Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21](O)=[O:22])=[N:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21]([C:16]3[CH:17]=[CH:18][C:19](=[O:20])[N:14]([CH3:13])[N:15]=3)=[O:22])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cn1nc(C(=O)O)ccc1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 0.87 mmol, Example 1, Step H), 1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (0.16 g, 1.04 mmol) and BOP-Cl (0.29 g, 1.13 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (5 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (0.223 g, 70% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[NH2:17][C:18]([C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:23]([C:20]2([C:18]([NH2:17])=[O:19])[CH2:22][CH2:21]2)=[O:24])=[CH:11][CH:12]=1
Reactant: NC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(COc2cccc(F)c2)cc1
Product: NC(=O)C1(C(=O)Nc2ccc(COc3cccc(F)c3)cc2)CC1
Yield: 42 %

Procedure:
The title compound is prepared in analogy to example 2 from 4-(3-Fluoro-phenoxymethyl)-phenylamine and 1-(aminocarbonyl)-1-cyclopropane-carboxylic acid. Yield=42%. Colorless solid. MS: m/e=329.3 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:41][O:40][C:36](=[O:39])/[CH:37]=[CH:38]/[C:24]1[N:22]2[N:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][C:21]2=[N:26][C:25]=1[CH3:27]
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Temperature: 110 °C
Reaction time: 3 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, intermediate example Int-2-3, 64.5 mg (0.75 mmol) methyl acrylate, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol) triethylamine in 2.6 mL degassed acetonitrile were heated in the microwave at 110° C. for three hours. Due to an incomplete reaction additional 32.2 mg (0.375 mmol) methyl acrylate and 8.5 mg (0.037 mmol) palladium(II) acetate were added, and heating in the microwave was continued for three hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed twice with brine, dried, and the solvent was removed. The crude product (300 mg) was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:20])[C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CC(C)(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-dimethyl-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC=C(C)N=1>>[CH3:33][C:29]1[N:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:26][CH:25]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)n1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Cc1cccc(Br)n1
Product: Cc1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)n1
Yield: 57 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(6-methylpyridin-2-yl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (70 mg, 0.106 mmol) and 2-bromo-6-methylpyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a white solid (26 mg, 57%): 1H NMR (CDCl3, 400 MHz) δ 7.64 (s, 1H), 7.64 (t, 1H, J=7.6 Hz), 7.47 (d, 1H, J=7.6 Hz), 7.30-7.26 (m, 2H), 7.19-7.16 (m, 3H), 7.08 (d, 1H, J=7.6 Hz), 4.85 (dd, 1H, J=7.3, 5.8 Hz), 2.60 (t, 2H, J=7.6 Hz), 2.59 (s, 3H), 1.93 (m, 2H), 1.65 (m, 2H), 1.36 (m, 4H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.4, 158.8, 150.9, 146.8, 142.8, 137.0, 128.4, 128.2, 125.5, 124.8, 122.5, 116.1, 68.7, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 24.5, 13.6, −5.0, −5.2.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.C(N(CC)C(C)C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>C(#N)C>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1F
Yield: 52 %

Procedure:
2-Methylimidazole (9.02 g, 0.11 M) and N,N-diisopropylethylamine (32.2 g, 0.25 M) were dissolved in acetonitrile (160 ml), and 3.4-difluoronitrobenzene (15.9 g, 0.1 M) added. The mixture was stirred and heated to reflux under nitrogen for 24 hours. Solvent was evaporated, the residue dissolved in EtOAc (300 ml), washed with water (150 ml), brine (150 ml), and dried (magnesium sulfate). The residue was recrystallised from a mixture of EtOAc (25 ml) and cyclohexane (150 ml) with the addition of charcoal to give the title compound (11.5 g), mp 106-107°.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH:4]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[C:23]([C:25]1[CH:30]=[C:29]([CH:28]=[CH:27][CH:26]=1)[O:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:3]([N:2]([CH3:1])[CH3:22])=[O:21])[CH:11]=[CH:10][CH:9]=1)#[N:24]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(C)C(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)C(Cc1cccc(Oc2cccc(C#N)c2)c1)NC(=O)OC(C)(C)C
Yield: 135.7 %

