Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([F:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(F)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(=O)OCC
Yield: 80 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.10 gm, 0.3 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (0.7 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 90 mg (80%) of 2-(p-methoxybenzyl)-3-methyl-4-ethoxycarbonyloxy-5-propyl-7-fluorobenzofuran, mp. 85°-88° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[O:16]1[C:20]2[CH:21]=[CH:22][C:23](/[C:25](=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][OH:47])=[C:31]([O:48][CH3:49])[CH:30]=3)/[C:26]#[N:27])=[CH:24][C:19]=2[O:18][CH2:17]1.N1C=CC=CC=1.CO>C1(C)C=CC=CC=1.CN(C=O)C.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:32]1[CH:33]=[CH:34][C:29](/[CH:28]=[C:25](/[C:23]2[CH:22]=[CH:21][C:20]3[O:16][CH2:17][O:18][C:19]=3[CH:24]=2)\[C:26]#[N:27])=[CH:30][C:31]=1[O:48][CH3:49])=[O:8])([O-:3])=[O:2]
Reactant: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.9 %

Procedure:
1.98 g (8.6 mmol) of 3,5-dinitrobenzoyl chloride are dissolved in 16 mL of toluene and 3 drops of DMF were incorporated. 4 g (8.6 mmol) of (2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}prop-2-enenitrile from example 7, 0.052 g (0.4 mmol) of 4-dimethylaminopyridine and 1.03 mL (13 mmol) of pyridine are added. The mixture is stirred at room temperature for 96 hours. The solution is then heated up to 60° C. and 6.5 ml of MeOH are added. The suspension is stirred at room temperature for 1 hour and at 0° C. for 1 hour. The precipitate is filtered off. Recristallisation of the residue in acetonitrile yielded 5.1 g (90%) of pure 11-{4-[(Z)-2-(1,3-benzodioxol-5-yl)-2-cyanoethenyl]-2-methoxyphenoxy}undecyl 3,5-dinitrobenzoate as yellowish powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.I[C:21]1[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:21]4[CH:29]=[CH:28][C:24]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN(C)c1ccc(I)cc1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2ccc(N(C)C)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 41.1 %

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (25 mg, 0.097 mmol), 4-iodo-N,N-dimethylaniline (20 mg, 0.097 mmol), N1,N2-dimethylethane-1,2-diamine (5 mg, 0.049 mmol), copper iodide (5 mg, 0.020 mmol), and potassium phosphate (40 mg, 0.191 mmol) in 0.5 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (15 h) at 70° C., the reaction was complete and allowed to cool to room temperature. The reaction was extracted with EtOAc (3×5 mL) and with NaHCO3 (2×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and the concentrated in vacuo. The crude mixture was then purified using the ISCO flash chromatography system using an 0-100% gradient EtOAc/100-0% gradient Hexane. Following concentration of the appropriate fractions in vacuo the product was further purified by recrystallization using a Et2O/Hexane solvent mixture to give the title compound as a light grey solid (15 mg, 39%). 1H NMR (DMSO) δ: 7.90 (s, 1H), 7.46-7.53 (m, 2H), 7.43 (d, J=6.7 Hz, 1H), 7.22-7.30 (m, 2H), 6.28 (s, 2H), 6.17 (d, J=7.0 Hz, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 3.02 (s, 6H) 2.65(t, j=5.3 Hz, 2H), 2.17 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[F:11].C([Li])CCC.CN([CH:20]=[O:21])C>C1COCC1>[F:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([F:8])=[CH:7][C:2]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: COc1cc(F)c(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C=O)cc1F
Temperature: -78 °C
Yield: 99.4 %

