Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][C:23]#[N:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(#N)C.O.F[B-](F)(F)F.[Li+].[OH-].[NH4+]>>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][C:23]#[N:24])[CH:20]=2)=[N:14][CH:13]=1
Reactant: CCCCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: F[B-](F)(F)F
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCCCCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a solution of 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]octanenitrile (13 g, 0.030 mol) (peak 2 from chiral separation in Step 2) in acetonitrile (200.0 mL, 3.829 mol) and water (16.0 mL, 0.888 mol, ˜8% acetonitrile/water) was added lithium tetrafluoroborate (28.4 g, 0.297 mol). The reaction was refluxed at 100° C. overnight. The mixture was cooled down and 7.2 M of ammonium hydroxide in water (17 mL, 0.12 mol) was added in portions over a period of 5 minutes at room temperature, adjusting pH to 9-10 with stirring for 2 h. The solid was removed by filtration and the filtrate was diluted with acetonitrile, water and MeOH for purification by preparative LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (5.9 g, 64%). MS calculated for C17H21N6(M+H)+: m/z=309.183. Found: 309.3. 1H NMR (300 MHz, DMSO-D6) δ 12.10 (1H, s), 8.78 (1H, s), 8.66 (1H, s), 8.36 (1H, s), 7.458 (1H), m), 6.97 (1H, m), 4.71 (1H, m), 3.18 (1H, m), 3.16 (1H, br s), 1.93 (1H, m), 1.81 (1H, m) 1.19 (5H, m), 0.97 (1H, m), 0.78 (3H, t, J=6.3 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH3:12])[CH2:6]1)=[O:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][C@H:8]([NH:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:7]([CH3:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(=O)C(C)C1
Reactant: NCc1ccccc1
Product: COC(=O)N1CC[C@H](NCc2ccccc2)[C@H](C)C1

Procedure:
Racemic cis 4-benzylamino-3-methyl-piperidine-1-carboxylic acid methyl ester was prepared in the same manner from racemic 3-methyl-4-oxo-piperidine-1-carboxylic acid methyl ester. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([OH:22])[CH2:11][P:12]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:14])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[O:25]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[O:33]=[C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]([O:14][P:12]([CH2:11][C@H:10]([OH:22])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:13])[O:25]1
Reactant: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1
Reactant: O=C1OC(Br)c2ccccc21
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OC1OC(=O)c2ccccc21
Temperature: 120 °C
Yield: 21.5 %

Procedure:
To a solution of ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (0.5 g, 1.49 mmol) in 30 mL toluene was added 3-bromo-3H-isobenzofuran-1-one (952 mg, 4.47 mmol) and silver carbonate (1.23 g, 4.47 mmol). The reaction mixture was heated to 120° C. for 2 h. After filtering hot and concentrating in vacuo the crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a 35 g RediSep disposable column to give ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid 3-oxo-1,3-dihydro-isobenzofuran-1-yl ester (150 mg, 0.32 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.92 (m, 1H), 7.73 (m, 2H), 7.12 (m, 1H), 5.1 (m, 1H), 4.40 (m, 1H), 4.2 (m, 1H), 3.4-3.22 (m, 1H), 3.20-3.04 (m, 1H), 2.01-1.58 (m, 10H), 1.48 (s, 9H), 1.40-0.95 (m, 6H). LC/MS m/z: [M+H]+=468.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3ccc(Cl)cc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=1.01 min; [M+H]+=426.06.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[O:16])[CH:6]=1>C(O)(=O)C>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([C:17]2[CH:22]=[C:21]([N+:1]([O-:4])=[O:2])[C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[O:16])[CH:6]=1
Reactant: COc1cc(C(=O)c2cnc3ccccc3c2)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cnc3ccccc3c2)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1.91 ml of 65 percent nitric acid in 20 ml of glacial acetic acid is added dropwise to a solution of 5.5 g of 4-hydroxy-3-methoxyphenyl (3-quinolinyl) ketone in 300 ml of glacial acetic acid at 150° and the mixture is then stirred at this temperature for an additional 2 hours. The mixture is then poured into ice-water and extracted three times with 300 ml of ethyl acetate each time. The organic phase is washed five times with 100 ml of water each time, dried over sodium sulfate and evaporated. After treatment of the residue with ethyl acetate, there is obtained 4-hydroxy-3-methoxy-5-nitrophenyl (3-quinolinyl) ketone in the form of yellow crystals of m.p. 220°-221° (dec.).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([Cl:11])[N:3]=1.FC(F)(F)C(O)=O.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C.O>CC(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Clc1cc2nccn2c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: O
Product: N#Cc1ccc(NCCNc2nc(Cl)cc3nccn23)nc1
Temperature: 80 °C

