Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[CH3:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[NH:27]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[C@H:26]([CH3:25])[CH2:30][CH2:29][S:28]4(=[O:32])=[O:31])=[CH:19][C:18]=3[CH3:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3C)CC2)c(C)c1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 51.8 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodo-2-methylphenyl)methanone (562 mg) described in Preparation Example 154 and (R)-3-methylisothiazolidine 1,1-dioxide (175 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (296 mg) was obtained.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][CH2:6][C@@H:7]1[C@@H:14]2[C@@H:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][C@H:8]1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[OH:5][CH2:6][C@@H:7]1[C@@H:14]2[C@@H:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][C@H:8]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)[Si](OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](CO)[C@H](OCc3ccccc3)C[C@@H]2O1
Reaction time: 2 h

Procedure:
To a solution of (3aR,4S,5R,6aS)-hexahydro-4-(triisopropylsilyloxymethyl)-5-(phenylmethoxy)-2H-cyclopenta[b]furan-2-one (4, R1 is phenyl, R2 and R3 are H, and R8 is TIPS, 49 g, 0.117 mol) in tetrahydrofuran (7 vol) at 0° C. was added TBAF (128 mL, 0.129 mol) and the mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was concentrated to dryness and purified by column chromatography [55% ethyl acetate in heptanes] to yield (3aR,4S,5R,6aS)-hexahydro-4-(hydroxymethyl)-5-(phenylmethoxy)-2H-cyclopenta[b]furan-2-one (5, R1 is phenyl, and R2 and R3 are H) in quantitative yield. 1H NMR (CDCl3): δ 2.12 (m, 3H), 2.53 (m, 2H), 2.74 (m, 2H), 3.51 (m, 2H), 3.89 (m, 1H), 4.48 (dd, J=47.9, 11.5 Hz, 2H), 4.92 (m, 1H), 7.27 (m, 5H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Li+].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][CH:8]=1>O1CCCC1.O>[CH3:16][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium tert-butoxide (1M in hexanes, 178 mL, 0.178 mol) was added dropwise at room temperature to p-toluoyl chloride (25 g, 0.162 mol) in tetrahydrofuran (150 mL). The mixture was stirred at room temperature overnight and then diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), and evaporated to give product as an oil which crystallized on standing (31 g, 98%)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:44])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:23](=[O:36])[C:22]([C:37]([O:39][CH3:40])=[O:38])=[C:21]([OH:41])[C:20]=1[CH2:42][CH3:43])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[S:52](Cl)([C:55]1[CH:61]=[CH:60][C:58]([CH3:59])=[CH:57][CH:56]=1)(=[O:54])=[O:53]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH3:44])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([C:19]1[N:24]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[O:34][CH3:35])[C:23](=[O:36])[C:22]([C:37]([O:39][CH3:40])=[O:38])=[C:21]([O:41][S:52]([C:55]3[CH:61]=[CH:60][C:58]([CH3:59])=[CH:57][CH:56]=3)(=[O:54])=[O:53])[C:20]=1[CH2:42][CH3:43])=[CH:14][CH:13]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCc1c(O)c(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1c(OS(=O)(=O)c2ccc(C)cc2)c(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CO[Si](C)(C)C(C)(C)C)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a stirred solution of methyl 6-(2-((tert-butyldimethylsilyloxy)methyl)-1-methyl-1H-indol-5-yl)-1-(2,4-dimethoxybenzyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate (2.0 g, 3.2 mmol), prepared according to procedure described in Example 164, Step 2, in CH2Cl2 (15 mL) was added Et3N (0.68 mL, 4.9 mmol, 1.5 eq) and TsCl (0.74 g, 3.9 mmol, 1.2 eq) at 0° C. The mixture was allowed to warm to room temperature then stirred for 2 h. The solvent was removed and the residue was purified by flash column chromatography (0-25% EtOAc in CH2Cl2) to give the title compound (2.12 g, 85%). LC-MS 775.3 [M+H]+, RT 1.80 min.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH3:14].C(Cl)(Cl)Cl>>[F:13][C:11]1[CH:12]=[C:7]([F:6])[C:8]([CH3:14])=[CH:9][C:10]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: Cc1ccc(F)cc1F
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(S(=O)(=O)Cl)c(F)cc1F
Reaction time: 2 h
Yield: 75.1 %