Procedure:
The tert-butyl [2-(dimethylamino)-1-(3-hydroxybenzyl)-2-oxoethyl]carbamate (0.025 g, 0.081 mmol) from Example 169, step 4, was combined with (3-cyanophenyl)boronic acid (Aldich, Cat. #513016) (0.024 g, 0.16 mmol) and triethylamine (0.022 mL, 0.16 mmol), and copper(II)diacetate (0.015 g, 0.081 mmol) in methylene chloride (1.0 mL) at r.t. The reaction was vigorously stirred exposed to the atmosphere. After stirring for 48 h. this was taken up in ethyl acetate, washed with 1N HCl, brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude tert-butyl 3-(3-(3-cyanophenoxy)phenyl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.045 g) as a semisolid residue. Analytical LCMS (M+H-Boc)+: m/z=310.0.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.N.[Cl:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[N:39]([C:45]1[CH:46]=[C:47]([O:51][CH2:52][C:53](O)=[O:54])[CH:48]=[N:49][CH:50]=1)[CH2:38][CH2:37]2>CN(C=O)C.O>[Cl:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[N:39]([C:45]1[CH:46]=[C:47]([O:51][CH2:52][C:53]([NH2:2])=[O:54])[CH:48]=[N:49][CH:50]=1)[CH2:38][CH2:37]2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)COc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)COc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
HATU (38 mg, 0.1 mmol), Et3N (10.1 mg, 0.1 mmol) and ammonia (1.6 M in 1,4-dioxane, 125 μL, 0.2 mmol) were added to a solution of [5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yloxy]-acetic acid (33.2 mg, 0.1 mmol) in DMF (2 mL). The reaction mixture was stirred at RT overnight before it was poured into water and extracted with EtOAc (2×5 mL). The organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (5.4 mg, 16%) as a white solid. MS: 332.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Ic1ccccc1
Reactant: O=C1CCCN1
Product: O=C1CCCN1c1ccccc1

Procedure:
Example 2.1 was repeated, replacing the oxazolidin-2-one with 152 μl of pyrrolidin-2-one (2 mmoles) and operating with 336 μl of iodobenzene (3 mmoles), the latter being added at the same time as the pyrrolidin-2-one.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11](F)[CH:10]=2)=[N:7][CH:8]=1.Br.[CH:21]1([CH2:24][S:25]C(=N)N)[CH2:23][CH2:22]1.[OH-].[Na+]>CN(C)C=O>[CH:21]1([CH2:24][S:25][C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=3)[CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:23][CH2:22]1
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1F
Reactant: N=C(N)SCC1CC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(C(F)(F)F)cn2)cc1SCC1CC1
Yield: 96.8 %

Procedure:
1.8 g (6.8 mmol) of 4-(5-trifluoromethylpyridin-2-yl)-2-fluorobenzonitrile, 1.6 g (7.6 mmol) of S-cyclopropylmethylisothiourea hydrobromide salt and 50 ml of N,N-dimethylformamide were put into a round-bottomed flask and stirred together with 1.6 g (B mmol) of 20% aqueous sodium hydroxide overnight. The solvent was distilled off under reduced pressure, and the reaction mixture was separated with 50 ml of water and 50 ml of ethyl acetate. The organic layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.2 g of 2-cyclopropylmethylthio-4-(5-trifluoromethylpyridin-2-yl)benzonitrile (yield 96%) as pale yellow feathery crystals (m.p. 135-136° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH2:22]([O:24][P:25]([CH2:30][O:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([CH:39]=O)=[C:34]([Cl:41])[CH:33]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]>>[CH2:22]([O:24][P:25]([CH2:30][O:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([C:39]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:34]([Cl:41])[CH:33]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: CCOP(=O)(COc1cc(Cl)c(C=O)c(Cl)c1)OCC
Product: CCOP(=O)(COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1)OCC