Procedure:
707 mg (3.20 mmol) of 5,7-dichloroimidazo[1,2-c]pyrimidine (Example 11A) are suspended in 25 ml of 2-propanol, and 1.35 g (3.52 mmol) of 6-[(2-aminoethyl)amino]nicotinonitrile trifluoroacetate (Example 13A) and 1.03 g (7.99 mmol) of DIPEA are added. The mixture is heated at 80° C. for 16 h. After this time, water is added and the precipitate which has separated out is filtered off with suction. It is washed with a little 2-propanol/water and the resulting solid is dried under high vacuum. 523 mg (50% of theory) of the product are obtained.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[S:22][C:21]([S:23]([OH:26])(=[O:25])=[O:24])=[C:20]([CH3:27])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:28])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:14]([C:13]([C:18]1[S:22][C:21]([S:23]([OH:26])(=[O:25])=[O:24])=[C:20]([CH3:27])[CH:19]=1)([C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([CH3:28])[CH:9]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)O)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc(C)c(S(=O)(=O)O)s1
Temperature: 25 °C
Yield: 111.8 %

Procedure:
To a 0° C. solution of 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide (6.1 g, 11.68 mmol) in THF (150 ml) is added dropwise tetrabutylammonium fluoride (15.62 ml, 15.62 mmol, 1.0 M in THF) and is warmed to RT for 1 h. The reaction is quenched with satd aqueous NH4Cl (100 ml) and extracted with Et2O (2×200 ml). The combined organic layers are dried MgSO4 dried, concentrated and chromatographed (120 g SiO2, 50% EtOAc/Hex) to yield the title compound (4.63 g, 97%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)=[N:15][NH:14][C:13](=[O:25])[CH2:12]1.ClC1C=CC=CC=1>C(O)(=O)C>[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]3[N:23]=[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)[NH:24][C:19]=3[CH:18]=2)=[N:15][NH:14][C:13](=[O:25])[CH2:12]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccncc3)[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 17 g of isonicotinoyl chloride, 21.8 g of 5-methyl-6-(3,4-diaminophenyl)-4,5-dihydropyridazin-3-one ("IIa"; m.p. 195°-196°) and 400 ml of chlorobenzene is boiled for 2 hours. After having been cooled, the usual working up is carried out and, initially, an oily mixture of 5-methyl-6-(3-amino-4-isonicotinamidophenyl)- and 5-methyl-6-(3-isonicotinamido-4-aminophenyl)-4,5-dihydropyridazin-3-one is obtained, which is dissolved in 400 ml of acetic acid and boiled for 3 hours. After having been cooled, 5-methyl-6-[2-(4-pyridyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one ("M"), dihydrate, m.p. 195°-198° (decomposition) is obtained. Dihydrochloride-dihydrate, m.p. 224°-227°. Methanesulphonate, m.p. 282°-285°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OC2C=CC=CC=2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:22]>C(Cl)Cl>[Br:22][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCCCCOc2ccccc2)cc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(CCCCCBr)cc1

