Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[Cl:15])=[O:7])=[CH:4][N:3]=[CH:2]1.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[C:6]([C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:7])[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(C(=O)c2cncs2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(C(=O)c4cncs4)c(Cl)c3)c2cc1OC
Yield: 31 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-amino-2-chlorophenyl 5-thiazolyl ketone was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-[3-chloro-4-(5-thiazolylcarbonyl)anilino]-6,7-dimethoxyquinazoline hydrochloride salt in 31% yield, m.p. 254°-257° C.;
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:15][C:16]1[N:17]=[CH:18][NH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)OC1C=CC(N2C(C)=CN=C2)=C(C=1)C#N>>[F:12][C:11]([F:14])([F:13])[O:10][C:7]1[CH:8]=[CH:9][C:2]([N:19]2[CH:20]=[C:16]([CH3:15])[N:17]=[CH:18]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1cc(OC(F)(F)F)ccc1F
Agent: Cc1cncn1-c1ccc(OC(F)(F)F)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(OC(F)(F)F)cc2C#N)cn1

Procedure:
In analogy to example 5a, 2-fluoro-5-trifluoromethoxy-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. Aqueous workup afforded a 3:1 mixture of the title compound and its regioisomer [5-trifluoromethoxy-2-(5-methyl-imidazol-1-yl)-benzonitrile] as a light brown viscous oil (yield: 100%). 1H-NMR (300 MHz, DMSO): δ=2.19 (s, 3H), 7.37 (s, 1H), 7.75-7.90 (m, 2H), 8.02 (s, 1H), 8.27 (d, J=2.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:22]([CH3:24])[CH3:23].O>CN(C)C=O>[Br:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:22]([CH3:24])[CH3:23])=[CH:12][CH:13]=2)=[N:4][N:3]=1
Reactant: CC(C)I
Reactant: Oc1ccc(Oc2nnc(Br)s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2nnc(Br)s2)cc1
Temperature: 85 °C
Yield: 99.3 %

Procedure:
A solution of Example 24B (1.4 g, 5.11 mmol) in N,N-dimethyl formamide (20 mL) was treated with K2CO3 (1.06 g, 7.66 mmol) and 2-iodopropane (5.1 mL, 51.1 mmol) and the reaction mixture was sealed in a screw-top pressure vessel and heated at 85° C. for 2 hours. The reaction was cooled to 25° C., poured into water (200 mL), and extracted with diethyl ether (2×100 mL). The combined organic layers were washed with water (3×80 mL) and brine (80 mL), dried (Na2SO4), filtered and evaporated to provide 1.6 g of a light brown solid. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient from 1% to 14% ethyl acetate in hexanes to provide 0.8 g (50%) of the title compound as a clear colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.37 (d, J=9.19 Hz, 2H) 7.01 (d, J=9.19 Hz, 2H) 4.63 (heptet, J=5.88 Hz, 1H) 1.27 (d, J=5.88 Hz, 6H); MS (ESI) m/z 316.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:28])([C:24]([O:26][CH3:27])=[O:25])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[H-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH3:28])([C:24]([O:26][CH3:27])=[O:25])[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@]1(C)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reaction time: 2 h

Procedure:
To a stirred solution of (1R,3S)-methyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate, 52i, (0.085 g, 0.149 mmol) in 10 mL of MeOH was added NaH (0.004 g, 0.178 mmol) at room temperature. The resulting suspension was stirred for 2 hrs, quenched with solid NH4Cl. The mixture was concentrated in vacuo and purified via silica gel chromatography (3:1 Hexane:EtOAc), yielding 55 mg of the desired product, 52j.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]4[N:22]=[CH:23][CH:24]=[CH:25][C:13]=4[N:12]3[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]3([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:45].O1CCOCC1>C(Cl)Cl>[ClH:45].[ClH:45].[ClH:45].[ClH:45].[NH2:37][C:33]1([C:30]2[CH:29]=[CH:28][C:27]([C:26]3[N:12]4[C:13]5[CH:25]=[CH:24][CH:23]=[N:22][C:14]=5[NH:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:11]4=[N:10][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=3)[NH2:1])=[CH:32][CH:31]=2)[CH2:34][CH2:35][CH2:36]1
Reactant: Cc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
tert-Butyl (1-{4-[2-(3-amino-4-methylphenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (28.2 mg, 0.0482 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 2 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (30.2 mg, 99.3%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.86-8.70 (m, 2H), 8.63 (s, 1H), 8.11 (dd, J=4.8, 1.4 Hz, 1H), 7.92 (dd, J=8.0, 1.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.57-7.52 (m, 2H), 7.41-7.35 (m, 1H), 7.35-7.28 (m, 3H), 7.19-7.10 (m, 3H), 6.91 (dd, J=8.0, 1.4 Hz, 1H), 6.75 (dd, J=8.0, 4.8 Hz, 1H), 2.64-2.37 (m, 4H), 2.30 (s, 3H), 2.26-2.13 (m, 1H), 1.89-1.75 (m, 1H); LCMS: 485 [M+H].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NC(CO)CO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1NC(CO)CO
Temperature: 60 °C
Yield: 11 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.4 g of 2-amino-1,3-propanediol, and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 0.32 g of 2-(4-nitro-2-methylphenylamino)propane-1,3-diol (13) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH2:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1/[C:11](=[CH:13]/[CH:14]([CH3:16])[CH3:15])/[CH3:12].NC1C=CSC=1/C(=C\C(C)C)/C>>[NH2:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH2:12]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Agent: [Al+3]
Agent: [Cl-]
Product: C=C(CC(C)C)c1sccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 12 %