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide (from Example 6-17) and (3,5-dichloro-4-formylphenoxymethyl)-phosphonic acid diethyl ester analogous to Example 6-17. 1H NMR (Methanol-d4, 400 MHz): δ 8.77 (d, 1H), 8.54 (d, 1H), 8.17 (t, 1H), 8.16 (t, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.99 (m, 1H), 7.86 (d, 1H), 7.77 (m, 1H), 7.38 (s, 2H), 4.62 (d, 2H), 4.30 (m, 4H), 1.42 (t, 6H). MS (m/z) 599.5 (M+1); Retention time: 1.40 min (Method 10).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH3:15])=[CH:5][N:4]([CH3:16])[C:3]=1[C:17]([O:19]CC)=O.O.[CH:23]([NH2:25])=O>>[CH3:16][N:4]1[C:3]2[C:17]([OH:19])=[N:25][CH:23]=[N:1][C:2]=2[C:6]([C:7]2[C:8]([CH3:15])=[CH:9][C:10]([CH3:14])=[CH:11][C:12]=2[CH3:13])=[CH:5]1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)c(-c2c(C)cc(C)cc2C)cn1C
Solvent: O
Product: Cc1cc(C)c(-c2cn(C)c3c(O)ncnc23)c(C)c1

Procedure:
A solution of 3-Amino-2-ethoxycarbonyl-1-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrrole (2.0 g, 7 mmol) in 20 mL of formamide was heated at 140° C. for 12 h. After cooling the mixture was poured into water and the resulting solid was collected and washed with more water and dried to afford 5-Methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol as a tan solid melting at 230°-232° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)=[CH:21][CH:20]=3)[N:16]=2)=[CH:6][CH:5]=1.[CH3:36][S:37]([OH:40])(=[O:39])=[O:38].C(OCC)C>O1CCCC1>[CH3:36][S:37]([O-:40])(=[O:39])=[O:38].[F:34][C:2]([F:1])([F:35])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][NH+:29]4[CH:33]=[CH:32][N:31]=[N:30]4)=[CH:21][CH:20]=3)[N:16]=2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Reactant: CS(=O)(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CS(=O)(=O)[O-]
Product: FC(F)(F)Oc1ccc(C=Cc2nc(COc3ccc(CCCC[NH+]4C=CN=N4)cc3)co2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
12.1 g (25 mmol) 1-[4-(4-{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole were dissolved in 150 ml tetrahydrofuran at 50° C., cooled to room temperature, treated with 1.625 ml (25 mmol) methanesulfonic acid and stirred for lh. After the addition of 300 ml diethyl ether stirring was continued for 1 h, the precipitate collected and washed with diethyl ether. Drying over phosphorus pentoxide yielded 12.4 g (85%) 1-[4-(4-{2-[2-(4-Trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazolium methanesulfonat.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:20])[N:12]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1>CN(C=O)C.CCOCC.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>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:20])[N:12]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)#[N:2]
Reactant: N#C[Cu]
Reactant: COC(=O)Cn1c(=O)ccc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)ccc2ccc(C#N)cc21
Reaction time: 18 h
Yield: 71.4 %