Procedure:
5-Bromo-1-(4-hydroxy-phenyl)-pentane (9.4) was synthesized as in 9.1 using 8.4 (3.43 g, 12.7 mmol) in anhydrous CH2Cl2 (120 mL), and BBr3 (1M solution in CH2Cl2, 32 mL, 32 mmol). The title compound (9.4) was isolated as a viscous liquid after purification by flash column chromatography (2.84 g, 92% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:29][CH:30]=[CH2:31])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:35]I>CN(C=O)C.C1OCCOCCOCCOCCOC1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:29][CH:30]=[CH2:31])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH3:35])=[CH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CI
Reactant: C=CCN(CCc1ccc(NS(=O)(=O)c2ccc(C(C)C)cc2)cc1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCc1ccc(N(C)S(=O)(=O)c2ccc(C(C)C)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a solution of allyl-{2-[4-(4-isopropyl-benzenesulfonylamino)-phenyl]-ethyl}-carbamic acid tert-butyl ester (200 mg, 0.44 mmol) in DMF (5 ml), 15-crown-5, and sodium hydride (20 mg, 0.48 mmol) were added, and the mixture was stirred at room temperature for 30 min. Methyliodide (60 mg, 0.44 mmol) was added and the mixture was stirred for 3 h at room temperature. After concentration in vacuo the residue was partitioned between dichloromethane and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give the product as a yellow oil (200 mg, 97%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([OH:28])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:35][NH:36][O:37][CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([C:26]([N:36]([O:37][CH3:38])[CH3:35])=[O:28])=[CH:15][CH:14]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(=O)O)ccc2c1=O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.4 %

Procedure:
To a mixture of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxylic acid (0.81 g, 1.8 mmol), N,O-dimethylhydroxylamine hydrochloride (0.211 g, 2.16 mmol), 1-hydroxy-1H-benzotriazole monohydrate (0.365 g, 2.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.517 g, 2.7 mmol) and N,N-dimethylformamide (10 mL) was added triethylamine (0.301 mL, 2.16 mmol), and the mixture was stirred at room temperature for 17 h. The reaction mixture was poured into 0.1 M aqueous citric acid solution (100 mL) and extracted 3 times with ethyl acetate (50 mL). The organic layers were combined, washed once with 0.1 M aqueous citric acid solution (50 mL), twice with saturated aqueous sodium hydrogencarbonate (50 mL) and once with saturated brine (50 mL), dried over anhydrous magnesium sulfate (15 g), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:4 (v/v)) to give tert-butyl(2-isobutyl-6-{[methoxy(methyl)amino]carbonyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.83 g, 94%) as a colorless, solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2CO3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was partitioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%). mp 143°-144° C.; 1H NMR (CD3OD, 400MHz) δ 1.65 (dq, J1 =3.16 Hz, J2 =11.9 Hz, 2H), 1.90-2.00 (m, 4H) , 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H), 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.
Reaction SMILES: [K+].[CH3:2][S:3][C:4]1[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([C:17]([O-:19])=O)=[CH:6][N:5]=1.[C:20]1([C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][C:27]=2[NH2:40])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]1([C:26]2[CH:31]=[C:30]([CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH:29]=[CH:28][C:27]=2[NH:40][C:17]([C:7]2[N:8]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[C:4]([S:3][CH3:2])=[N:5][CH:6]=2)=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: Nc1ccc(CCN2CCOCC2)cc1C1=CCCCC1
Reactant: CSc1ncc(C(=O)[O-])n1COCC[Si](C)(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ncc(C(=O)Nc2ccc(CCN3CCOCC3)cc2C2=CCCCC2)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 2-methylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylate potassium salt (90 mg, 0.28 mmol)(as prepared in the previous step), 2-cyclohex-1-enyl-4-(2-morpholin-4-yl-ethyl)-phenylamine (81 mg, 0.28 mmol)(as prepared in Example 33, step (c)), PyBrOP (170 mg, 0.37 mmol), and DIEA (0.10 mL, 0.57 mmol) in 1.5 mL of DCM was stirred for 8 h at RT. The mixture was diluted with 20 mL of DCM and washed with NaHCO3 (2×30 mL) and brine (30 mL) and dried over Na2SO4. Flash chromatography of the residue on Si gel with 100% EtOAc gave the title compound as a white solid (107 mg, 70%). Mass spectrum (ESI, m/z): Calcd. for C29H44N4O3SSi, 557.3 (M+H). found 556.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:24][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]Br
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)c(F)cc21
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Temperature: 38 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(6-fluoro-1-methyl-1H-indazol-5-yl)-methanone ((ii), 25.45 g, 74 mmol) and THF (4 L) was added methyl magnesium bromide (3 M, 43 mL) at 38° C. during 15 min. The mixture was stirred at 38° C. for 20 min. The RM was cooled to RT, quenched with 1M NaHCO3 and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The title compound was obtained after crystallization in DCM-TBME (1:2) as a beige solid (tR 3.30 min (conditions 1); MH+=346).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCc1ccc2c(c1)OCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc2c(c1)OCO2
Yield: 100.5 %

