Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].I[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:31]2[CH:40]=[CH:39][C:34]3[O:35][C:36]([CH3:38])=[CH:37][C:33]=3[CH:32]=2)=[CH:15]/[CH2:16][O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:20]([CH3:30])[CH:19]=2)=[CH:10][CH:9]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[CH3:30][C:20]1[CH:19]=[C:18]([O:17][CH2:16]/[CH:15]=[C:14](/[C:31]2[CH:40]=[CH:39][C:34]3[O:35][C:36]([CH3:38])=[CH:37][C:33]=3[CH:32]=2)\[C:11]2[CH:12]=[CH:13][C:8]([C:6]#[C:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:9][CH:10]=2)[CH:29]=[CH:28][C:21]=1[O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Under nitrogen atmosphere, 3-(N,N-dimethylamino)propyne (250 mg, 3.00 mmol) was added to a degassed solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]-furan-5-yl)allyloxy]-2-methylphenoxy]acetate (370 mg, 0.63 mmol; prepared as described in example 25) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooled to 0° C., tetrakis(triphenylphosphine)palladium (71 mg, 0.06 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[2-methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(dimethylamino)propynyl]phenyl]-allyloxy]phenoxy]acetate.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([C:17]([C:19]2[CH2:20][N:21]([CH3:26])[C:22](=[O:25])[C:23]=2[OH:24])=[O:18])[O:15][CH3:16])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:24][C:23]1[C:22](=[O:25])[N:21]([CH3:26])[CH2:20][C:19]=1[C:17]([N:14]([CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:27])=[O:5])=[CH:12][CH:11]=1)[O:15][CH3:16])=[O:18]
Reactant: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON(Cc1ccc(C(=O)O)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 4-{[(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-methoxyamino]-methyl}-benzoic acid tert-butyl ester (0.062 g, 0.16 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (0.6 ml) and stirred at 25° C. for 2 h. The solvent was then evaporated in vacuo and the residue was triturated with acetonitrile to give 0.041 g (80% yield) of the title material as a white solid; mp 196–197° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.97 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.19 (2H, s, NCH2), 4.96 (2H, s, NCH2), 7.42 (2H, d, J=8.3 Hz, aromatics), 7.91 (2H, d, J=8.3 Hz, aromatics), 11.4 (1H, broad s, OH), 12.9 (1H, broad s, OH). Anal. calcd for C15H16N2O6.H2O: C, 53.25; H, 5.36; N, 8.28. Found: C, 53.59; H, 4.79; N, 8.19.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Li][CH3:10].[NH4+].[Cl-].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH3:10])[S:5][CH:6]=1
Reactant: [Li]C
Reactant: O=Cc1cc(Br)cs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cc(Br)cs1
Yield: 98.5 %

Procedure:
A solution of 4-bromo-2-thiophenecarboxaldehyde (Aldrich, 1.20 g, 6.28 mmol) in 15 ml of anhydrous ethyl ether is brought to −70° C. in a flask fitted with a thermometer, under an atmosphere of argon and with magnetic stirring. Then a 1.6 M solution of MeLi in ether (4.12 ml, 6.59 mmol) is added drop by drop between −70° C. and −60° C. The reaction is followed by CCM (eluent ether:petroleum ether=20:80). The mixture is hydrolysed in the cold with 5 ml of saturated NH4Cl solution, 20 ml of distilled water is added and the mixture is extracted with ether (3×40 ml). The ether phase is dried over MgSO4, filtered and evaporated to obtain 1.28 g of a slightly yellowish oil, 4-bromo-2-(1′-hydroxyethyl)thiophene (gross yield=98.5%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH2:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH3:11].C([O-])([O-])=O.[K+].[K+].CC(O)C>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.C1(C)C=CC=CC=1>[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([OH:9])=[O:8])=[CH:14][CH:13]=1)[CH3:11]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C(O)c1ccsc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2sccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-3-thiophenecarboxylic acid (3 g, 14.1 mmol), (4-ethylphenyl)boronic acid (2.28 g, 15.2 mmol), K2CO3 aqueous solution (35 mL, 2M, 70.2 mmol), Pd(PPh3)4 (496 mg, 0.429 mmol), IPA (30 mL) and toluene (30 mL). The resulting solution was stirred overnight at 80° C. in an oil bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:6). The solids were filtered out and washed by 20 mL ethyl acetate. Collected the organic phases and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 2.33 g (71%) of 2-(4-ethylphenyl)thiophene-3-carboxylic acid as light yellow oil.
Reaction SMILES: [Na].O1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3]1=[O:11].CO[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].O.[CH2:23]([OH:25])C>C(O)(=O)C>[CH3:23][O:25][C:9]1[CH:10]=[C:5]([CH:4]2[C:3](=[O:11])[C:19]3[C:16](=[CH:15][CH:14]=[CH:21][CH:20]=3)[C:17]2=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: O=C1Cc2ccccc2O1
Reactant: COc1cccc(C=O)c1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C2C(=O)c3ccccc3C2=O)c1
Temperature: 20 °C

