Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[CH3:27][C:28]1([CH3:34])[O:33][CH2:32][CH2:31][NH:30][CH2:29]1.CCN(C(C)C)C(C)C.[I-].[Na+]>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:30]3[CH2:31][CH2:32][O:33][C:28]([CH3:34])([CH3:27])[CH2:29]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: CC1(C)CNCCO1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CCO1
Temperature: 70 °C
Yield: 91.1 %

Procedure:
To a solution of 6-bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (200 mg, 0.441 mmol) in acetonitrile (2 ml) was added 2,2-dimethylmorpholine (102 mg, 0.882 mmol, available from Chembridge Corporation) and the mixture heated at 70° C. for 18 hr. The mixture was cooled to room temperature and a further portion of 2,2-dimethylmorpholine (102 mg, 0.882 mmol), DIPEA (0.154 mL, 0.882 mmol) and sodium iodide (66.1 mg, 0.441 mmol) were added. The mixture was then heated again at 70° C. for 2 hours. The mixture was cooled to room temperature, diluted with DCM and washed with water. The organic layer was separated through a hydrophobic frit and the solvent removed in vacuo. The resulting yellow oil was dried in a vacuum oven at 60° C. overnight to give a pale yellow solid, which was dissolved in DCM (10 ml) and washed with dilute HCl (10 ml) followed by water (10 ml), separating the layers using a hydrophobic frit. The DCM was removed in vacuo to give the title compound as a cream solid (214 mg).
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3](Cl)(Cl)[Cl:4].[CH2:13]([O:20][C:21]([NH:23][C@H:24]([C:28]([O:30][CH2:31][CH:32]([CH2:34][O:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[OH:33])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CCCCCC>ClCCl>[CH2:13]([O:20][C:21]([NH:23][C@H:24]([C:28]([O:30][CH2:31][CH:32]([O:33][C:3]([Cl:4])=[O:2])[CH2:34][O:35][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OC(=O)Cl
Reaction time: 1 h
Yield: 89 %

Procedure:
Bis(trichloromethyl) carbonate (160 mg; 0.54 mmol) was added with stirring to a solution of 1-(N-benzyloxycarbonyl-L-valyl)-3-stearoylglycerol; 1-(N-benzyloxycarbonyl-L-valyloxy)-3-stearoyloxy-2-propanol; preparative example 4; (660 mg; 1.12 mmol) and triethylamine (200 mg; 2.0 mmol) in dichloromethane (5 ml) at room temperature. After 1 h, n-hexane (10 ml) was added and the precipitated triethylamine hydrochloride was filtered off through a short column of silica gel, the product eluted with a further amount of n-hexane, and the solvent evaporated in vacuum to yield 650 mg (89%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH:25]=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[C-:27]#[N:28].[Na+].[C:30]([O:33]C(=O)C)(=O)[CH3:31].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[C:30]([O:26][CH:25]([CH2:24][CH2:23][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:27]#[N:28])(=[O:33])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CCC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(CCC(C#N)OC(C)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.4 %

Procedure:
A mixture of 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propionaldehyde (1.79 g), sodium cyanide (0.3 g), acetic anhydride (0.62 g), benzyltributylammonium chloride (0.79 g), water (12 ml) and dichloromethane (35 ml) was stirred for 15 hours at room temperature. The organic layer was separated, which was washed with water and dried (MgSO4), followed by distilling off the solvent. The resulting oily product was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:3, v/v), was obtained 2-acetoxy-4-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyronitrile (2.0 g, 94%),
Reaction SMILES: Cl(O)(=O)(=O)=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=NC)[C:14]2[N:18]([CH3:19])[C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][C:15]=2[CH3:25])=[CH:9][CH:8]=1.S(OC)(OC)(=O)=[O:29].C(=O)(O)[O-].[Na+:39].O>C(Cl)(Cl)Cl.CO>[OH2:2].[OH2:22].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]2[N:18]([CH3:19])[C:17]([CH2:20][C:21]([O-:23])=[O:22])=[CH:16][C:15]=2[CH3:25])=[O:29])=[CH:9][CH:8]=1.[Na+:39]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: COS(=O)(=O)OC
Reactant: CN=C(c1ccc(Cl)cc1)c1c(C)cc(CC(=O)OC)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(CC(=O)[O-])n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Methyl 5-[(4-chlorophenyl)(methylimino)methyl]-1,4-dimethyl-1H-pyrrole-2-acetate perchlorate (1.5 g, 3.6 mmole) was dissolved in chloroform, extracted with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated. The residue was treated with dimethyl sulfate (0.5 g, 3.9 mmole) and allowed to stand at 18°-30° C. for two hours. The reaction was dissolved in methanol (10 ml) and treated with saturated aqueous sodium bicarbonate (5 ml) and water (2 ml). The solution was heated at reflux overnight, then allowed to cool to room temperature. The solid was isolated by filtration, washed with water, and air dried to yield 0.95 g (76%) of the title compound as a light tan solid, m.p. >230° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:29]O>>[CH3:29][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=3)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(O)c3)cn2)cc1
Reactant: CO
Product: CCCCCCCCOc1ccc(-c2ncc(-c3cccc(OC)c3)cn2)cc1

