Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14]3(OCC[O:21]3)[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[C:6]([CH3:25])=[CH:5][CH:4]=1.[H-].C([Al+]CC)C>C1(C)C=CC=CC=1>[CH3:25][C:6]1[C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[C:3]([OH:2])=[CH:4][CH:5]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[OH:21]
Reactant: COc1ccc(C)c2c1[C@H]1CC[C@@]3(C)[C@@H](CCC34OCCO4)[C@@H]1CC2
Agent: CC[Al+]CC
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c2c1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
2.0 g. of 1-methoxy-17,17-ethylenedioxy-4-methyl-1,3,5(10)-estratriene is heated for 24 hours under reflux and nitrogen purging in 20 ml. of toluene with 25 ml. of diethylaluminum hydride (20% in toluene). The reaction mixture is decomposed and worked up as described in Example 3. The dried residue is extracted with a methylene chloride-methanol mixture (1:1), concentrated to dryness under vacuum, and crystallized from hexane. After recrystallization from methylene chloride-isopropyl ether with carbon, 1.57 g. of 4-methyl-1,3,5(10)-estratriene-1,17β-diol, m.p. 226°-229° C., is obtained. [α]D = +177.9° (dioxane); ε280 = 1930.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.Cl>CC(O)C>[ClH:11].[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Ic1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(I)cc43)c2cc1OC
Yield: 78 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 78% yield from 6-iodo-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to the procedure given in Example 2 (M.P. >230° C.; GC/MS: 433 (M+); anal. RP18-HPLC RT: 5.20 min.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:24]([Cl:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].Cl.C(OCC)C>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])[C:24]([Cl:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)(=O)C(C)C)cc3n2COCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)(=O)C(C)C)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of 1-[5-chloro-1-(2-methoxy-ethoxymethyl)-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.243 g, 0.501 mmol) in ethanol (1.8 mL) was added 4M HCl in dioxane (1.8 mL). The reaction mixture was stirred at 23° C. for 1.5 h. Diethyl ether was added and the precipitate collected to yield the titled compound (0.183 g, 92% yield). MS (ESI/CI): mass calcd. for C16H17ClN4O4S, 369.1; m/z found, 397.1 [M+H]+. 1H NMR (400 MHz, DMSO): 9.03 (d, J=0.6 Hz, 1H), 8.42 (d, J=0.6 Hz, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.89-3.76 (m, 1H), 1.33 (t, J=7.1 Hz, 3H), 1.21 (d, J=6.8 Hz, 6H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].C(N(CC)CC)C.[CH2:15]([S:27][C:28]([S:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33])=[S:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][O:7][C:32](=[O:33])[C:31]([S:30][C:28]([S:27][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[S:29])([CH3:36])[CH3:35])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCO
Reactant: CCCCCCCCCCCCSC(=S)SC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCSC(=S)SC(C)(C)C(=O)OCCCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
3-Azidopropanol (265 mg, 2.62 mmol, 1.0 equiv) is dissolved in methylene chloride (5 mL) in a 50 mL round-bottom flask, and the solution is cooled to approximately 0° C. A solution of triethylamine (0.73 mL) in methylene chloride (5 mL) is added dropwise over 10 min. A solution of DMP-Cl (1.0 g, 2.6 mmol) in methylene chloride (5 mL) is added dropwise, and the solution is allowed to reach room temperature while stirring for 3 h. The solution is concentrated under reduced pressure, diluted with ethyl ether (100 mL), and washed with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and saturated NaCl solution (50 mL), successively. The organic layer is separated, dried over MgSO4 (1.0 g), and filtered. The supernatant is concentrated under reduced pressure to yield the product (1.05 g, 90% yield) as a residual oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.N[C:13](N)=[S:14].[OH-].[Na+].CI>C(O)C>[Cl:8][C:7]1[C:2]([S:14][CH3:13])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Product: CSc1ncc([N+](=O)[O-])cc1Cl
Temperature: 10 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
2,3-Dichloro-5-nitropyridine (7.90 g, 0.041 mol) (Synthesis, 1990, 499) was dissolved in ethanol (150 ml) and was treated with thiourea (3.43 g, 0.045 mol). The resultant mixture was then heated to reflux with stirring under argon. After 3 h, the reaction mixture was allowed to cool, and was left stirring at room temp. for 16 h. 10% Sodium hydroxide solution (160 ml) was then added and the reaction mixture was heated to reflux with stirring. After 1 h, the reaction mixture was cooled to 10° C., and methyl iodide (2.80 ml, 0.045 mol) was added. After 1 h, the resultant precipitate was filtered off to give the title compound as an orange solid (5.90 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CO[CH:17](OC)[CH2:18][CH:19](OC)OC>C(O)(=O)C>[C:9]1([C:7]([C:6]2[CH:5]=[N:4][N:3]3[CH:19]=[CH:18][CH:17]=[N:1][C:2]=23)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: COC(CC(OC)OC)OC
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnn2cccnc12
Yield: 76.2 %

