Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:11][C@@H:12]([CH2:14][OH:15])[CH3:13].[BH4-].[Na+].O>CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:11][C@H:12]([CH3:13])[CH2:14][OH:15])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[C@@H](N)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CN[C@H](C)CO)cc1
Temperature: 0 °C
Yield: 100 %

Procedure:
4-Anisaldehyde (18.1 g, 133 mmol) was added to a solution of D-alaninol (10 g, 133 mmol) in methanol (100 ml) with vigorous stirring and the mixture was stirred for 30 minutes. Sodium borohydride (5.0 g, 132 mmol) was added to the ice-cooled solution and stirred for one hour at room temperature. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate. Removal of the solvent under reduced pressure afforded (2R)-2-(4-Methoxybenzylamino)-propan-1-ol (26 g, 133 mmol, 100%) as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH:4]=[CH:5][C:6]1[N:7]=[C:8]([Br:11])[S:9][CH:10]=1.[OH-].[Li+]>O1CCCC1.O>[Br:11][C:8]1[S:9][CH:10]=[C:6]([CH:5]=[CH:4][C:3]([OH:12])=[O:2])[N:7]=1
Reactant: COC(=O)C=Cc1csc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=Cc1csc(Br)n1
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Dissolve 3-(2-bromo-thiazol-4-yl)-acrylic acid methyl ester (5.9 g, 23.78 mmol) in tetrahydrofuran (48 mL) and add a solution of lithium hydroxide (636 mg, 26.16 mmol) in water (10 mL). Stir the mixture overnight. Extract the mixture with ethyl acetate and wash twice with water. Acidify the aqueous layer with 1N HCl in water until the mixture is at pH 3-4. Filter the resulting white solid, then wash the solid with ethyl acetate, followed by diethyl ether and then water. Dry the white solid to give 5.05 g (91%) of the desired material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: COc1ccc(O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(OCC(O)CCc2cccnc2)cc1OC
Yield: 6.6 %

Procedure:
Prepared according to the method described in Example 24b) from 3,4-dimethoxyphenol (0.77 g), (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g) and sodium hydroxide (0.2 g) in ethanol (45 ml) and water (5 ml) with heating at reflux for 1 hour. After work up the residue was purified by column chromatography over silica eluting with hexane:acetone (2:1) to give the title compound as a colourless oil (0.10 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH3:14][NH2:15]>C(O)C>[CH3:14][NH:15][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: BrCCCn1ccc2ccccc21
Reactant: CN
Solvent: CCO
Product: CNCCCn1ccc2ccccc21
Reaction time: 6 h

Procedure:
3 g of 1-(3-bromopropyl)indole were treated with a 33% solution of methylamine in ethanol. The resulting solution was stirred for 6 hours. The solvent was evaporated and the residue was dissolved in 50 ml of dichloromethane and washed with a saturated sodium bicarbonate solution. The organic phase was dried and evaporated to give 2.30 g of 1-(3-methylaminopropyl)indole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].[CH2:23]([O:30][C@H:31]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]([CH2:43]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:23]([O:30][C@H:31]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:33]([CH2:43][O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH2:32]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(CCc2ccccc2OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)c1
Yield: 59.2 %

Procedure:
Following a procedure similar to that described in Example 40(a), 400 mg of 2-[2-(3-methylphenyl)ethyl]phenol (prepared as described in Preparation 25), 232 mg of potassium t-butoxide and 870 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine were reacted in 25 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 560 mg (yield 59%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[H-].[Na+].[CH3:26]I>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:26])[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: C=C=CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C=CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)C(C)C)cc1
Reaction time: 15 h
Yield: 83.9 %

Procedure:
A solution of product from Example 11 (400 mg, 1.18 mmol) in tetrahydrofuran (10 ml) was added to a suspension of 60% sodium hydride (57 mg, 1.42 mmol) in tetrahydrofuran (2 ml) and the resulting mixture was stirred for 30 minutes, at which time methyl iodide (335 mg, 2.36 mmol) was added. The resulting mixture was stirred for 15 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and the crude residue was purified by flash chromatography to give 350 mg (84%) of the product.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1.[Li]CCCC.C[O:17][B:18](OC)[O:19]C>Cl.C(OCC)(=O)C>[F:10][C:4]1[CH:3]=[CH:2][C:9]([B:18]([OH:19])[OH:17])=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: OCc1ccc(Br)cc1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: OCc1cc(B(O)O)ccc1F
Temperature: 21 °C
Reaction time: 0.42 h