Procedure:
5-(3-Hydroxyphenyl)-2-(4-octyloxyphenyl)pyrimidine is reacted with methanol analogously to Example 1 to give 5-(3-methoxyphenyl)-2-(4-octyloxyphenyl)pyrimidine. ##STR37## The compound has the phase sequence: X98 I
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].CCN(C(C)C)C(C)C.[CH3:33][C:34]1[C:35]([C@@H:40]2[CH2:45][CH2:44][CH2:43][C@H:42]([C:46]3[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][N:47]=3)[N:41]2[CH2:53][CH2:54][CH2:55][CH2:56][NH2:57])=[N:36][CH:37]=[CH:38][CH:39]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:52][C:51]1[C:46]([C@@H:42]2[CH2:43][CH2:44][CH2:45][C@H:40]([C:35]3[C:34]([CH3:33])=[CH:39][CH:38]=[CH:37][N:36]=3)[N:41]2[CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:12]([NH:6][C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)=[O:13])=[N:47][CH:48]=[CH:49][CH:50]=1
Reactant: Nc1ncc[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCCCN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCCCNC(=O)Nc1ncc[nH]1
Temperature: 75 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
A mixture of 2-aminoimidazole sulfate (0.100 g, 0.757 mmol), 1,1′-carbonyldiimidazole (0.129 g, 0.796 mmol) and DIPEA (0.293 g, 2.27 mmol) in CH2Cl2 (10 mL) was stirred for 5 h, and then the solvent was removed. The residue was dissolved in DMF (6 mL), and 4-((2′S,6′R)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-butylamine (0.130 g, 0.384 mmol) and DIPEA (0.293 g, 2.27 mmol) were added. The mixture was heated at 75° C. for 16 h, and then cooled to room temperature. Saturated aqueous NaHCO3 (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (100:5:2 CH2Cl2/CH3OH/NH4OH), affording a pale yellow solid (0.115 g, 67%) after precipitation from CH2Cl2/hexanes by evaporation under vacuum. 1H NMR(CDCl3) δ 0.70-0.85 (m, 4H), 1.46-1.66 (m, 3H), 1.90-2.00 (m, 2H), 2.15-2.19 (m, 2H), 2.41 (s, 6H), 2.53-2.70 (m, 1H), 2.75-2.83 (m, 2H), 3.95-4.00 (m, 2H), 6.69 (s, 2H), 6.90-7.02 (m, 2H), 7.30-7.40 (m, 2H), 8.34-8.42 (m, 2H); 13C NMR(CDCl3) δ 18.96, 22.82, 25.22, 27.67, 31.30, 39.41, 50.56, 63.61, 122.03, 131.12, 138.63, 144.22, 146.85, 155.71, 160.40. ES-MS m/z 448 (M+H). Anal. Calcd. for C25H33N7O.0.1CH2Cl2.0.1C6H14: C, 66.43; H, 7.50; N, 21.10. Found: C, 66.41; H, 7.46; N, 20.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:4]=1[C:5]#N.[OH-:13].[K+].[OH2:15]>C(O)C>[CH3:1][O:2][C:3]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:4]=1[C:5]([OH:15])=[O:13]
Reactant: O
Reactant: COc1nc(C)cc(C)c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: COc1nc(C)cc(C)c1C(=O)O

