodophenyl)-N-methyl-N-(3-hydroxypropyl)-3-isoquinolinecarbo-xamide (20 mg, 0.045 mmol), DMAP (5.5 mg, 0.045 mmol), and Et3N (0.02 mL, 0.14 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise MsCl (0.006 mL, 0.77 mmol). The resulting mixture was stirred at 0° C. and monitored by TLC. After stirring at 0° C. for 4 h, TLC showed that no starting material left. Then, it was transferred into separatory funnel and washed with H2O (15 mL) The organic layer was dried (MgSO4), and filtered. The filtrate was concentrated in vacuo. The residue was purified on column (silica gel, 2% MeOH/CH2Cl2, 0.1% Et3N), thereby affording an oil (16 mg, 68%). 1H NMR (CDCl3) d 2.12-2.22 (m, 2 H, CH2), 2.77, 3.06 (two s, total 3 H, --SO2Me), 3.17, 3.20 (two s, total 3 H, N--Me), 3.62-3.82 (m, 2 H, N--CH2), 4.15 (t, J=6.0 Hz, 1 H, CH2O), 4.39 (t, J=6.0 Hz, 1 H, CH2O), 7.19-7.27 (m, 1 H, aromatic), 7.39-7.41 (m, 1 H, aromatic), 7.48-7.64 (m, 3 H, aromatic), 7.73-7.79 (m, 1 H, aromatic), 7.96-8.05 (m, 2 H, aromatic), 8.12, 8.24 (two s, total 1 H, aromatic). HRFABMS Cacld. for C21H21ILiN2O4S: 531.0427 (M+Li)+. Found: 531.0443.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][O:17][P@@:18]([NH:27][C@@H:28]([CH3:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([OH:36])[C@:12]2([OH:38])[CH3:37])=[C:4]([O:39]C)[N:3]=1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[I-].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:39])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17][P@@:18]([NH:27][C@@H:28]([CH3:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:19])[C@@H:13]([OH:36])[C@:12]3([OH:38])[CH3:37])[C:9]=2[N:10]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)Oc2ccccc2)[C@@H](O)[C@@]1(C)O
Agent: [Ce+3]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Product: CC(C)OC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@](C)(O)[C@@H]1O)Oc1ccccc1
Temperature: 85 °C
Yield: 34.7 %

Procedure:
To a stirred solution of 133 (160 mg, 0.28 mmol) was added cerium(III)chloride heptahydrate (154 mg, 0.414 mmol) and sodium iodide (41 mg, 0.276 mmol) at room temperature (21° C.). The mixture was heated at 85° C. for 6 h. The solvent was evaporated and the residue was chromatographed using 0-15% methanol/dichloromethane gradient to give pure product 134 as a white solid (55 mg, 35% yield).
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]([CH2:17][NH2:18])[OH:16]>C(O)C>[CH2:8]([O:7][CH2:6][CH2:5][CH2:4][NH:18][CH2:17][CH2:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCO
Reactant: BrCCCOCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: OCCNCCCOCc1ccccc1
Temperature: 25 °C
Yield: 90 %

Procedure:
Sodium iodide (1.67 g, 11.1 mmol) was added to a solution of benzyl 3-bromopropyl ether (26.0 g, 111 mmol) and ethanolamine (35.0 g, 556 mmol) in ethanol (250 ml). The reaction mixture was heated at reflux for 1 h, then cooled to room temperature and evaporated under vacuum. The residue was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The aqueous layer was basified with 40% aq. sodium hydroxide solution and extracted three times with ethyl acetate. The organic phases were pooled, dried (MgSO4), filtered, and evaporated to afford the title compound (20.9 g, 90%). Light yellow liquid, MS (ISP)=210.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[C:11]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][C:21]3[C:22]4[C:27]([CH:18]=[CH:19][C:20]=3[CH:9]=[CH:8]2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1cccc2ccccc12
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Product: C1=CC(c2ccccc2)(c2ccccc2)Oc2c1ccc1ccccc21