Procedure:
To a solution of 4-bromo-2-fluoro-benzyl alcohol (10 g, 49 mmol) in TBF (500 mL) at −78° C. was added BuLi (2.5M, 43 mL, 107 mmol) dropwise keeping the internal temperature below −73° C. After 25 min., trimethylborate (25 mL, 107 mmol) was added and the resulting reaction mixture stirred for 15 h at −78° C., 1 h at 21° C., then diluted with HCl 10% and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. The residue was solidified from hexane/ethyl acetate with water (5 drops) to afford the 4-fluoro-3-hydroxymethyl-benzene-boronic acid compound as a white solid.
Reaction SMILES: Br.Br[CH:3]1[C:8](=[O:9])[CH:7](Br)[C:6]([CH3:12])([CH3:11])[NH:5][C:4]1([CH3:14])[CH3:13].[OH-].[K+].[OH-].[NH4+:18]>>[C:8]([CH:7]1[CH2:14][C:4]([CH3:3])([CH3:13])[NH:5][C:6]1([CH3:11])[CH3:12])(=[O:9])[NH2:18]
Reactant: [NH4+]
Reactant: CC1(C)NC(C)(C)C(Br)C(=O)C1Br
Agent: Br
Agent: [K+]
Agent: [OH-]
Product: CC1(C)CC(C(N)=O)C(C)(C)N1

Procedure:
3,5-Dibromo-4-oxo-2,2,6,6-tetramethylpiperidine (II, 30 gm) was added slowly, with stirring, to ammonium hydroxide (500 mL). When the solid is dissolved, potassium hydroxide is added, which results in the precipitation of (III). After filtering the solid, additional potassium hydroxide is added to the remaining solution until the precipitation of more material no longer is observed. The precipitates are combined, dried and recrystallized from benzene, giving a white solid (III, 10 gm, 68%) mp 176°-178° C. (lit ref. [1, except pg. 204] mp 180°-181° C). Both I.R. and NMR confirm the structure of (III).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].S(=O)(=O)(O)O.II.[I:21](O)(=O)(=O)=O>C(O)(=O)C.O>[I:21][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][CH:10]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CS(=O)(=O)NCCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)NCCc1ccc(I)cc1
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 300.1 %

Procedure:
To a stirring room temperature solution of N-(methylsulfonyl)-N-(2-phenylethyl)amine (205 g, 1.03 moles), water (200 mL), 95% sulfuric acid (111 g, 1.08 moles) in acetic acid (1 L), was added iodine (111 g, 0.438 mol) and periodic acid (45.6 g, 0.206 mol). The reaction mixture was warmed to 70-75° C. for 3 h. The heat was removed and the dark violet reaction mixture was allowed to proceed overnight at room temperature. Potassium hydroxide pellets (85%, 143 g, 2.16 moles) were added to neutralized the sulfuric acid and then enough saturated aqueous sodium sulfite was added to decolorize the mixture to afford a white suspension. The suspension was cooled to 15° C. and filtered. The filter cake was triturated thoroughly with water and was then dissolved in CH2Cl2 (1 L) and extracted with additional water (2×200 mL). The organic phase was concentrated under reduced pressure to provide N-(2-(4-iodophenyl)ethyl)-N-(methylsulfonyl)amine, (201 g, 60.2%) as a white powder. 1H NMR (300 MHz) 7.64 (d, 2H, J=4.8), 6.97 (d, 2H, J=5.1), 4.37 (br t, 1H, J=4), 3.36 (app. q, 2H, J=3.9), 2.85 (s, 3H), 2.82 (t, 2H, J=3.9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:10][CH3:11])[C:7]=1[CH2:8]O.[Br:12]P(Br)Br>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:6]([CH2:10][CH3:11])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: CCc1cncc(Cl)c1CO
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCc1cncc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-chloro-5-ethylpyridin-4-yl)methanol (1.83 g, 10.66 mmol) in anhydrous chloroform (40 mL) was added dropwise tribromophosphane (2.91 g, 1.01 mL, 10.75 mmol) at 0° C. The reaction mixture was allowed to stir overnight at room temperature. The solvent was then evaporated to provide crude 4-(bromomethyl)-3-chloro-5-ethylpyridine, which was used for the next step without any further purification.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH3:11][CH:12]([CH3:16])[CH2:13][CH2:14][OH:15]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:14][CH2:13][CH:12]([CH3:16])[CH3:11])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:14][CH2:13][CH:12]([CH3:16])[CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)CCO
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn](CCCC)(OCCC(C)C)O[Sn](CCCC)(CCCC)OCCC(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
688 g (3.0 mol) of di-n-butyl tin oxide (Sankyo Organic Chemicals Co., Ltd., Japan) and 2222 g (25.0 mol) of 3-methyl-1-butanol (Kuraray Co., Ltd., Japan) were placed in a 5000 mL volumetric pear-shaped flask. The flask was connected to an evaporator (R-144, Shibata Co., Ltd., Japan) to which was connected an oil bath (OBH-24, Masuda Corp., Japan) equipped with a temperature controller, a vacuum pump (G-50A, ULVAC Inc., Japan) and a vacuum controller (VC-10S, Okano Seisakusho Co., Ltd.). The purge valve outlet of this evaporator was connected to a line containing nitrogen gas flowing at normal pressure. After closing the purge valve of the evaporator to reduce pressure inside the system, the purge valve was opened gradually to allow nitrogen to flow into the system and return to normal pressure. The oil bath temperature was set to about 145° C., the flask was immersed in the oil bath and rotation of the evaporator was started. After heating for about 40 minutes in the presence of atmospheric pressure nitrogen with the purge valve of the evaporator left open, distillation of 3-methyl-1-butanol containing water began. After maintaining in this state for 7 hours, the purge valve was closed, pressure inside the system was gradually reduced, and excess 3-methyl-1-butanol was distilled with the pressure inside the system at 74 to 35 kPa. After the fraction no longer appeared, the flask was taken out of the oil bath. After allowing the flask to cool to the vicinity of room temperature (25° C.), the flask was taken out of the oil bath, the purge valve was opened gradually and the pressure inside the system was returned to atmospheric pressure. 1290 g of reaction liquid were obtained in the flask. Based on the results of119Sn-, 1H- and 13C-NMR analyses, 1,1,3,3-tetra-n-butyl- 1,3-bis(3-methylbutyloxy) distannoxane was confirmed to have been obtained at a yield of 99% based on di-n-butyl tin oxide. The same procedure was then repeated 12 times to obtain a total of 11368 g of 1,1,3,3-tetra-n-butyl-1,3-bis(3-methylbutyloxy) distannoxane.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:32]=[CH:31][C:10]([O:11][C@H:12]([C@H:14]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH3:13])=[CH:9][CH:8]=1.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C>O1CCCC1>[Si:24]([O:23][C@H:14]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:12]([CH3:13])[O:11][C:10]1[CH:31]=[CH:32][C:7]([B:37]([OH:38])[OH:36])=[CH:8][CH:9]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyllithium (3.95 ml, 1.7M in hexanes) was added over a 1 hour period to a solution of (2S,3R)-2-(4-bromophenoxy)-3-tert-butyldimethylsilyloxy-5-pyridin-3-ylpentane (2.518 g, Example 15e)) and tri-isopropylborate (1.68 ml) in tetrahydrofuran (20 ml) at -78° C. The resulting solution was stirred at -78° C. for 2 hours and was then quenched by the addition of a saturated solution of ammonium chloride in water (50 ml). The mixture was poured into water (50 ml) and extracted into ethyl acetate (2×50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate and then ethyl acetate:methanol (4:1) to afford the sub-title compound as a foam (1.22 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([C:26](Cl)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([C:26]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:27])[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cccs1
Yield: 69.7 %