Procedure:
A solution of alcohol (a) (1.90 g, 11 mmol) in dichloromethane (25 ml) was treated at 0° C. with triethylamine (1.9 ml, 13.7 mmol) and methanesulfonyl chloride (1.1 ml, 13.7 mmol). After 1.5 hours at room temperature the mixture was partitioned between dichloromethane and water. The organic extract was dried and evaporated to give a yellow oil (2.7 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=2[Cl:1])=[CH:17][CH:16]=1)(=[O:14])[CH3:12]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CC(=O)c1ccc(N)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)c2cc(Cl)ccc2Cl)cc1
Yield: 76.2 %

Procedure:
Reaction of 2,5-dichlorobenzoic acid (300 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 4-aminoacetophenone (85 mg, 0.63 mmol) in presence of triethylamine (90 μL, 0.65 mmol) in THF (6 mL) according to method B gave N-(4-Acetyl-phenyl)-2,5-dichloro-benzamide (150 mg, 0.48 mmol, 76% yield) as a orange powder after purification by crystallisation in DCM.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23]N1C(=O)CCC1=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([Cl:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2cc3n(c2n1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cc1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reaction time: 18 h

Procedure:
To a solution of 0.20 g (0.66 mmol) (R)-4,6-dimethyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2 mL tetrahydrofuran was added 92.1 μg (0.69 mmol) N-chlorosuccinimide. The reaction was stirred at 50 deg C. for 18 h, then the solvent was evaporated and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:dichloromethane (1:19) as eluant.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][CH:16]3[CH:21]([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:23])=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9](O)=[O:10])[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[N:47]1([S:51]([NH2:54])(=[O:53])=[O:52])[CH2:50][CH2:49][CH2:48]1.Cl>O1CCCC1>[N:47]1([S:51]([NH:54][C:9](=[O:10])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[C:5]([O:14][CH2:15][CH:16]3[CH:21]([CH3:22])[CH2:20][CH2:19][CH2:18][CH:17]3[CH3:23])=[CH:6][C:7]=2[F:13])(=[O:53])=[O:52])[CH2:50][CH2:49][CH2:48]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC1CCCC(C)C1COc1cc(F)c(C(=O)O)cc1C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)NS(=O)(=O)N2CCC2)cc1C1CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a stirred solution of 5-cyclopropyl-4-((2,6-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid (0.07 g, 0.22 mmol) in tetrahydrofuran (2 mL) and under an atmosphere of nitrogen was added carbonyldiimidazole (0.053 g, 0.33 mmol) and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled down to ambient temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL, 0.45 mmol) was added followed by azetidine-1-sulfonamide (0.051 g, 0.37 mmol) and the stirring continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and directly purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.022 g, 22%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.75-8.55 (m, 1H), 7.57 (d, J=9.1 Hz, 1H), 6.62 (d, J=14.5 Hz, 1H), 4.23 (t, J=7.7 Hz, 4H), 4.01 (d, J=4.5 Hz, 2H), 2.35-2.17 (m, 2H), 2.07-1.95 (m, 2H), 1.86-0.56 (m, 20H); MS (ES+) m/z 439.1 (M+1); MS (ES−) m/z 437.2 (M−1).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)(O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([C:4]1[CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(O)(c2cccc(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1=CCC(c2cccc(F)c2)CC1
Temperature: 30 °C
Yield: 61.7 %

Procedure:
The compound (18) (13.5 g), p-toluenesulfonic acid (0.4 g) and toluene (250 ml) were mixed, and the mixture was heated under reflux for 2 hours while water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (300 ml) and toluene (500 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder and dried, giving 7.7 g of 4-propyl-1-(3-fluorophenyl)-3-cyclohexene (19). The yield based on the compound (18) was 61.7%.