Procedure:
Chlorosulfonic acid (5.2 mL, 0.078 mol) was added dropwise to a solution of 2,4-difluorotoluene (4.00 g, 0.0312 mol) in chloroform (75 mL, 0.94 mol). The reaction was stirred 2 hours. Additional chlorosulfonic acid (3.1 mL, 0.047 mol) was added and stirring was continued for 18 hours. The reaction was evaporated to an oil and poured onto ice. The mixture was extracted two times with ethyl ether. The combined organic phase was dried over magnesium sulfate and treated with activated carbon. The mixture was filtered through diatomaceous earth and the filtrate was evaporated to give 5.31 g of light brown oil.
Reaction SMILES: [CH:1]([O:14][C:15]([CH:17]1[CH2:21][C@@H:20]([C:22](=[O:24])[CH3:23])[CH:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=2)[NH:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C/N=C/C1C=CC(OC)=C(OCCCOC)C=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([O:14][C:15]([CH:17]1[CH2:21][C@H:20]([C:22](=[O:24])[CH3:23])[CH:19]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH:26]=2)[NH:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCOc1cc(C2NC(C(=O)OC(c3ccccc3)c3ccccc3)C[C@H]2C(C)=O)ccc1OC
Agent: COCCCOc1cc(/C=N/CC(=O)OC(c2ccccc2)c2ccccc2)ccc1OC
Product: COCCCOc1cc(C2NC(C(=O)OC(c3ccccc3)c3ccccc3)C[C@@H]2C(C)=O)ccc1OC

Procedure:
In a similar fashion 4(R)-Acetyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-2-carboxylic acid benzhydryl ester, IVa is prepared as a racemate from {[1-[4-Methoxy-3-(3-methoxy-propoxy)-phenyl]-meth-(E)-ylidene]-amino}-acetic acid benzhydryl ester. 1H-NMR, δ CDCl3: 7.45-7.25 (10H, m, Ph), 7.01 (1H, Brs, NH), 6.80 (3H, m, Ph), 4.55 (1H, d, NCHCO), 4.10-4.03 (3H, m, CH2O), 3.45 (1H, q, CHCO), 3.35 (3H, s, MeO), 2.45 (1H, dd, CH), 2.35 (1H, dd, CH), 2.10-2.05 (5H, m, CH2+CH3), 1.65 (3H, s, CH3). The epimer at the 4 position, 4(S)-Acetyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-2-carboxylic acid benzhydryl ester 1H-NMR, δ CDCl3: 7.40-7.25 (10H, m, Ph), 6.941 (1H, Brs, NH), 6.80 (3H, m, Ph), 4.68 (1H, d, NCHCO), 4.35 (1H, dd, PhCHN), 4.10-4.03 (3H, m, CH2O+CH), 3.85 (3H, s, MeO), 3.8 (2H, t, CH2C), 3.38-3.30 (4H, m, MeO+CHCO), 2.75 (2H, m, CH2), 2.08 (5H, m, CH2+CH3), 1.58 (3H, s, CH3), can also be isolated from this reaction.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.Cl.[OH-].[Na+]>C(OCC)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:5][C:6]([F:16])([F:17])[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]2([NH2:13])[CH2:2][CH2:1]2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: NC1(c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Ethylmagnesium bromide (3.0 M in diethyl ether, 7.33 ml, 22.0 mmol) was added over 50 minutes to a solution of 4-(trifluoromethoxy)benzonitrile (1.87 g, 10.0 mmol) and tetraisopropoxytitanium (3.22 ml, 11.0 mmol) in diethyl ether (50 ml) at −70° C., and the whole was stirred at room temperature for 1 hour. Boranetrifluoride diethyl ether complex (2.53 ml, 20.0 mmol) was added over 15 minutes to the reaction mixture and the whole was stirred at room temperature for 3 hours. 1N aqueous HCl solution (30 ml) and diethyl ether (90 ml) were added to the reaction mixture, and the whole was poured into aqueous 10% NaOH solution (100 ml), extracted with diethyl ether (150 ml×2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 55/45 to 75/25) to give 1-(4-(trifluoromethoxy)phenyl)cyclopropanamine (1.38 g, 63%).
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]#[C:5][CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].Cl/C=C\C#CC(OCC)OCC.C(N)CCC.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32]>C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu](I)I.C(OCC)C.O>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[C:5]#[C:4]/[CH:3]=[CH:2]\[C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[CH3:9]
Reactant: CCOC(C#CC=CCl)OCC
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Pd]
Agent: CCOC(C#C/C=C\Cl)OCC
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(C#C/C=C\C#C[Si](C)(C)C)OCC
Temperature: 25 °C
Reaction time: 4.25 h
Yield: 53.9 %