Procedure:
Into a solution obtained by dissolving 3-aminothiophene (2.0 g, 20.6 mmol) in 4-methyl-2-pentanone (28.3 g), which was obtained by the method in Example 14 using methyl 3-aminothiophene-2-carboxylate as a starting material was added aluminum chloride (1.3 g, 24.5 mmol) at room temperature, and the resulting solution was stirred under nitrogen atmosphere at 60 degree centigrade for 5 hours. The reaction solution was cooled to room temperature, and then washed with a 10% aqueous sodium hydroxide solution, and separated. As a result of the analysis by the HPLC internal standard method of the obtained organic layer, 0.4 g was produced as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene (yield: 12%).
Reaction SMILES: C(OC(=O)C[CH2:8][C:9]1[C:14](C)=[CH:13][C:12]([C:16](=[NH:19])[NH:17][OH:18])=[CH:11][C:10]=1C)(C)(C)C.[OH:22]CC1C=CC(C#N)=CC=1>>[OH:18][NH:17][C:16](=[NH:19])[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:22])=[CH:10][CH:11]=1
Reactant: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CO)cc1
Product: N=C(NO)c1ccc(CO)cc1

Procedure:
The title compound is prepared in analogy to 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid tert-butyl ester (step g) starting from 4-hydroxymethyl-benzonitrile; LC-MS: tR=0.21 min, [M+1]+=167.04.
Reaction SMILES: Cl[Sn]Cl.Cl.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[N:13][C:12]=2[CH:16]=1)([O-])=O.[OH-].[Na+]>>[NH2:5][C:8]1[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[N:13][C:12]=2[CH:16]=1
Reactant: O=[N+]([O-])c1ccc2scnc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Nc1ccc2scnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of SnCl2 (7.0 g, 8.8 mmol) and 14 mL of con.HCl was added 5-nitrobenzothiazole (0.65 g, 3.6 mmol) in a portion and resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was basified with aqueous NaOH and extracted with EtOAc. Combined organic layers were dried over Na2SO4 and concentrated in vacuo yielding an oil (0.47 g, 3.2 mmol, 89%) which was identified as the amine (>95% pure)and subjected to the following reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O>C1C=CC=CC=1.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[CH:15][C:14]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:13]=2[Cl:12])[C:9](=[O:10])[CH3:11])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(=O)Cc1ccc(Br)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CC(=O)C(=Cc1ccc(Cl)cc1Cl)c1ccc(Br)cc1
Yield: 98.2 %