Procedure:
Sodium (18.9 parts) was dissolved in absolute ethanol (380 parts) with stirring and was cooled to 20° C. and benzofuranone (100 parts) and 3-methoxybenzaldehyde were added. The reaction mixture was stirred under reflu for 15 minutes and cooled to 20° C. over 1 hour. The reaction mixture was poured into water (900 parts) and the ethanol was removed by evaporation under reduced pressure. Hydrochloric acid was added to the solution until acid and the aqueous phase was decanted to leave a red gum. The gum was dissolved in hot acetic acid (300 parts) and the solution was cooled to 20° C. and a solid was precipitated. The solid was isolated by filtration, washed with ethanol (74 OP) and dried to give 2-(3-methoxyphenyl)-1,3-indandione (55.8 parts) m.pt. 142°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]([C@H:5]1[C@@H:14]([CH3:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1nc2ccccc2cc1C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1Nc2ccccc2C[C@@H]1C
Yield: 78.2 %

Procedure:
2-Methoxycarbonyl-3-methylquinoline (30 g, 0.149 mol) in acetic acid (300 mL) was hydrogenated over platinum oxide (1 g) under atmospheric pressure of hydrogen at room temperature until the theoretical amount of hydrogen was consumed. The mixture was passed through celite and concentrated in vacuo. The residue was purified by silica gel column chromatography with 20:1 to 10:1 hexane/ethyl acetate to give 23.93 g of cis-2-methoxycarbonyl-3-methyltetrahydroquinoline (78%): 1H NMR (270 MHz, CDCl3) d 6.99 (m, 2H), 6.64 (t, 1H, J=7.9 Hz), 6.58 (d, 1H, J=7.9 Hz), 4.34 (s, 1H), 4.09 (t, 1H, J=2.5 Hz), 3.06 (dd, 1H, J =16.9, 5.8 Hz), 2.55 (m, 1H), 2.50 (dd, 1H, J=16.9, 3.3 Hz), 0.88 (d, 3H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:15])=O.[CH2:17](O)[CH2:18][CH3:19]>>[ClH:15].[CH2:17]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH2:18][CH3:19]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CCCO
Product: CCCOC(=O)[C@@H](N)Cc1ccccc1
Product: Cl
Temperature: 50 °C
Yield: 99 %

Procedure:
A suspension of 2.0 g of L-phenylalanine in 30 ml of n-propyl alcohol was heated to 50° C., 3.5 ml of thionyl chloride added thereto, and the reaction then continued for 5 hours until the L-phenylalanine crystals were dissolved. After completion of the reaction, the mixture was concentrated under a reduced pressure to obtain crude crystals. These crystals were then recrystallized from a solvent mixture of methanol-ether to give 2.93 g of L-phenyl alanine n-propyl ester hydrochloride as colorless crystals (yield: 99%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[CH:6]=1.CS[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17].C(N(CC)CC)C.[NH2:27][CH:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[N:30]([CH2:39][C:40]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:41])[C:29]1=[O:47]>C(O)C>[C:16]([C:15]([C:18]#[N:19])=[C:14]([NH:27][CH:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[N:30]([CH2:39][C:40]([N:42]2[CH2:43][CH2:44][CH2:45][CH2:46]2)=[O:41])[C:29]1=[O:47])[NH:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([CH3:1])=[CH:6][C:5]=2[CH:7]=1)#[N:17]
Reactant: NC1CCc2ccccc2N(CC(=O)N2CCCC2)C1=O
Reactant: Cc1cc2cc(N)ccc2o1
Reactant: CSC=C(C#N)C#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2cc(NC(NC3CCc4ccccc4N(CC(=O)N4CCCC4)C3=O)=C(C#N)C#N)ccc2o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 2.9 %