Procedure:
CuCN (0.211 g, 2.36 mmol) and Pd(PPh3)4 (0.136 g, 0.118 mmol) were added to a solution of methyl 2-(7-bromo-2-oxoquinolin-1(2H)-yl)acetate (0.35 g, 1.18 mmol) in DMF (1 mL) in a screw cap vial. The vial was sealed and placed into a oil bath at 120° C. and the reaction mixture was stirred for 18 h. The resulting mixture was diluted with Et2O and washed with brine. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column to give methyl 2-(7-cyano-2-oxoquinolin-1(2H)-yl)acetate (0.204 g, 71%). Retention time (min)=1.464, method [1], MS(ESI) 243.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][C:6](N2CCOCC2)=[CH:5][CH2:4][CH2:3]1.CC1(C)CCCC(N2CC[O:25]CC2)=C1.[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1)[CH3:30].ClCCl>C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([CH:5]2[CH2:4][CH2:3][C:2]([CH3:14])([CH3:1])[CH2:7][C:6]2=[O:25])=[O:40])=[CH:34][CH:33]=1)[CH3:30]
Reactant: CC1(C)CCC=C(N2CCOCC2)C1
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: CC1(C)C=C(N2CCOCC2)CCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(NC(=O)C2CCC(C)(C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Compound I1, a mixture of 4-(5,5-dimethyl-cyclohex-1-enyl)-morpholine/4-(3,3-Dimethyl-cyclohex-1-enyl)-morpholine (3:1), (1.28 g, 6.55 mmol.) and 4-ethoxyphenyl isocyanate (1.20 g, 7.20 mmol.) in 32 mL of chloroform was stirred at room temperature for 20 h. Upon completion, 50 mL of dichloromethane was added and the resulting solution was washed with water twice and brine, dried over anhydrous sodium sulfate and concentrated. There was obtained 2.04 g of I2, which was used in next step without purification. MS (ESI+) 290 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:34](=[O:33])[CH2:35][OH:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CC(=O)OCC(=O)Cl
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CO)c1

Procedure:
The title compound was prepared analogous to the method described in Example 21 starting from (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a) (511 mg, 1.31 mmol), and Acetoxyacetyl chloride (155 μL, 1.44 mmol). Yield 429 mg (73%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:18](S(C2C=CC=CC=2)(=O)=O)[C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.[OH-].[K+].O>O1CCCC1.O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:18][C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccco1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ccco3)cc2c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of the compound obtained in the step of Example 1 (3) (675 mg) in a mixture of tetrahydrofuran/dioxane (5:1, 120 ml), a 1N aqueous potassium hydroxide solution (5 ml) was added and the mixture was stirred at 60° C. for 15 hours. The reaction solution was then poured into water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 431 mg (98%) of the desired product as a brown powder.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:18]1[CH2:30]O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.[OH-].[Na+]>ClCCl>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:18]1[CH2:30][F:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a solution of diethylaminosulfur trifluoride (1.5 ml, 12.16 mmol) in dichloromethane (10 ml) at −72° C. was added 1,4-dibenzyl-2-(hydroxymethyl)piperazine (3 g, 10.1 mmol) in dichloromethane (20 ml) over 10 minutes. The mixture was stirred for 16 h whilst warming to room temperature and treated with water (20 ml). The aqueous phase was basified to pH 9 using 4 M sodium hydroxide and the organic phase separated. The aqueous phase was extracted with dichloromethane (2×30 ml) and the combined organic layers dried with sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 20% (v/v) ethyl acetate in hexane to afford 1,4-dibenzyl-2-(fluoromethyl)piperazine (0.94 g) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C[O-].[Na+].Cl.[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28]>CCOCC>[CH3:26][N:27]([CH3:28])[CH2:29][CH2:30][O:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2nc3ncccc3o2)c1
Reactant: CN(C)CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CCOc1cccc(-c2nc3ncccc3o2)c1
Temperature: 25 °C

Procedure:
To a solution of 1.1 g. (0.005 mole) of 2-(3-hydroxyphenyl)oxazolo[4,5-b]pyridine in 15 ml. dried dimethylformamide is added 0.6 g. (0.011 mole) of sodium methoxide in portions over about 10 min. To the reddish-orange solution cooled in an ice-bath is added 0.72 g. (0.005 mole) of N,N-dimethyl-2-chloroethylamine hydrochloride in portions over 15 minutes. The resultant mixture is then stirred 10 minutes, set in an oil-bath at 75° C., and kept at 75°-90° C. (bath) for 20 hours. After cooling to room temperature, 15 ml. of dried ether is added with stirring, and the resultant mixture is filtered. The filtrate is then stripped of solvent, and the residue distributed between methylene chloride and water. The organic layer is dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-[3-(2-dimethylaminoethoxy)phenyl]oxazolo[4,5-b]pyridine.