Procedure:
A mixture of 1.87 g of (3-amino-1H-pyrazol-4-yl)phenylmethanone (prepared as described in U.S. Patent application Ser. No. 612,811, filed May 24, 1984), 1.64 g of malonaldehyde bis(dimethyl acetal) and 25 ml of glacial acetic acid was heated at reflux for 6 hours. The solvent was evaporated and the solid was worked up as described in Example 50 and gave 1.70 g of phenylpyrazolo[1,5-a]pyrimidin-3-yl-methanone, mp 174°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH:32]=[CH2:33])=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 111 %

Procedure:
N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-vinylpyridin-2-amine (76.3 mg, 0.172 mmol) was dissolved in DCM (2.9 mL) and trifluoroacetic acid (Aldrich, St. Louis, Mo., hplc grade, 0.60 mL, 7.8 mmol) was added via syringe. The reaction was stirred at room temperature for 35 minutes, concentrated, treated with MeOH, and filtered. The solid was washed with Et2O, but was not sufficiently (>95% by HPLC) pure. So, the solid and filtrate were combined, concentrated, treated with 2 N ammonia in MeOH, and concentrated again. The material was treated with Et2O, but this did not precipitate product. So, it was concentrated, treated with water, and filtered. The solid was washed with water, but was still not 95% pure. So, the solid was collected and purified on HPLC (10% to 100% MeCN/water over 30 minutes using a total flow rate of 100 mL/min) to afford N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-vinylpyridin-2-amine (68.6 mg). MS (ESI pos. ion) m/z 360 (M+H)+. 1H NMR (d6-DMSO) δ 12.70 (s, 1H), 9.98 (s, 1H), 8.65 (s, 1H), 8.55 (d, J=2.54 Hz, 1H), 8.40 (d, J=2.35 Hz, 1H), 8.19 (dd, J=8.8 Hz, 2.74 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.79 (dd, J=17.5 Hz, 10.9 Hz, 1H), 5.78 (d, J=16.4 Hz, 1H), 5.26 (d, J=11.0 Hz, 1H), 3.85 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=1)=[CH2:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:17])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[S:11][CH:12]=1)[CH3:2]
Reactant: C=Cc1cnn(C)c1-c1csc(C(=O)OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cnn(C)c1-c1csc(C(=O)OC)c1
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate and 10% Pd/C in ethyl acetate (15 mL). The mixture was evacuated slightly, refilled with H2 from a balloon and stirred vigorously under an atmosphere of H2 for 1 hour. The reaction was filtered through a 0.2 μm PTFE membrane filter and used without further purification (153 mg, 0.60 mmol, 87%): LC-MS (ES) m/z=251 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:15][CH2:14][C:13]([OH:19])([CH:16]([CH3:18])[CH3:17])[C:12]3[S:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:26]([C@:28]1([OH:35])[CH2:32][CH2:31][N:30]([CH3:33])[C:29]1=[O:34])#[CH:27]>>[F:25][C:3]1[C:2]([C:27]#[C:26][C@:28]2([OH:35])[CH2:32][CH2:31][N:30]([CH3:33])[C:29]2=[O:34])=[CH:7][C:6]2[C:8]3[N:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:11][C:12]=3[C:13]([OH:19])([CH:16]([CH3:18])[CH3:17])[CH2:14][O:15][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1nc2c(s1)C(O)(C(C)C)COc1cc(F)c(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CCOC(=O)c1nc2c(s1)C(O)(C(C)C)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (133 mg) was reacted with isopropylmagnesium bromide similarly to as described in the synthesis of 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo {e}azulene-2-carboxylic amide with non-critical modifications to afford ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-8-fluoro-4-hydroxy-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (80 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 8-fluoro-4-hydroxy-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-isopropyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 12 mg and 13 mg (29% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-hydroxyl substitution position for each isomer was not determined.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:15]1[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[C:11]([Cl:10])[CH:16]=1)=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCCCCBr)cc1Cl
Yield: 32.8 %