Procedure:
Preparation of title compound. A solution of 2-methyl-5-benzofuranamine (0.24 mmol), 1,1-bis(methylthio-2,2-dicyanoethylene (34 mg, 0.20 mmol) and triethylamine (0.035 mL, 0.25 mmol) in ethanol (0.35 mL) was stirred at 80° C. for 4 h. To the mixture was added 1-[(3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl)acetyl]pyrrolidine (70 mg, 0.24 mmol) and the resulting reaction was stirred at 80° C. overnight. The reaction mixture was purified by column chromatography (silica, 5% methanol/ethyl acetate) to afford the title compound (3 mg, 3% yield): MS (ESI, pos. ion spectrum) m/z 509; HPLC (method A) tR 3.80 min.
Reaction SMILES: [C-:1]#N.[Na+].[CH:4]1(Br)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C[N:12]([CH:14]=O)C>>[CH:4]1([CH2:1][C:14]#[N:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: [C-]#N
Reactant: BrC1CCCCC1
Reactant: CN(C)C=O
Agent: [Na+]
Product: N#CCC1CCCCC1

Procedure:
A solution of sodium cyanide (2.77 g, 56.5 mmol) in 70 ml of DMF was treated with cyclohexyl bromide (7.9 ml, 56.5 mmol), under N2. The reaction mixture was reacted for 48 hours and then partitioned between EtOAc and H2O. The resultant layers were separated and the organic layer was concentrated in vacuo. The crude material was purified using flash chromatography (eluent of 5% EtOAc in hexanes).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:57]4[CH2:58][CH2:59][N:54]([CH3:53])[CH2:55][CH2:56]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN4CCN(C)CC4)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (22 μl, 0.13 mmol) was added N-methyl piperazine (9.3 μl, 0.08 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 20% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 91% conversion to product. A further portion of N-methyl piperazine (9.0 μl, 0.08 mmol) was added and the reaction mixture continued to stir at 40° C. for 5 hr. LC-MS indicated 98% conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (Example 9) as a light orange solid (26 mg, 47%): m/z 661 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.69-2.60 (3H, bm), 2.88-2.73 (3H, bm), 3.17-2.95 (4H, bm), 5.39 (2H, s), 6.34 (1H, s), 7.00 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.45 (2H, d), 7.66-7.56 (3H, m), 7.98 (1H, d), 8.37-8.28 (3H, m), 8.73 (1H, s), 8.91 (1H, s), 10.12 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C[O:12][CH:13](Cl)Cl.[Cl-].[NH4+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:10][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=1[CH:13]=[O:12]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1cc(C)c(C=O)c(O)c1C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A solution of 2,3,5-trimethylphenol (13.6 g, 100 mmol,) in dichloromethane (20 mL) was ice-cooled, titanium tetrachloride (41.7 g, 220 mmol) was added dropwise over 0.5 hr under nitrogen atmosphere, and the reaction mixture was stirred for 1 hr. Dichloromethyl methyl ether (11.5 g, 100 mmol) was added dropwise, and the mixture was further stirred for 6 hr. The reaction mixture was treated with saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The extract was washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-50:50) to give the title compound (6.58 g, yield 40%) as pale-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>C(Cl)Cl>[C:33]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (300 mg, 0.82 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Propionyl chloride (0.358 mL, 4.1 mmol) was then added dropwise and the mixture was stirred at room temperature for 48 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.382 g, 98%). 1H NMR (Acetone d6, 400 MHz) δ 8.01 (d, J=8 Hz, 2H), 7.64-7.53 (m, 4H), 7.02 (d, J=9 Hz, 1H), 5.73 (d, J=9 Hz, 1H), 5.69-5.62 (m, 1H), 5.44 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3H), 2.35 (q, J=7 Hz, 1H), 2.34 (q, J=7 Hz, 1H), 1.46 (d, J=6 Hz, 3H) and 1.03 (t, J=8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)([O:27][CH3:28])C3C=CC(C#N)=CC=3F)=[C:15]3[C:10]([CH:11]=[C:12]([F:36])[C:13]([F:35])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+].Cl.C([N:44]([CH2:47][CH3:48])CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[O:27][CH2:28][C:12]3[CH:11]=[CH:10][C:48]([C:47]4[N:37]=[N:38][NH:39][N:44]=4)=[CH:14][C:13]=3[F:35])=[C:15]3[C:10]([CH:11]=[C:12]([F:36])[C:13]([F:35])=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(c1ccc(C#N)cc1F)(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(C(OCc3ccc(-c4nn[nH]n4)cc3F)C3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxymethyl}-3-fluoro-benzonitrile (example 41) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as yellow foam. MS: m/e=553.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1)[CH2:14][CH2:15][OH:16].C(N(CC)CC)C.O>C(#N)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH:13]([NH:12][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])[CH2:14][CH2:15][OH:16])=[CH:22][CH:21]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)c1ccc(C(N)CCO)cc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(CCO)NC(=O)c2c(F)cccc2F)cc1
Reaction time: 7 h
Yield: 86.4 %