Procedure:
To a 250 mL three RB flask fitted with magnetic stirrer was charged 1-Bromo-2,5-difluoro-4-methoxybenzene (1.0 g, 4.5 mmol) in 10 mL of THF, cooled −78° C. To the stirred solvent was added n-butyl lithium (3.09 mL, 1.6M solution, 4.95 mmol) drop wise and stirred at same temperature, was added DMF (0.375 g, 5.13 mmol), once the temperature to reached room temperature and stirred about 16 h. Then reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4. The removal of solvent under reduced pressure to obtain liquid product (0.77 g, yield: 100.0%).
Reaction SMILES: [C:1](=[S:3])=[S:2].[OH-].[K+].[N+:6]([C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1S)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O.CO>[F:16][C:15]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]2[S:2][C:1]([SH:3])=[N:6][C:9]=2[CH:14]=1
Reactant: S=C=S
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: FC(F)(F)c1ccc2sc(S)nc2c1
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
Carbon disulphide (2.28 g, 30 mmol) was added dropwise over a period of 1 minute to a solution of potassium hydroxide (0.33 g, 5.9 mmol) in a mixture of water (2 ml) and methanol (5 ml), and the resulting yellow solution stirred for 5 minutes, followed by the addition of 2-nitro-4-trifluoromethyl thiophenol (1.10 g, 5 mmol). To this mixture was added dropwise over a period of 5 minutes a solution of potassium hydroxide (1.97 g, 35 mmol) and sodium dithionite (3.1 g, 15 mmol) in water (14 ml), so that the temperature did not exceed 40° C. The resultant orange mixture was stirred at 40°-50° C. for 2 hours. The reaction mixture was cooled to 10° C. and slowly acidified to pH 5-6 with concentrated HCl, and the mixture stirred for half an hour at this temperature. The off-white solid was washed with water and air dried to give the product. The yield was 0.81 g (70%).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH:17]1([C:22]([OH:24])=[O:23])[CH2:21][CH:20]=[CH:19][CH2:18]1>C1CCCCC1.C(Cl)Cl>[CH:17]1([C:22]([O:24][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:7])[CH3:6])=[O:23])[CH2:21][CH:20]=[CH:19][CH2:18]1
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccccc1
Reactant: O=C(O)C1CC=CC1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(OC(=O)C1CC=CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A solution of 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.85 g, 85 mmol) in cyclohexane (85 mL) was treated with a solution of cyclopent-3-enecarboxylic acid (4.77 g, 42.5 mmol) in methylene chloride (43 mL), and the mixture was stirred for about 16 hours at room temperature during which time a colorless solid precipitated. The precipitate was collected by filtration and rinsed with hexanes. The combined filtrates were concentrated in vacuo to yield a residue. The residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 0-5% ethyl acetate/hexanes gradient over 2 column volumes, then 5% ethyl acetate/hexanes for 2 column volumes, then a 5-40% ethyl acetate/hexanes gradient over 10 column volumes to yield 2-phenylpropan-2-yl cyclopent-3-enecarboxylate (8.84 g, 38.4 mmol, 90% yield) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25]([CH3:26])=[N:24][N:23]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[C:18]=3[N:19]=[C:20](Cl)[CH:21]=2)=[O:15])[C:10]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]1[O:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.[F-].[Cs+]>CN(C=O)C.C1(C)C=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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25]([CH3:26])=[N:24][N:23]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)[C:18]=3[N:19]=[C:20]([C:50]3[CH:51]=[CH:52][C:47]([O:46][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][O:40]4)=[CH:48][CH:49]=3)[CH:21]=2)=[O:15])[C:10]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Reactant: Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)c3ccccc3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3(C)c3ccccc3)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 936785.19 %