Procedure:
A solution of 5-chloro-1,1-diethoxy-4-pentene-2-yne (compound B, 3.8 g, 20 mmol) in 10 mL of benzene was added via cannula to a solution of palladium tetrakis(triphenyl-phosphine) (1.1 g, 0.95 mmol) and copper iodide (0.47 g, 2.46 mmol) in 20 mL benzene stirring at 25° C. under argon. Immediately thereafter, butylamine (4 mL, 40 mmol), followed by trimethylsilylacetylene (5 mL, 40 mmol) was added via syringe. The reaction vessel was wrapped in foil, and the reaction mixture was stirred at 25° C. for 4.25 h. The reaction mixture was poured into 100 mL water and 100 mL diethyl ether and extracted. The aqueous layer was reextracted with 2×40 mL of diethyl ether. The combined organic extracts were washed with 50 mL saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. Flash chromatography over SiO2 using 2%, then 4%, and then 5 % diethylether/pentane as eluent provided the title compound (2.7 g, 54%) as a light brown oil.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.F[C:26](F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[CH:14]=1)[C:10]([O:12][CH3:26])=[O:11]
Reactant: COc1ccc2cc([C@H](NC(=O)OC(C)(C)C)C(=O)O)ccc2c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)c1ccc2cc(OC)ccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)acetic acid was then converted into the methyl ester using General Procedure G below. The methyl ester was then dissolved in CH2Cl2 and this solution cooled to 0° C. Trifluoroacetic acid (50 molar eq.) was added and the reaction was allowed to warm to room temperature and stirring was continued for 2 hrs. The reaction mixture was then concentrated and the residue extracted into CH2Cl2 and washed with sodium bicarbonate solution. The organic layer was dried over Na2SO4, filtered and concentrated to yield methyl (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1ccc(Cl)cc1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccc(Cl)cc1
Yield: 72 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.3 g, 0.83 mmol) prepared in example 4b was reacted with 1-(4-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 7a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-2′-(4-chlorophenyl)-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow solid (Yield 0.45 g, 72%).
Reaction SMILES: [CH:1]([NH:3][C:4]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.COCCO[AlH2-]OCCOC.[Na+].O.[ClH:34]>C1C=CC=CC=1.CCOCC>[ClH:34].[CH3:1][NH:3][C:4]([CH3:20])([CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CNC(C)(C)c1ccc(C#Cc2ccccc2)cc1

Procedure:
A solution of 2.92 grams of N-formyl-α,α-dimethyl-4-(phenylethynyl)-benzylamine in 30 ml. of benzene is placed in a dry flask. The solution is stirred. A solution of 6.6 grams of a 70% "Red-Al" solution in benzene is diluted with 30 ml. of benzene; this solution is added dropwise over approximately 30 minutes to the solution of N-formyl-α,α-dimethyl-4-(phenylethynyl)-benzylamine. The reaction is hydrolyzed with water and is extracted thoroughly with a 1:1 benzene-ether solvent mixture. The combined extracts are dried over magnesium sulfate, filtered, and the solvent is evaporated to give 3.34 gm. of an oil. This oil is dissolved in ether and treated with ethanolic hydrogen chloride. The precipitate is collected and recrystallized from isopropanol to give N,α,α-trimethyl-4-(phenylethynyl)-benzylamine hydrochloride, m.p. 266°-268° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12].[CH:29]1(Br)[CH2:31][CH2:30]1>>[CH2:31]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])[CH:29]=[CH2:30]
Reactant: O=C(c1cc([N+](=O)[O-])ccc1O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: BrC1CC1
Product: C=CCOc1ccc([N+](=O)[O-])cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in analogy to example 62 from (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound 2.1) and cyclopropyl bromide. MS (m/e): 436.5 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:43]=[C:42]([NH:44][CH:45]3[CH2:50][CH2:49][CH:48]([OH:51])[CH2:47][CH2:46]3)[N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][N:39]3[CH2:52][CH3:53])[CH:31]=[CH:32][CH:33]=1>CN(C=O)C>[CH2:52]([N:39]1[CH:38]=[N:37][C:36]2[C:40]1=[N:41][C:42]([NH:44][C@H:45]1[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]1)=[N:43][C:35]=2[NH:34][C:30]1[CH:29]=[C:28]([NH:27][C:10](=[O:12])[C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:33]=[CH:32][CH:31]=1)[CH3:53]
Reactant: O=C(O)C#Cc1ccc(Cl)cc1
Reactant: CCn1cnc2c(Nc3cccc(N)c3)nc(NC3CCC(O)CC3)nc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCn1cnc2c(Nc3cccc(NC(=O)C#Cc4ccc(Cl)cc4)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Reaction time: 3 h