Procedure:
A mixture of 15.9 g of 1-(4-bromophenyl)acetone, 13 g of 2,4-dichlorobenzaldehyde and 0.5 g of piperidine in 300 ml of benzene is heated under reflux for 18 hours, removing the water that forms by means of a Dean Stark. 0.3 g of piperidine is added, and it is refluxed for a further 24 hours. The reaction mixture is concentrated under vacuum, obtaining 27 g of the expected compound in the form of oil.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN(C)[CH:21]=[C:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>O1CCCC1.CCOCC>[C:1]1([CH2:21][CH:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=C1C=CC=C1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C1=CC(Cc2cccc3c2Cc2ccccc2-3)C=C1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
A second batch of the cyclopentadienyl-type ligand, (fluorenyl)(cyclopentadienyl)methane was prepared as follows. A solution of 13.7 g (0.0824 moles) fluorene in 200 mL tetrahydrofuran (THF) was treated with (0.0826 moles) n-butyllithium at room temperature. After 14.5 hours, 10.00 g (0.0825 moles) solid 6-(dimethylamino)fulvene were added to the orange-brown solution and the mixture was stirred at room temperature for 8.5 hours. The mixture was then reacted with 6.50 g (0.171 moles) LiAlH4 and refluxed 15.5 hours. Then 0.0032 moles n-butyllithium was added and the mixture was stirred for 10 minutes. The mixture was hydrolysed with 500 g ice, 500 mL ether and 200 mL concentrated HCl. The aqueous phase was extracted 3 times with 300 mL ether. The ether extracts were combined and the ether evaporated. The solid residue was mixed with pentane and filtered over silica. The yield was 5.7 g (fluorenyl)(cyclopentadienyl)methane having a gas chromatographic purity of 98%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[C:19](OC)=[O:20])=[CH:4][CH:3]=1.[BH4-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH2:19][OH:20])=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1nc(-c2ccc(F)cc2)oc1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A mixture of 5-(5-chlorothiophen-2-yl)-2-(4-fluorophenyl)-4-methoxycarbonyloxazole (1.8 g) and lithium borohydride (580 mg) in tetrahydrofuran (40 ml) was stirred at room temperature for one hour, and then, refluxed for 1.5 hours. After cooling, water and 10% hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether-ethyl acetate to obtain 5-(5-chlorothiophen-2-yl)-2-(4-fluoro-phenyl)-4-hydroxymethyloxazole (1.48 g) as colorless powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18]>>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Product: COc1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 100 °C
Yield: 18.6 %

Procedure:
Mix morpholine (1.50 mL, 17.20 mmol) and 1-chloro-2-methoxy-4-nitro-benzene (1.06 g, 5.65 mmol) and heat to 100° C. for 4 h while stirring. Cool the solution to room temperature, then partition between EtOAc (40 mL) and 1N HCl (20 mL). Wash the organic solution with water (20 mL) and brine (20 mL), dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 50% EtOAc/hexanes, to give the title compound as a yellow solid (250 mg, 18%). MS (ES+) 239.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 7.86 (dd, 1H, J=8.8, 2.6 Hz), 7.71 (d, 1H, J=2.2 Hz), 6.87 (d, 1H, J=9.2 Hz), 3.94 (s, 31), 3.87 (m, 4H), 3.21 (m, 4H).
Reaction SMILES: [H-].[Na+].C[CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[CH3:4][O:5][C:6](=[O:7])[C:8](=[C:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]1)[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% NaH (2.005 g; 50.00 mmol) in anhydrous THF (100 mL), under an atmosphere of argon, was added triethyl 2-phosphonopropionate (10.73 mL; 50.00 mmol), at such a rate as to keep the reaction temperature below 30° C. The resulting mixture was stirred at room temperature for a further 1 hr. A solution of N-Boc-4-piperidone (9.965 g; 50.00 mmol), in anhydrous THF (50 mL), was added dropwise over five minutes. The resulting clear solution was stirred at ambient temperature for ˜1 hr. The reaction was quenched by the addition of water (100 mL). The resulting mixture was partitioned, the aq layer extracted once with EtOAc and the combined organics washed with saturated brine. The organics were dried over MgSO4, filtered and evaporated to a colourless oil; 14.76 g. (˜quantitative yield). This was used in the next stage without further purification. 1H NMR δ 1.19 (t, 3H), 1.36 (s, 9H), 1.77 (s, 3H), 2.25-2.37 (m, 2H), 2.51-2.56 (m, 2H), 3.22-3.44 (m, 4H), 4.11 (q, 2H). MS m/e [MH—(CO2, C4H8)]+=184.31.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=O)[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([CH2:32][CH:33]=[CH2:34])[CH2:29][NH:30][CH3:31])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([N:30]([CH2:29][C@H:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[CH2:32][CH:33]=[CH2:34])[CH3:31])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:2]
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Reactant: N#Cc1cc2c(c(C(=O)O)c1)CCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2c1CCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
6-Cyanoindane-4-carboxylic acid (150 mg, 0.8 mmol) and oxalyl chloride (130 mg, 1.0 mmol) were mixed with CH2Cl2 (20 mL) whereupon DMF (100 mg) was added. After 1 h at room temperature [(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]methylamine (Bioorg. Med. Chem. Lett; 2001; 265-270; 200 mg, 1.0 mmol) and triethylamine (200 mg, 2.0 mmol) were added to the mixture in the given order. The mixture was stirred at room temperature for 20 min and then the solvent was evaporated. The product was purified by chromatography on silica gel using hexane and ethyl acetate (1:1). There was obtained 180 mg (62%) of 6-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylindane-4-carboxamide as an oil. 1H NMR (300 MHz, CDCl3): 2.0-2.1 (m, 2H), 2.2 (t, 1H), 2.4 (m, 2H), 2.6 (s, 4H), 2.8-3.4 (m, 4H), 3.7 (dd, 1H), 3.8-3.9 (dd, 1H), 4.9-5.1 (m, 2H), 5.4-5.8 (m, 1H), 6.8-7.1 (m, 4H), 7.2 (m, 1H), 7.5 (s, 1H).
Reaction SMILES: [CH2:1]([OH:5])[C@@H:2]([OH:4])[CH3:3].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].N1C=CN=C1>CN(C=O)C>[Si:6]([O:5][CH2:1][C@H:2]([OH:4])[CH3:3])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C[C@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (s)-(+)-1,2-propanediol (2.0 g, 26.3 mmol) in DMF (5 mL) was added TBS-Cl (5.94 g, 39.4 mmol) and imidazole (2.147 g, 31.5 mmol). The reaction was stirred at 25° C. for 18 h. The reaction mixture was partitioned between ethyl acetate and sat. ammonium chloride. The organic phase was washed with sat ammonium chloride and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography to give 33A (4.0 g, 80% yield) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH:27]([OH:37])[CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)C.CO.O.O.[OH-].[Li+]>C1COCC1>[OH:37][CH:27]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3([CH2:5][C:4]([OH:38])=[O:3])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1)[CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(-c4ccncc4C(O)CCCc4ccccc4)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1(c2ccc(-c3ccc(-c4ccncc4C(O)CCCc4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1-{4′-[3-(1-Hydroxy-4-phenyl-butyl)-pyridin-4-yl]-biphenyl-4-yl}-cyclopropyl)-acetic acid ethyl ester (0.240 g, 0.475 mmol) was dissolved in THF (5 mL), MeOH (2 mL) and H2O (2 mL) then lithium hydroxide monohydrate (0.100 g, 2.38 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was submitted to standard aqueous workup then triturated with CH2Cl2:hexanes to afford the product as a solid that was recovered by filtration.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)[CH2:8][CH2:7][CH2:6]2)#[N:2].S(Cl)(Cl)=O.N1CCOCC1>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[S:17][N:16]=[CH:15][CH:14]=1)=[CH:8][CH2:7][CH2:6]2)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1ccns1
Solvent: C1COCCN1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: N#Cc1ccc2c(c1)CCC=C2c1ccns1

