Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32])([CH2:24][CH3:25])[CH3:23].N1CCCCC1>ClCCl>[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32][C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8])([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)c1ccccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCC(C)c1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.6 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.7 mmol of 2-sec-butylbenzenethiol, and 1.7 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 161°-162° C.). 1H NMR (DMSO-d6) δ 0.81 (t, 3 H), 1.15 (d, 3 H), 1.43-1.64 (m, 2 H), 2.98 (m, 1 H), 3.77 (s, 2 H), 5.65 (dd, 1 H), 6.47 (t, 1 H), 6.92 (t, 1 H), 7.07 (d, 1 H), 7.34-7.48 (m, 10 H), 12.4 (bs, 1 H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]2[CH2:7][N:8]([C:10]3[N:11]=[C:12]([C:31]4[O:32][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[N:34][N:35]=4)[C:13]([N:16](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:14][CH:15]=3)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C:13]1[N:14]=[CH:15][C:10]([N:8]2[CH2:9][C@@H:5]3[CH2:4][CH2:3][C:2](=[O:1])[C@@H:6]3[CH2:7]2)=[N:11][C:12]=1[C:31]1[O:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:34][N:35]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2C[C@@H]3CCC(=O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(N2C[C@@H]3CCC(=O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl N-[5-[(3aR,6aS)-6-oxo-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-2-yl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (57 mg, 0.10 mmol) in DCM (1 mL) was treated with TFA (1.5 g, 1 mL, 13 mmol) The reaction mixture was stirred at room temperature for 1 h. The solvents were evaporated and the residue was dissolved in DMF and purified by reverse phase column chromatography to obtain (3aR,6aS)-2-[5-amino-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-6-one. LC/MS m/z 363.1 [M+H]+
Reaction SMILES: [ClH:1].Cl.C([O:6][CH:7]([CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]4[O:27][CH2:28][O:29][C:22]=34)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31])(=O)C.N.Cl.C(OCC)C>C(Cl)Cl.C(O)(C)C>[ClH:1].[ClH:1].[OH:6][CH:7]([CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]4[O:27][CH2:28][O:29][C:22]=34)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:30][CH3:31]
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCC(CN1CCOCC1)OC(C)=O
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCC(O)CN1CCOCC1

Procedure:
A mixture of 7-(2-acetoxy-3-morpholinopropoxy)-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline dihydrochloride (0.104 g) and a saturated methanolic ammonia solution (3 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on silica (Isolute ammonia-treated silica from International Sorbent Technology Limited, catalogue reference 9470-0100) using a 19:1 mixture of methylene chloride and methanol as eluent. The material so obtained was dissolved in methylene chloride (3 ml) and a 6M solution of hydrogen chloride in isopropanol (0.3 ml) was added with stirring. Diethyl ether (10 ml) was added and the resultant precipitate was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.095 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 3.15–3.45 (m, 4H), 3.54 (d, 2H), 3.74–3.91 (d, 2H), 3.97 (d, 2H), 4.02 (s, 3H), 4.24 (d, 2H), 4.49–4.58 (m, 1H), 6.08 (s, 2H), 6.96–7.04 (m, 3H), 7.47 (s, 1H), 8.23 (s, 1H), 8.88 (s, 1H); Mass Spectrum: M+H+ 455.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol), (prepared as described for the starting material in Example 1), 5-hydroxyindole (42 mg, 0.32 mmol) and cesium carbonate (129 mg, 0.39 mmol) in DMF (1 ml) was stirred for 10 minutes at ambient temperature followed by 1.5 hours at 70° C. After cooling, water (5 ml) was added. The precipitate was filtered, washed with water and dried under vacuum. The solid was purified by column chromatography, eluting with methanol/methylene chloride/ethyl acetate (5/45/50) to give 6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-yloxy)quinoline (28 mg, 22%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14]([Cl:24])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
15.0 g (50 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionic acid were dissolved in 127.5 ml dichloromethane in the presence of 0.75 ml DMF. 8.76 ml (2 eq.) Oxalyl chloride were added and after 4.5 hours, the solution was rotary evaporated to dryness. 9 ml Toluene were added and the resulting solution was again rotary evaporated, then dried under high vacuum yielding 16.25 g (quant.) of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride as a yellow oil of 86% purity according to HPLC analysis. NMR (250 MHz, CDCl3): 7.86 (br s, 1H); 7.77, (br s, 2H, 3Harom); 1.77 (s, 6H, 2 CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32]OS(C)(=O)=O)[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=3)[C:11](=[O:29])[N:10]2[CH3:30])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:38]1([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O.Cl>CN(C=O)C.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:31][CH2:32][N:47]3[CH2:48][CH2:49][CH:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:45][CH2:46]3)[CH2:13][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=3)[C:11](=[O:29])[N:10]2[CH3:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1(CCN1CCC(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Yield: 77.6 %