Procedure:
To the solution of 190 mg (1 mmol) of (4-chlorophenyl)-propargylic acid in 20 ml of DMF at 0° C. is added 165 mg (1.1 mmol) of HOBT and 210 mg (1.1 mmol) of EDC. After 3 h at 0° C., 367 mg (1 mmol) of 4-[6-(3-Amino-phenylamino)-9-ethyl-9H-purin-2-ylamino]-cyclohexanol (example 77, stage 1.2) is added. After 1 h at 0° C. and 2.5 h at RT, the solvent was removed under reduced pressure. The crude product is purified by means of column chromatography on silica gel, trituration in diethyl ether and recrystallisation from ethanol to obtain 110 mg (0.21 mmol) of N-{3-[9-Ethyl-2-(trans-4-hydroxy-cyclohexylamino)-9H-purin-6yl-amino]-phenyl}-3-(4-chlorophenyl)-propargylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)=[CH:28][CH:27]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]4)=[CH:30][CH:31]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c2cnc(Nc3ccc(C4CCCCN4)cc3)nc2n2ccnc2n1-c1ccccc1Cl
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 2-(4-aminophenyl)piperidine-1-carboxylate (0.059 g, 0.213 mmol) was heated in a capped vial at 120° C. for 1 hour. The reaction mixture was treated with ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. for 5 hours, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 1.89-1.72 (m, 2H), 2.16-1.96 (m, 4H), 3.25-3.16 (m, 1H), 3.51-3.43 (m, 1H), 4.29-4.22 (m, 1H), 7.08 (d, J=1.9 Hz, 1H), 7.62-7.50 (m, 5H), 7.72-7.66 (m, 1H), 7.97-7.86 (m, 3H), 9.19 (s, 1H). MS (ESI+) m/z 472.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: c1ccc(C(c2ccccc2)N2CC(N3CCOCC3)C2)cc1
Temperature: 25 °C
Yield: 693 %

Procedure:
A solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (Preparation 1(b)) (24.46 g, 7.72 mmol), potassium carbonate (32 g, 3 mol equiv) and morpholine (7.34 ml, 1.09 mol equiv) in acetonitrile (200 ml) was heated under reflux for 4 hours. The solution was then cooled to room temperature, water (50 ml) added and the mixture concentrated in vacuo. The residue was then partitioned between ethyl acetate (400 ml) and water (400 ml) and the organic phase washed with water (2×400 ml). The organic phase was dried over MgSO4, and the solvent removed in vacuo. The residue was chromatographed using silica gel eluting with hexane: diethyl ether (1:1) to give the title compound (16.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[C:12]([C:22]([O:24]C)=[O:23])[CH:11]=1)#[N:2].[OH-].[Li+].Cl>O1CCCC1>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([O:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[C:12]([C:22]([OH:24])=[O:23])[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cc2C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)c(C#N)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2′-cyano-4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylate (112 mg, 0.32 mmol) in tetrahydrofuran (2 mL) was added 2.5 M of aqueous lithium hydroxide solution (0.72 mL, 1.8 mmol). The reaction mixture was stirred at 60° C. overnight. The aqueous solution was acidified with 15% HCl (aq.) to pH=5, and extracted with EtOAc. The combined organic layers were concentrated in vacuo to get the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[OH:40])[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=1[OH:40])[C:33]([O:35][CH3:36])=[O:34])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D,L-alanine (3.40 g, 17.9 mmol) and triethylamine (2.50 mL, 17.9 mmol) in THF (20 mL) was added 2-methylpropyl chlorocarbonate (2.33 mL, 17.9 mmol) under ice-cooling, and the mixture was stirred for 1 hr. To this solution was added dropwise a solution of methyl 3-amino-4-hydroxybenzoate (3.00 g, 17.9 mmol) in THF (10 mL) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 0.5N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was triturated with hexane-chloroform (1:1) to give the title compound (2.57 g, yield 42%).
Reaction SMILES: [F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5]([NH2:11])=[N:4][C@@:3]1([C:13]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12].[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>[Pd]>[F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5]([NH2:11])=[N:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)OCC(N)=N[C@](C)(c2cc(I)ccc2F)C1(F)F
Agent: [Pd]
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(C#C[Si](C)(C)C)ccc2F)C1(F)F
Yield: 78 %

Procedure:
In a manner analogous to that described in Example 9a), palladium-catalyzed coupling of (R)-6,6-Difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (485 mg, 1.18 mmol) with ethynyltrimethylsilane yielded the title compound (350 mg, 78% yield) as a yellow oil. MS (ISP): m/z=383.2 [M+H]+.