Procedure:
To a solution of 10.0 g (41.5 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 27.7 ml (200 mmol) of triethylamine in 10.0 ml of methylene chloride, 5.35 ml (50.0 mmol) of 2-thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:20) to obtain powder. The powder was recrystallized from methanol/ethyl acetate (=1:20) to obtain 8.05 g of the desired compound (yield: 70.5%, yellow prisms).
Reaction SMILES: [C:1]([N:4]([CH2:6][C:7]([OH:9])=[O:8])[CH3:5])(=O)C.[P:10]([OH:13])([OH:12])[OH:11].Cl.C=O>>[P:10]([CH2:1][N:4]([CH3:5])[CH2:6][C:7]([OH:9])=[O:8])([OH:13])([OH:12])=[O:11]
Reactant: OP(O)O
Reactant: CC(=O)N(C)CC(=O)O
Agent: C=O
Agent: Cl
Product: CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Reaction time: 19 h
Yield: 99 %

Procedure:
N-acetyl sarcosine (XX) (20.0 g, 152.5 mmole), phosphorous acid (12.59, 152.4 mmole), and concentrated HCl (37.6 g) were mixed and refluxed in a 120° C. oil bath. Formalin, 37% (13.6 g, 167.6 mmole) was added dropwise over 20 min. and the reaction was continued for an additional 19 h. HPLC analysis indicated a-99% yield of N-methylglyphosate (XXI) based on moles of (XX) charged.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CS(C)=O>[CH3:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: CSc1ncnc2c(N3CCCCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: CSc1ncnc2c(N3CCCCC3)nc(N3CCNCC3)nc12