Procedure:
6-Bromohexanoyl chloride (2.0 g), 2-chloroanisole (1.17 g) and aluminum chloride (1.12 g) were reacted and treated in the same manner as in Preparation Example 105 to give 0.86 g of 6-bromo-1-(3-chloro-4-methoxyphenyl)-1-hexanone.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH:29]=[O:30])[CH2:24][CH2:23][CH2:22][CH2:21]1.[Cl-].[NH4+]>O1CCCC1>[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH:29]([OH:30])[CH2:19][C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Cc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(O)Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A stirred solution of diisopropylamine (14 mL)in dry tetrahydrofuran (150 mL), is treated dropwise with a solution of butyl lithium in hexanes (40 mL; 2.5M), under nitrogen, while keeping the temperature at below -70° C. The resulting mixture is then stirred for a further period of 30 minutes at below -70° C. The stirred mixture, while it is still maintained at below -70° C., is then treated dropwise with a solution of 4-picoline (9.3 g) in dry tetrahydrofuran (20 mL). The stirred mixture is maintained at below -70° C. for a further 45 minutes. The stirred mixture, while it is still maintained at below -70° C., is then treated with a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (22.0 g) in dry tetrahydrofuran (100 mL), and it is stirred at below -70° C. for a further 30 minutes. The resulting mixture is then allowed to warm to room temperature overnight, and then treated with saturated aqueous ammonium chloride solution (200 mL). The layers are separated and the aqueous layer is further extracted with ethyl acetate (3×300 mL). The combined organic extracts are dried over magnesium sulfate and evaporated to dryness. The resulting residue is recrystallized fromethyl acetate, to give (±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (28.5 g), in the form of a cream solid, m.p. 102°-103° C.
Reaction SMILES: [CH:1]1([CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][NH:5]2)[CH2:3][CH2:2]1.[CH:18]1(C(Cl)=O)CCC1.C1(C(Cl)=O)CC1>>[CH:1]1([CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][NH:5]2)[CH2:3][CH2:2][CH2:18]1
Reactant: O=C(Cl)C1CCC1
Reactant: COc1cc2c(cc1OC)C(C1CC1)NCC2
Agent: O=C(Cl)C1CC1
Product: COc1cc2c(cc1OC)C(C1CCC1)NCC2

Procedure:
1,2,3,4-Tetrahydro-1-cyclobutyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1,2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxy- isoquinoline but substituting in the first step cyclobutylcarbonyl chloride for cyclopropyl- carbonyl chloride.
Reaction SMILES: C([N:8]([C@H:16]([CH3:29])[C@@H:17]([OH:28])[CH2:18][C@@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21])CC1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[CH3:29][C@@H:16]([NH2:8])[C@@H:17]([OH:28])[CH2:18][C@@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21]
Reactant: CC[C@@H](C[C@H](O)[C@@H](C)N(Cc1ccccc1)Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H](C[C@H](O)[C@@H](C)N)c1ccccc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
The N,N-dibenzyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexyl amine (1.46 g, 3.77 mmol) obtained above was dissolved in methanol (25 ml). Subsequently, acetic acid (0.43 ml, 7.53 mmol) and 5% Pd-C (palladium carbon; containing 50% of water) (0.6 g) were added to the dissolved solution. This reaction solution was stirred for 16 hours at 50° C. under a hydrogen atmosphere, and the catalyst was filtered off. The liquid filtrate thus obtained was concentrated under reduced pressure. To the resulting residue, a saturated sodium hydrogen carbonate aqueous solution (15 ml) was added and two 50 ml methylene chloride extractions were performed. The resulting organic layer was dried with anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the liquid filtrate was concentrated under reduced pressure to yield (1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexyl amine (0.61 g, 2.96 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)benzyl alcohol (2.87 g, 13.63 mmol) in DMF (40 mL) is added sodium hydride (60% in mineral oil, 654 mg, 16.36 mmol) at 0° C. and the reaction mixture is stirred at 0° C. for 30 minutes. 4-methoxy-benzyl chloride (2.35 g, 15 mmol) in DMF (10 mL) is added and the reaction mixture is stirred at 0° C. for 1 h and at room temperature for 3 hours. The reaction mixture is poured into saturated aqueous NH4Cl (300 mL) and extracted with EtOAc. The combined extracts are washed with brine (2×80 mL) and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (8:1 hexanes/EtOAc) to give 1-Chloro-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1I.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])=[C:6]([O:10][CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:13]
Reactant: COC(=O)c1cccc(OC)c1I
Reactant: COc1ccccc1B(O)O
Product: COC(=O)c1cccc(OC)c1-c1ccccc1OC