Procedure:
97 g (0.6 mole) of 2-methoxy-4,6-dimethylnicotinonitrile and 230 g of solid potassium hydroxide are dissolved in 1000 ml of ethanol and 120 ml of water and the solution is refluxed under nitrogen for 82 hours. The mixture is cooled, the precipitated substance collected by filtration, and the bulk of the ethanol is distilled off from the filtrate in vacuo. The residue is dissolved in 500 ml of water and extracted with methylene chloride. The alkaline aqueous phase is adjusted to pH 3.3 with concentrated hydrochloric acid and the precipitated crude product is collected by filtration. Recrystallisation of this crude product from ethanol yields pure 2-methoxy-4,6-dimethylnicotinic acid (m.p. 210°-215° C).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]([O:20]C)=[N:18][C:17]2[C:12]1=[N:13][C:14]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:15][C:16]=2[NH2:22])(C)(C)C.Cl>C(OCC)C.CCCC(C)C.O1CCOCC1>[NH2:22][C:16]1[N:15]=[C:14]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:13]=[C:12]2[C:17]=1[NH:18][C:19](=[O:20])[N:11]2[CH2:10][CH2:9][CH2:8][NH2:7]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNC(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCCC(C)C
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN)c2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The product from step (i) (1.1 g) was dissolved in methanol/DCM (1/1, 40 ml). 4N—HCl in dioxane (10 ml) was added and the mixture stirred at rt for 20 h. The resultant was concentrated under reduced pressure, which afforded the subtitle compound. Yield 0.9 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:37]1[CH2:36][CH2:35][N:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCOC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 8 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalent of ethyl piperazine-1-carboxylate as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [O:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27].C([O-])(O)=O.[Na+]>CC(O)=O.CCO>[O:1]([C:8]1[CH2:13][CH2:12][C:11]2[C:14]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:26][NH:27][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(C=Cc1ccccc1)C1CCC(Oc2ccccc2)=CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: C(=Cc1n[nH]c2c1CCC(Oc1ccccc1)=C2)c1ccccc1
Temperature: 70 °C
Yield: 36.4 %

Procedure:
To a stirred solution of 3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone (1.13 g, 3.55 mmol) in 20 mL of HOAc/EtOH (1:1) was added hydrazine monohydrate (0.21 mL, 4.3 mmol). The reaction was heated at 70° C. for 3 h, cooled and poured cautiously into saturated NaHCO3 solution and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) to give 6-phenoxy-3-styryl-4,5-dihydro-1H-indazole (3) as an off-white solid (406 mg, 36%): 1H NMR (DMSO-d6) δ 2.64 (t, 2H, J=8.0 Hz), 2.95 (t, 2H, J=8.0 Hz), 5.46 (s,1H), 7.04 (AB, 2H, J=16.8 Hz), 7.15 (d, 2H, J=8.1 Hz), 7.25 (m, 2H), 7.42 (m, 4H), 7.55 (d, 2H, J=7.7 Hz), 12.44 (s, 1H). Anal. Calc. for C2H18N2O.0.2H2O: C, 79.32; H, 5.83, N, 8.81. Found: C, 79.36; H, 5.85; N, 8.84.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl-].[CH:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl.C(OCC)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][N:12]([C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1CC1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 9.1 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and of 4.04 g of triethylamine in 40 ml of methylene chloride cooled to 0° C., a solution of 4.2 g of chloride of cyclopropanecarboxylic acid in 20 ml of methylene chloride is added dropwise, while ensuring that the temperature does not exceed 5° C. The reaction mixture is left for 30 minutes at 0°-5° C., then for one hour at room temperature. 200 ml of diethyl ether are added, the mixture is filtered, the organic phase is washed three times with water, dried and evaporated to dryness under reduced pressure. Thus 11.5 g of 4-(3-trifluoromethylphenyl)-1-cyclopropylcarbonyl-1,2,3,6-tetrahydropyridine are obtained: yellow/brown oil containing traces of impurities.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].C[Si](C)(C)[C:30]([F:33])([F:32])[F:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:31][C:30]([F:33])([F:32])[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][CH2:21]2)[N:13]=3)=[C:2]([F:1])[CH:3]=1)[OH:6]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a mixture of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (2.00 g, 5.34 mmol) and trimethyl(trifluoromethyl)silane (0.911 g, 6.41 mmol) in 20 mL THF under nitrogen at 0° C. was added TBAF 1.0 M in THF (0.534 mL, 0.534 mmol). The reaction mixture became immediately dark brown and homogeneous. The water bath was removed and the reaction mixture was allowed to stir for 3 h. 1N aq. HCl (20 mL) was added and the reaction mixture allowed to stir overnight. The reaction mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (40 g) using 0-20% EtOAc/hexane. The product-containing fractions were concentrated to afford racemic 2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanol as a pale yellow foam. The racemic mixture were separated by Multigram II SFC (Column: Chiralpak ADH (21×250 mm, 5 um); A=supercritical CO2; B=Isopropanol; 30% B, 65 mL/min total flow, 40° C., 100 bar outlet pressure) to give (R)-2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanol and (S)-2,2,2-trifluoro-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanol. MS (ESI) m/z: calculated: 444.1; Observed: 445.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[CH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-:17].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2([O:17][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CO2

Procedure:
In analogy to example 11 step 1 with 4-methylene-azepane-1-carboxylic acid tert-butyl ester (MW: 211.307, 1.73 mmol), 1.16 g sodium bicarbonate (MW: 84.01 13.8 mmol) and 1.36 g of 80% m-chloroperbenzoic acid (MW 172.57, 6.05 mmol) in 5 ml of dichloromethane. Yield: 250 mg, 63%. MS: 228.8 (M+H)+, 127.8 (M-(CH3)3COCO) method ESI+.
Reaction SMILES: IC.[CH:3]1(/[C:7](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)\[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4]1.[C:37]([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:3]1(/[C:7](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)\[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:37])[N:13]=[CH:12]3)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(\c2ccccc2)C2CCC2)c2ccc3[nH]ncc3c2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)/C=C/c1ccc(/C(=C(\c2ccccc2)C2CCC2)c2ccc3c(cnn3C)c2)cc1
Reaction time: 8 h