Procedure:
2.0 g (6.8 mmol) of 2-chloro-8-methylthio-4-piperidino-pyrimido[5,4-d]pyrimidine is dissolved warm in 70 ml of dimethylsulphoxide and stirred with a solution of 6 g of piperazine in 70 ml of dimethylsulphoxide for 1 hour at ambient temperature. Then the solution is poured into 1 liter of water, the precipitate obtained is suction filtered and washed with water. The residue is taken up in 50 ml of methylene chloride and extracted with 50 ml of 0.05N sodium hydroxide solution. The organic phase is separated off, dried over sodium sulphate and concentrated in a rotary evaporator.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:20][C:21]([CH3:23])=[O:22])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1.Cl[C:25]1C=C2C(=CC=1)C1N(COCC[Si](C)(C)C)C(C3C(C#N)=CC=CC=3C#N)=NC=1C1C=CC(CC(=O)C)=CC2=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:20][C:21]([CH3:25])([OH:22])[CH3:23])=[CH:10][C:9]3=2)[CH2:2][CH2:3]1
Reactant: CC(=O)Cc1ccc2ccc3ccc(OCC4CC4)cc3c2c1
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Product: CC(C)(O)Cc1ccc2ccc3ccc(OCC4CC4)cc3c2c1

Procedure:
This phenanthrene was prepared as described in Step 3 of Example 135, substituting 1-[6-(cyclopropylmethoxy)-3-phenanthryl]acetone from Step 3 above for 2-(9-chloro-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl)-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile. The crude product was used directly in the next reaction.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[CH3:10][C:11]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]1=O>CO>[CH3:10][C:11]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]1=[N:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC1(C)CCCC1=O
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCCC1(C)C
Yield: 76.9 %

Procedure:
A solution of tert-butyl hydrazinecarboxylate (4.1 g) and 2,2-dimethylcyclopentanone (3.5 g) in methanol (50 mL) was stirred at 70° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to give the title compound (5.4 g). 1H NMR (400 MHz, CDCl3) δ 1.17 (6H, s), 1.50 (9H, s), 1.61-1.64 (2H, t, J=6.8 Hz), 1.80-1.87 (2H, m), 2.24-2.27 (2H, t, J=7.2 Hz), 7.12 (1H, brs).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:9]1[CH2:11][CH2:12][O:13][CH:8]1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[I:10]
Reactant: O=Cc1c(I)ccnc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1nccc(I)c1C1OCCO1
Temperature: 25 °C

Procedure:
In a three-necked flask equipped with a Dean Stark apparatus, a mixture of 5.1 g (20.3 mmol) of 2-fluoro-4-iodo-3-pyridinecarbaldehyde, 1.4 g (22.3 mmol) of ethane-1.2-diol, and 50 mg of para-toluenesulphonic acid in 100 ml of toluene is heated at reflux. When the theoretical amount of water has been collected, the reaction mixture is cooled to room temperature, washed with a saturated sodium hydrogen carbonate solution and dried over magnesium sulphate. The expected product is obtained by concentration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17](=O)[NH:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:35]=[C:36]([CH:39]4[CH2:43][CH2:42][CH2:41][N:40]4[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])[NH:37][CH:38]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:60]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]1[NH:60][C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:35]=[C:36]([CH:39]5[CH2:43][CH2:42][CH2:41][N:40]5[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:47])[CH3:48])[NH:37][CH:38]=4)=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[CH:19][N:18]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4c5ccccc5CN4C(=O)OC(C)(C)C)cc3)cc2)c[nH]1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(-c3ccc(-c4cnc(C5c6ccccc6CN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
1-[2-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (147.8 mg) was taken into m-xylenes (2.0 mL) and heated at 135° C. Solid ammonium acetate (120 mg, 1.5 mmol) was added and the reaction was stirred at 135° C. After 180 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was partitioned between EtOAc and water. The organic layer was collected and dried over sodium sulfate. Filtration and evaporation of solvents gave the crude product (142 mg).
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12]([O:17][CH3:18])=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([N:27]([CH3:40])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:41])=[CH:23][N:22]=1>>[Cl:41][C:24]1[C:25]([N:27]([CH3:40])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:38])[CH3:39])(=[O:36])=[O:35])=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:19])[F:1])[CH2:11][CH2:10][C:9]=3[C:12]=2[O:17][CH3:18])=[N:22][CH:23]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N(C)c1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Product: COc1c(Nc2ncc(Cl)c(N(C)c3ccccc3S(=O)(=O)C(C)C)n2)ccc2c1CCC(NCC(F)F)CC2
Yield: 4.4 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-methyl-[2-(propane-2-sulfonyl)-phenyl]-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-methyl-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (4.71 mg, 4.4% yield) as a brown oil. 1H-NMR (CDCl3) δ 9.57 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.65 (m, 1H), 7.47 (s, 1H), 7.27 (m, 1H), 6.83 (d, J=7.8 Hz, 1H), 5.83 (m, 1H), 3.73 (m, 3H), 3.22 (m, 2H), 3.02 (m, 2H), 2.83 (m, 2H), 2.67 (m, 1H), 2.49 (m, 1H), 2.11 (m, 2H), 1.32 (m, 10H). LC/MS (ESI+)=580 (M+H).