Procedure:
The procedure of Step 2 of Example 1 was followed except that 1,1-diphenyl-2-propyn-1-ol was used in place of 1,1-bis(4-methoxyphenyl)-2-propyn-1-ol and 1-hydroxynaphthalene was used in place of methyl-4-dihydroxy-2-naphthoate to produce 2,2-diphenyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[Br:13][C:14]1[CH:25]=[CH:24][C:17]2[C:18](=O)[O:19]C(=O)[NH:21][C:16]=2[CH:15]=1>CCCCCC.O1CCCC1>[NH2:21][C:16]1[CH:15]=[C:14]([Br:13])[CH:25]=[CH:24][C:17]=1[C:18](=[O:19])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 104 ml) was added slowly to a stirred solution of 1,5-dimethyltetrazole (27.5 g) in dry tetrahydrofuran (500 ml) at -5° to 0° under nitrogen. After stirring for 1.5 hours, 7-bromo-1H-3,1-benzoxazine-2,4-dione (22.6 g) was added and stirring continued for 18 hours at room temperature and for 3.5 hours at 40° to 50°. The mixture was cooled to room temperature, industrial methylated spirit (15 ml) added and most of the solvents distilled off. The residue was added to water (200 ml) and acidified with 5N hydrochloric acid to pH 1. The resulting solid was collected by filtration and crystallised from ethyl acetate to give the novel compound 1-(2-amino-4-bromophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 159°-160°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:10].C(=O)(O)[O-].[Na+].[Br:23][CH2:24][C:25](Br)=[O:26]>C(Cl)(Cl)Cl>[Br:23][CH2:24][C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:26]
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1F
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (2-amino-5-bromophenyl)(2-fluorophenyl)methanone (15 g, 51.0 mmol) and sodium bicarbonate (12.85 g, 153 mmol) in CHCl3 (150 mL) was cooled in an ice bath to 0° C. A solution of 2-bromoacetyl bromide (4.89 mL, 56.1 mmol) was added drop-wise slowly and washed in with CHCl3 (30 ml). The cooling was removed and the mixture was stirred for 2 hr.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17](Cl)(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Product: CCCCCCCC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and octanoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(octanoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(octanoyloxy)-alpha-(isopropylaminomethyl) benzyl alcohol hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:29])([C:17](=[CH:26][CH2:27][OH:28])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:29])([C:17](=[CH:26][CH2:27][O:28][CH3:34])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCO)CCC12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCOC)CCC12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(3-Benzyloxy-2-ethyl-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-ylidene)-ethanol (0.62 g, 1.5 mmol) in 10 ml dry THF was cooled to 0° C. under nitrogen. NaH (0.08 g, 2 mmol of NaH 60% dispersion in mineral oil) was added portion wise and the solution stirred for 30 minutes before CH3I (0.19 ml, 3 mmol) was added dropwise. The solution was then allowed to warm to room temperature and stirred for 18 hours. After addition of water (20 ml) the organics were extracted with ethylacetate. The organic layer was washed with water, brine, dried over MgSO4 and the solvents were evaporated under vacuum. The crude oil was purified by chromatography (hexane/ethylacetate 20/1) to give 3-benzyloxy-2-ethyl-17-(2-methoxy-ethylidene)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene, 0.59 g (91%), as a colourless oil; 1H NMR (CDCl3, 270 MHz): 0.84 (s, 3H, CH3), 1.24 (t, J=7.4 Hz, 3H, CH3), 1.26-1.66 (m, 6H), 1.82-2.02 (m, 3H), 2.20-2.51 (m, 3H), 2.70 (q, J=7.4 Hz, 2H, CH2), 2.87 (m, 2H, H6), 3.36 (s, 3H, CH3O), 3.94 (m, 2H, CH2OMe), 5.06 (s, 2H, CH2Ph), 5.27 (m, 1H, CHCH2OH), 6.66 (s, 1H, ArH), 7.15 (s, 1H, ArH), 7.31-7.48 (m, 5H, Ph).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][CH:7]([CH3:19])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:18])[CH2:16][OH:17])=[CH:11][CH:10]=1>>[CH3:6][CH:7]([CH3:19])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:18])[CH2:16][OH:17])=[CH:13][CH:14]=1.[S:1](=[O:4])(=[O:17])([O-:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Agent: CC(C)Cc1ccc(C(C)CO)cc1
Product: NS(=O)(=O)[O-]