Procedure:
Iodomethane (80 mg, 0.84 mmol) was added to a mixture of (E)-ethyl 3-(4-((E)-2-cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylate (0.25 g, 0.56 mmol; intermediate in the preparation of Compound 84), K2CO3 (0.12 g, 0.84 mmol), and DMF (5.6 mL) at room temperature. The resulting mixture was stirred overnight, diluted with water, and extracted with EtOAc. The extract was washed with water, washed with brine, dried over sodium sulfate, filtered, concentrated, and then purified on a silica gel column using 0-50% EtOAc in hexanes to afford the title compound. LCMS: 463 (M+H)+.
Reaction SMILES: CO[C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14]Br)=[N:5]/[O:6][CH3:7].[Cl:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][NH2:32].Cl>CN(C=O)C.CO>[CH3:31][NH:32][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=1)=[N:5]/[O:6][CH3:7]
Reactant: Oc1cccc(Cl)c1
Reactant: CN
Reactant: CO/N=C(/C(=O)OC)c1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cccc(Cl)c1
Reaction time: 10 h

Procedure:
Methyl-(E)-2-(bromomethylphenyl)-2-methoxyiminoacetate as obtained in Example 27 (1) (250 mg), 3-chlorophenol (225 mg) and potassium carbonate (482 mg) were dissolved in DMF, and the resultant mixture was stirred at room temperature for 10 hours. A solution (677 mg) of methylamine in 30% methanol was added thereto, and stirring was continued for 10 hours. The reaction mixture was neutralized with dilute hydrochloric acid, extracted with diethyl ether. The solvent was dried and evaporated, and the residue was purified by silica gel column chromatography to give 265 mg of the objective compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([C@@H:49]5[CH2:53][CH2:52][CH2:51][N:50]5[CH3:54])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][Si](C(C)(C)C)(C)C)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([C@@H:49]5[CH2:53][CH2:52][CH2:51][N:50]5[CH3:54])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:8]([C:10]2[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([Cl:16])[CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c4)c4ccccc43)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cc(O)cc(Cl)c4)c4ccccc43)cn12
Yield: 30 %

Procedure:
A solution of Intermediate 62e (265 mg, 0.32 mmol) and TBAF (1M in THF, 0.38 mL, 0.38 mmol) in THF (3 mL) was stirred at RT for 1.3 h, then diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the impure product. This residue was purified further by HPLC (XBridge C18 column, 35-98% MeCN in H2O, 0.1% NH4OH) to give the product. This residue purified further by HPLC (XBridge C18 column, 20-98% MeCN in H2O, 0.1% NH4OH) to give the title compound (63 mg, 30%). LCMS (Method 5): Rt 3.61 min, m/z 655 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.93-2.12 (5H, m), 2.13 (3H, s), 2.14-2.25 (3H, m), 2.34-2.37 (1H, m), 3.12-3.15 (1H, m), 3.99 (1H, t, J=8.2 Hz), 4.80-4.83 (1H, m), 5.39 (1H, t, J=4.2 Hz), 6.31 (1H, s), 6.78 (1H, s), 6.89 (1H, s), 6.96 (1H, s), 7.15 (1H, d, J=8.6 Hz), 7.29-7.41 (5H, m), 7.75 (1H, dd, J=9.9, 0.8 Hz), 8.14 (1H, s), 8.25 (1H, d, J=2.1 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[N:16].[CH3:18][S:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](OCC)=[O:31])=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH:6]([OH:17])[CH2:5][NH:4][CH2:3][CH2:2][NH:1][C:30](=[O:31])[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:28][CH:27]=1)#[N:16]
Reactant: N#Cc1ccccc1OCC(O)CNCCN
Reactant: CCOC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Product: CS(=O)(=O)Nc1ccc(CC(=O)NCCNCC(O)COc2ccccc2C#N)cc1

Procedure:
In a similar manner using 1.2 g. of 3-(β-aminoethylamino)-1-(2-cyanophenoxy)-2-propanol and 1.29 g. of ethyl 4-methanesulphonamidophenylacetate as starting materials there is obtained 1-(2-cyanophenoxy)-3-β-(4-methanesulphonamidophenylacetamido)ethylamino-2-propanol, isolated as its oxalate, m.p. 180°-182° C. after crystallisation from isopropanol.