Procedure:
A mixture of 0.55 g of the compound obtained in step C of EXAMPLE 30, 0.47 g of 4-phenylpiperidine and -0.5 g of K2Co3 in 4 ml of DMF is heated at 80 C for 5 hours. After cooling, the reaction mixture is poured into iced water and extracted with AcOEt, the organic phase is washed with 1 N NaOH solution and with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained is dissolved in ether, a saturated solution of gaseous HCl in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.25 g of the expected product. M.p.=208° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2([OH:23])[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[OH:23][C:17]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH2:22][CH2:21][CH2:20][N:19]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:18]1
Reactant: O=C(Cl)c1cccs1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccs3)C2)c1

Procedure:
The compound of Example 14 was prepared according to the general preparation protocol A from thiophene-2-carbonyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][C:19]([C:17]1[S:18][C:13]2[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:11][C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[N:2][NH:1]4)=[N:15][C:14]=2[CH:16]=1)=[O:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(NCc1ccccc1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to benzylamine via General Procedure B. The product was purified via reverse phase HPLC to give 8.9 mg of 245. MS (Q1) 470.8 (M)+
Reaction SMILES: [C:1]1([N:7]2[CH2:14][CH2:13][CH:12]3[CH:8]2[CH2:9][N:10](C(OCC)=O)[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([N:7]2[CH2:14][CH2:13][CH:12]3[CH:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CC2CCN(c3ccccc3)C2C1
Agent: Cl
Product: c1ccc(N2CCC3CNCC32)cc1

Procedure:
7.6 g (31.6 mmol) of ethyl 2-phenyl-2,7-diazabicyclo [3.3.0]octane-7-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is concentrated, the residue is taken up in 50 ml of 10% strength sodium hydroxide solution and the mixture is extracted five times using 50 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:9][CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCBr
Product: CCCCCCCCCCCCCOc1ccc(C=O)cc1
Yield: 178 %

Procedure:
General procedure K was used to convert 4-hydroxybenzaldehyde (8.2 mmols) and 1-bromononane (12.3 mmols) to 7.3 mmols (87%) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 9.88 (s, 1H), 7.83 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.04 (t, J=6.5 Hz, 2H), 1.76-1.88 (m, 2H), 1.52-1.08 (m, 20H), 0.88 (t, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:14]=[C:15]([NH:19][C:20]3[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=1)[CH:7]=[CH:6]2.[Br:29]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:29][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:13]1[CH:14]=[C:15]([NH:19][C:20]3[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=1)=[CH:9]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2cc(-c3cccc(Nc4ncccc4[N+](=O)[O-])c3)ccc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(-c3cccc(Nc4ncccc4[N+](=O)[O-])c3)ccc2c1Br
Yield: 52.3 %