Procedure:
Analogously to Example 13, 92 mg of 6-cyano-1-hydroxy-1-(5-isothiazolyl)-1,2,3,4-tetrahydronaphthalene (Example 15) and 0.051 ml of thionyl chloride in 0.32 of benzene, with the subsequent addition of 0.112 ml of morpholine, are converted into the crude title compound, which is purified by column chromatography (SiO2, 0.1 bar, hexane/ethyl acetate 4:1) and crystallisation from hexane; m.p. 77°-81°; 1H-NMR (CECl3): δ(ppm)=2.5 (m,2H), 2.92 (t,2H), 6.54 (t,2H), 7.2 (d,1H), 7.29 (d,1H), 7.5 (dd,1H), 7.55 (d,1H), 8.5 (d,1H).
Reaction SMILES: C[C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4](C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H:3]1[CH2:23][NH:24]C1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[N:57]=[CH:56][CH:55]=[N:54]1)=[O:45].ClC1N=C(C#N)C=CC=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[N:57]=[CH:56][CH:55]=[N:54]2)[C@@H:37]1[CH2:36][NH:35][C:5]1[N:4]=[C:3]([C:23]#[N:24])[CH:2]=[CH:7][CH:6]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Agent: N#Cc1cccc(Cl)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cccc(C#N)n2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 6-chloropicolinonitrile. ESI-MS (m/z): 416 [M+1]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([CH3:12])[CH:3]=1.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: Br
Reactant: Cc1cc(N)ccc1OC(F)F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)ccc1OC(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a stirred solution of 4-amino-1-difluoromethoxy-2-methyl-benzene (5 g, 28.90 mmol) in HBr (20 mL) and water (20 mL) at 0° C. was added a solution of sodium nitrite (2.07 g, 30.00 mmol) in H2O (10 ml) dropwise over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. Copper (I) bromide (4 g, 27.87 mmol) was then added and the mixture was heated at 60° C. for 30 minutes. The resulting solution was extracted with EtOAc (3×50 mL) and the combined organic layers washed with H2O (1× 20 mL), dried over Na2SO4 and concentrated to provide 2.5 g (37%) of 4-bromo-1-(difluoromethoxy)-2-methylbenzene.