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 2-[4-(2-methylpropyl)phenyl]-propan-1-ol. The oil obtained was further purified as in Example 38 to give the title compound as a white solid, mp 61°-63° C. in 45% yield.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[CH2:7][CH:8]=[CH2:9].CCN(CC)CC>>[CH2:6]([N:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=1)[C:1](=[O:4])[CH:2]=[CH2:3])[CH2:7][CH:8]=[CH2:9]
Reactant: C=CC(=O)Cl
Reactant: C=CCCNc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Product: C=CCCN(C(=O)C=C)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Acryloyl chloride (0.7 g, 7.8 mmol) was added dropwise to a solution of But-3-enyl-(4-trifluoromethoxy-phenyl)-amine (1.2 g, 5.2 mmol) and Et3N (1.1 g, 10.4 mmol). The mixture was stirred at ambient temperature overnight. The mixture was extracted with DCM, washed with brine, dried over anhydrous Na2SO4. The solvent was removed by reduced pressure and the residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=10/1) to give N-But-3-enyl-N-(4-trifluoromethoxy-phenyl)-acrylamide (0.8 g, 54%). 1H NMR (300 MHz, CDCl3): δ 7.35-7.18 (m, 4H), 6.38-6.35 (m, 1H), 5.96-5.93 (m, 1H), 5.78-5.74 (m, 1H), 5.68-5.64 (m, 1H), 5.08-5.01 (m, 2H), 3.84 (t, 2H, J=7.5 Hz), 2.31-2.27 (m, 2H). LC-MS: [M+1]+ 286.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)CCCCn1ccnc1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(NCCCCCn1ccnc1)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52d, a solution of N-[1-(4-chlorophenyl)-1-methylethyl]-5-(imidazol-1-yl)pentanamide (5.1 g) in THF (125 ml) was reduced with BH3 /THF (63.7 ml of a 1M solution) to give N-[1-(4-chlorophenyl)-1-methylethyl]-5-(imidazol-1-yl)pentylamine as an oil, b.p. 195° C. (0.05 mmHg).
Reaction SMILES: C[O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1.[BrH:19]>>[BrH:19].[NH2:9][C:8]1[C:3]([OH:2])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(N)cccc1-c1cccc(C(=O)O)c1
Agent: Br
Product: Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Temperature: 120 °C
Yield: 88.8 %

Procedure:
2′-Methoxy-3′-amino-biphenyl-3-carboxylic acid 1e (2.5 g, 10.3 mmol) was dissolved in 100 mL of hydrobromic acid (40%). The reaction mixture was heated to reflux at 120° C. overnight, and the reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 3′-amino-2′-hydroxy-biphenyl-3-carboxylic acid hydrobromide 1f (2.4 g, 88.8%) as a khaki solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: Cc1ccc(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1F

Procedure:
The title compound was prepared from (3R)(+)-3-(tert-butoxycarbonylamino)pyrrolidine and 4-bromo-2-fluorotoluene using the procedure outlined for Description 11.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].I[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH3:21]
Reactant: CCI
Reactant: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(O)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CC(OC)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of (3-hydroxy-4-nitrophenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 115, 250 mg, 1.007 mmol), iodoethane (185 mg, 1.208 mmol) and potassium carbonate (278 mg, 2.014 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate diluted with ethyl acetate (60 mL). The organic phase was washed with water (20 mL×2), brine (20 mL) and dried over sodium sulphate. The solvent was concentrated in vacuo and the residue purified by silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as a yellow powder (230 mg, 84%).