Procedure:
The mixture of 2-[3-(6-methoxy-2-naphthyl)phenylamino]-3-nitropyridine (5.2 g), N-bromosuccinimide (3.24 g) and benzoylperoxide (678 mg) in chloroform (30 ml) was refluxed for 3 hours. The mixture was concentrated in vacuo and was purified by column chromatography (silica gel) to obtain 2-[3-(5-bromo-6-methoxy-2-naphthyl)phenylamino]-3-nitropyridine (3.3 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:29]([N:31]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1)[CH2:32][CH3:33])[CH3:30]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 mmol), diethylamine (47 mg, 0.65 mmol) and acetic acid (39 mg, 0.65 mmol) in dichloromethane (50 mL) was stirred at room temperature for 60 min. Upon cooling the mixture to 0° C., sodium triacetoxyborohydride (69.3 mg, 0.33 mmol) was added. After the addition, the mixture was stirred at room temperature overnight. Dichloromethane was removed under reduced pressure. The crude product was purified by chromatography (silica gel, dichloromethane/Methanol=50:1) to give the title compound (34 mg, yield 36%). LC-MS (ESI) m/z: 425 (M+H)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.10 (t, 6H), 2.64 (q, 4H), 3.70 (s, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.75 (d, J=8.0 Hz, 1H), 7.06-7.09 (m, 2H), 7.13-7.20 (m, 4 H), 7.22-7.29 (m, 4H), 7.54-7.56 (dd, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H).
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[NH2:8][C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1

Procedure:
To a stirred solution of (2S,3S,5S)-2-(N,N-dibenzylamino)-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane (12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate (8.05 g, 128 mmol, 6.0 eq) and
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.BrC1C=CC(OCCN2CCCCCC2)=C(F)C=1.[N:40]1([CH2:47][CH2:48][O:49][C:50]2[CH:55]=[CH:54][C:53]([NH:56][C:57]3[CH:62]=[C:61]([O:63]C)[CH:60]=[CH:59][C:58]=3[CH:65]3[CH2:74][CH2:73][C:72]4[C:67](=[CH:68][CH:69]=[C:70]([O:75]C)[CH:71]=4)[CH2:66]3)=[CH:52][C:51]=2[F:77])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:47][CH2:48][O:49][C:50]2[CH:55]=[CH:54][C:53]([NH:56][C:57]3[CH:62]=[C:61]([OH:63])[CH:60]=[CH:59][C:58]=3[CH:65]3[CH2:74][CH2:73][C:72]4[CH:71]=[C:70]([OH:75])[CH:69]=[CH:68][C:67]=4[CH2:66]3)=[CH:52][C:51]=2[F:77])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCCC3)c(F)c1)C2
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1Nc1ccc(OCCN3CCCCCC3)c(F)c1)C2
Yield: 47.8 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]azepane according to an analogous synthetic method to Example 116, [4-(2-azepan-1-ylethoxy)-3-fluorophenyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (146 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (66 mg).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH2:25][OH:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[F:35][C:36]1[CH:43]=[C:42](F)[C:41]([F:45])=[CH:40][C:37]=1[C:38]#[N:39].O>O1CCCC1.C(O)(C)(C)C>[F:35][C:36]1[CH:43]=[C:42]([O:26][CH2:25][C:11]2[S:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:27])[F:28])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]2)[C:41]([F:45])=[CH:40][C:37]=1[C:38]#[N:39]
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Reactant: N#Cc1cc(F)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: N#Cc1cc(F)c(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a solution of 800 mg of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol in 4 mL of tetrahydrofuran at 5° C. was slowly added 2.13 mL of a molar solution of potassium tert-butoxide in tert-butanol. After stirring at 5° C. for 30 minutes, the resulting solution was slowly added to a solution of 296 mg of 2,4,5-trifluoro-benzonitrile in 1 mL of tetrahydrofuran at −60° C. The resulting mixture was stirred for 1 h at −60° C. then stirred overnight allowing the temperature to warm up to room temperature. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from methanol and washed with diisopropyl ether to give 890 mg of 2,5-difluoro-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.Br[C:33]1[CH:34]=[C:35]([CH2:39][C:40]([OH:42])=[O:41])[CH:36]=[CH:37][CH:38]=1.[OH-].[Na+]>O1CCOCC1>[N:1]1([C:33]2[CH:34]=[C:35]([CH2:39][C:40]([OH:42])=[O:41])[CH:36]=[CH:37][CH:38]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: c1cn[nH]c1
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc(-n2cccn2)c1
Yield: 65 %