Procedure:
Using the procedure outlined in Step A of Example 18, 201.7 mg (0.69 mmol) of methyl-2-iodo-3-methoxy-benzoate and 125.9 mg (0.82 mmol) of 2-methoxy-phenylboronic acid gave after 27 hours of reflux a quantitative yield of the title substance.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].Br[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[F:38]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])[CH2:25][C:24]2=[O:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2s1
Reactant: Fc1cc(Cl)ccc1Br
Agent: Cl
Product: O=C(NC1(C(=O)NC2CCN(c3ccc(Cl)cc3F)CC2=O)CCCCC1)c1cc2ccccc2s1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(benzothiophen-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-fluoro-4-chlorobenzene was used instead of 1-bromo-4-fluoro-2-thiomethoxybenzene in Step 1 thereof, 76 mg of the titled compound was prepared
Reaction SMILES: BrC1C([C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)CC2C=C(F)C=C(F)C=2)=NC(NCCOC)=NC=1.[CH:40]1([CH2:43][NH2:44])[CH2:42][CH2:41]1.[Br:45][C:46]1[C:47]([C@@H:56]([NH:66][C:67](=[O:85])[CH2:68][N:69]2[C:77]3[C:76]([F:79])([F:78])[CH2:75][CH2:74][C:73]([F:81])([F:80])[C:72]=3[C:71]([CH:82]([F:84])[F:83])=[N:70]2)[CH2:57][C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[C:60]([F:65])[CH:59]=2)=[N:48][C:49](S(C)(=O)=O)=[N:50][CH:51]=1>>[Br:45][C:46]1[C:47]([C@@H:56]([NH:66][C:67](=[O:85])[CH2:68][N:69]2[C:77]3[C:76]([F:78])([F:79])[CH2:75][CH2:74][C:73]([F:80])([F:81])[C:72]=3[C:71]([CH:82]([F:84])[F:83])=[N:70]2)[CH2:57][C:58]2[CH:59]=[C:60]([F:65])[CH:61]=[C:62]([F:64])[CH:63]=2)=[N:48][C:49]([NH:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)=[N:50][CH:51]=1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Agent: COCCNc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(NCC2CC2)ncc1Br

Procedure:
The title compound (13A) was prepared according to the method presented for the synthesis of compound 11I of Example 11 utilizing cyclopropylmethanamine and 12C. MS (m/z) 668.95 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.[F:27][C:28]([F:40])([F:39])[C@@:29]([O:34][Si:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([I:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:30](=[O:31])[C@:29]([O:34][Si:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[C:28]([F:39])([F:27])[F:40]
Reactant: Nc1ccc(I)c([N+](=O)[O-])c1Cl
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Solvent: ClCCl
Product: C[C@@](O[Si](C)(C)C)(C(=O)Nc1ccc(I)c([N+](=O)[O-])c1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.4 %

Procedure:
4-Iodo-3-nitro-2-chloroaniline (Method 70) (1269 mg) and 2,6-di-t-butylpyridine (1.5 ml) were added to a solution of (S)-3,3,3-trifluoro-2-(trimethylsilyloxy)-2-methylpropanoyl chloride (prepared from (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Method 25) as described in J. Med. Chem., 1999, 42, 2741-2746) (6 mmol) in DCM (40 ml). The mixture was stirred for 3 days at ambient temperature. The volatile material was removed by evaporation and the residue was purified by chromatography eluting with 10% EtOAc in hexane to give the title compound (1160 mg). NMR: 0.27 (s, 9H), 1.70 (s, 3H), 7.70 (d, 1H), 8.05 (d, 1H), 9.72 (brs, 1H); m/z 509.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[NH:6]2.CCN(P1(N(C)CCCN1C)=N[C:36]([CH3:39])([CH3:38])[CH3:37])CC.BrCC1CC1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:37][CH:36]1[CH2:39][CH2:38]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: BrCC1CC1
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1[nH]c(=O)n2CC1CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 11.8 %

Procedure:
200 mg (0.531 mmol) of the compound from example 33 and 145 mg (0.531 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 71 mg (0.531 mmol) of (bromomethyl)cyclopropane in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 10:90→90:10). 27 mg of the title compound were obtained (11% of theory).