Procedure:
2,6-Difluorobenzoyl chloride (2.65 g, 0.015 mol) is added in portions to a solution of 3-amino-3- (4-t-butylphenyl)-1-propanol (3.1 g, 0.015 mol) and triethylamine (3.03 g, 0.04 mol) in 30 ml of acetonitrile at room temperature (20° C.) in the course of 10 minutes. The reaction mixture is further stirred for 7 hours, water is added and the mixture is extracted with ethyl acetate. 4.5 g of N-[1-(4-t-butylphenyl)-3-hydroxy-propyl]-2,6-difluorobenzamide are isolated from the ethyl acetate phase as a crude product having a content of 28% according to GC/MS analysis, which is employed as such in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11]N3CCN(S(C)(=O)=O)CC3)[S:8][C:6]=2[N:7]=1.ClC1N=C(N2CC[O:41]CC2)C2C=CSC=2N=1.[Li]CCCC.CN(C=O)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH:11]=[O:41])[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -60 °C

Procedure:
Scheme 7 shows the synthesis of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 by formylation of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 in THF at −78° C. with n-BuLi in hexanes (1.2 equiv.). The resulting slurry was allowed to warm up to −60° C., cooled to −78° C. and DMF (1.5 equiv.) was added slowly to afford 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 19. To a suspension of 19, 4-(methylsulfonyl)piperazin-1-ium chloride 8 (alternatively named as 1-(methylsulfonyl)piperazine hydrochloride, 1.45 equiv.) and anhydrous sodium acetate in 1,2-dichloroethane was added trimethyl orthoformate (10 equiv.). The slurry was stirred at ambient temperature for at least 6 hours, then sodium triacetoxyborohydride was added and the reaction was stirred for 24 hours to give 20.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19]>CN(C)C=O>[C:3]([NH:6][C:7]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCOC(C)=O)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A stirred suspension of 95% sodium hydride (60.8 g, 2.532 mol) in anhydrous dimethylformamide (500 ml) under an atmosphere of argon was cooled to 0° C. (ice bath). A solution of diethyl acetamidomalonate (500 g, 2.302 mol) in anhydrous dimethylformamide (1.2 l) was added over a period of 45 minutes while keeping the reaction temperature below 18° C. After the addition was complete, the turbid solution was gradually warmed to room temperature. After stirring for one hour at room temperature, 4-bromobutyl acetate (471.5 g, 2.417 mol) was added. The mixture was then stirred at 59°-60° C. for 18 hours. The resulting slurry was cooled to room temperature, quenched with absolute ethanol (40 ml) and glacial acetic acid (4 ml), stirred for about 15 minutes, poured into a 10% lithium chloride solution and extracted with ethyl acetate (2×3 l). The combined ethyl acetate extracts were washed with 10% lithium chloride (3×3 l), dried (anhydrous sodium sulfate), and evaporated in vacuo to give 750 g of title product as an oil.
Reaction SMILES: Br.[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C(Cl)[Cl:35]>CO>[ClH:35].[CH2:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:25](=[O:26])[NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[CH2:6]1)[CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCCN1CCCC(c2cccc(O)c2)C1
Reactant: O=C=Nc1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCN1CCCC(c2cccc(OC(=O)Nc3ccccc3)c2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A mixture of N-n-propyl-3-(3-hydroxyphenyl)piperidine hydrobromide (0.76 g, 0.0025 mol), phenylisocyanate (5.45 g, 0.046 mol), triethylamine (0.5 g, 0.049 mol) and methylene chloride (2 ml) was stirred at r.t. for 18 h. The mixture was partitioned between water and ether. The ether phase was dried and evaporated giving a partly crystalline residue. The residue was dissolved in methanol and chromatographed on a silica gel column (200 g, SiO2) with methanol as eluant. The fractions which according to GLC contained the desired product in pure form were continued and the solvent evaporated. The residue was dissolved in ether and treated with HCl-saturated ether giving a crystalline precipitate. Filtration and washing gave 0.18 g (20%) of the desired hydrochloride, mp. 184°-190° C.