Procedure:
Pyrazole (1.2 eq), Cs2CO3 (2.5 eq), Cul (0.5 eq), trans-1,2-cyclohexanediamine (0.6 eq) and dodecane (1 eq), were added to a stirred solution of 3-bromophenylacetic acid (1 eq) in dioxane at room temperature under an inert atmosphere. The mixture was irradiated in a microwave reactor (PersonalChemistry EmryS™ Optimiser, 300W, 160° C., 20 min), then added to a 1N aqueous solution of NaOH, and extracted with Et2O. The aqueous phase was acidified to pH=3 with HCl 2N, then extracted with ethyl acetate; this phase was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified on SPE cartridge (Silica) eluting with a gradient from Cyclohexane/ethyl acetate 8:2, to Cyclohexane/ethyl acetate 1:1, affording the title compound in 65% yield.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13](C)([O-:15])[CH3:14].[K+].C([C@@H]1OC1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[CH2:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:13]1[O:15][CH2:14]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: ClC[C@H]1CO1
Agent: [Cl-]
Solvent: CC(C)O
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Yield: 16.3 %

Procedure:
Into a reaction vessel were put phthalimide (2.00 g, 13.6 mmol), benzyltrimethylammonium chloride (252 mg, 1.36 mol) and isopropanol (25 mL) and the mixture was ice cooled. Thereto were added potassium tert-butoxide (3.05 g, 27.2 mmol) in several divided portions and then (R)-epichlorohydrin (2.52 g, 27.2 mmol). The mixture was reacted at room temperature for 26 hours and then post-treatment was carried out to give crude (R)-glycidylphthalimide (0.45 g, yield 17%, optical purity 96% e.e.) as a yellow highly viscous product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([CH3:15])[CH3:14])[C:9]([F:12])=[CH:10][F:11])=[CH:4][CH:3]=1.C([Li])CCC.[C:21]1([O:27][C:28]2[CH:29]=[C:30]([CH2:34]Br)[CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1.CCCCCC.O.[Cl-].[Zn+2].[Cl-].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.CCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:13]([CH3:15])[CH3:14])[C:9]([F:12])=[C:10]([F:11])[CH2:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(F)=CF)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCCCC
Product: CC(C)C(C(F)=C(F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of 3-(p-chlorophenyl)-1,2-difluoro-4-methyl-1-pentene (0.69 g, 0.003 mol) in tetrahydrofuran is cooled to −70° C., treated with a 2.5 M solution of n-butyllithium in hexane (1.2 mL), stirred at −60° C. for 1 hour, treated with a 0.5 M solution of zinc chloride in tetrahydrofuran (6 mL), stirred at −60° C. for 1 hour, treated sequentially with a solution of tetrakis(triphenylphosphine)palladium(0) (0.081 g) in tetrahydrofuran and a solution of α-bromo-m-tolyl phenyl ether (0.789 g, 0.003 mol) in tetrahydrofuran, stirred at room temperature overnight, diluted with water, acidified with 10% hydrochloric acid, and extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and pentane affords an oil which is purified by Kugelrohr distillation to give the title product as a pale, yellow oil (0.46 g) which is identified by NMR spectral analyses.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:32][N:31]=[N:30]2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:32][N:31]=[N:30]4)[CH:24]=3)[CH2:20][C:19](=[O:38])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(Cl)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (4-chloro-5-dimethylamino-2-{3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert.-butyl ester (Example M19) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (34 mg).