Procedure:
4-[6-Chloro-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-3-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (255 mg) and 4-(tetrahydro-2H-pyran-2-yloxy)phenylboronic acid (153 mg) were dissolved in DMF/toluene (v/v=1/1, 7.5 mL). After inertisation of the mixture with argon; cesium fluoride (140 mg) and tetrakis(triphenylphosphine)palladium(0) (27 mg) were added. The mixture was stirred at 100° C. overnight. The mixture was filtered through a 0.2 μm membrane syringe filter, the filtrate was diluted with ethyl acetate and washed three times with water (15 mL each) and once with brine (10 mL). The organic phase was dried over magnesium sulfate and concentrated. The residue was absorbed on silica and purified by flash chromatography (heptane/ethylacetate v/v=1/1). 3000 g (94%) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=O)=[CH:8][N:9]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>O>[Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=[N:25][OH:26])=[CH:8][N:9]=1
Reactant: NO
Reactant: COc1ccc(Oc2ncc(C=O)s2)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Oc2ncc(C=NO)s2)c(Cl)c1
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of Example 30B (13.05 g, 48.4 mmol) in pyridine (38.8 g, 484 mmol) was added hydroxylamine hydrochloride (33.7 g, 484 mmol). The mixture was heated at 80° C. for 0.5 hours, cooled to ambient temperature, treated with water (1000 mL) and filtered. The collected solids were dried in a vacuum oven to provide 13.2 g of the title compound (96%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (s, 3H) 7.03 (dd, J=9.01, 3.13 Hz, 1H) 7.25 (d, J=2.94 Hz, 1H) 7.52 (d, J=8.82 Hz, 1H) 7.68 (s, 1H) 7.81 (s, 1H) 12.02 (s, 1H); MS (ESI) m/z 284.9 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11][C@@H:10]1[NH2:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[N:31]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=1)=[C:32]=[S:33]>C(#N)C>[CH2:2]([CH:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[NH:21][C:32]([NH:31][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=1)=[S:33])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)CC[C@H](N)[C@@H]2Cc1ccccc1
Reactant: COCOc1ccc(CN=C=S)cc1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCOc1ccc(CNC(=S)NC2CCc3cc(OC)ccc3C2Cc2ccccc2)cc1OC

Procedure:
A solution of cis-1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (0.306 g, 1.01 mmol), diisopropylethylamine (0.264 mL, 1.51 mmol) and 4-isothiocyanatomethyl-2-methoxy-1-methoxymethoxy-benzene (0.253 g, 1.06 mmol) in acetonitrile (10 mL) was stirred at ambient temperature overnight. The solvent was evaporated in vacuo, and the residue was purified by reverse phase preparative HPLC, on a C18 column eluted with a gradient of 40 to 90% acetonitrile in water with 0.1% TFA, to give the product, 1-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-methoxy-4-methoxymethoxy-benzyl)-thiourea, 0.21 g (41%). 1H NMR (CDCl3): δ 1.64 (br s, 1H), 1.85 (m, 1H), 2.04 (m, 1H), 2.63 (m, 1H), 2.82 (m, 2H), 2.98 (m, 1H), 3.33 (m, 1H), 3.49 (s, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 4.32 (br s, 2H), 5.19 (s, 2H), 5.7 (br s, 1H), 6.0 (br s, 1H), 6.64 (m, 3H), 6.80 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H) and 7.11 to 7.28 (m, 5H). MS: m/z 507 (M+H)+.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:1]1([O:7][CH2:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCOC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
To a solution of 2-(cyclohexyloxy)-1-ethanol (200 mg, 1.39 mmol) in pyridine (10 mL) at 0° C. was added p-toluenesulfonyl chloride (292 mg, 1.53 mmol) portionwise followed by 4-(dimethylamino)pyridine (a few crystals) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo to give a crude residue that was partitioned between dichloromethane and 2N aqueous hydrochloric acid. The two layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. This was purified by column chromatography on silica gel, eluting with dichloromethane, to give the title compound (226 mg, 54%) as a yellow oil.
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Cl[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[CH:9]=1>C(COC)OC>[CH3:14][C:12]1[CH:13]=[C:8]([Sn:3]([CH3:5])([CH3:4])[CH3:2])[CH:9]=[C:10]([CH3:15])[N:11]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1cc(Cl)cc(C)n1
Agent: [Na]
Solvent: COCCOC
Product: Cc1cc([Sn](C)(C)C)cc(C)n1
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
To a mixture of 100 g sodium (30% dispersion in toluene) and 400 ml dimethoxyethane (DME) cooled in an ice-salt bath and under nitrogen was added a solution of 121 g trimethyltin chloride in 50 ml DME over a 2 hour period while keeping the temperature below 5° C. The mixture was stirred at 0°-5° C. for 2.5 hours and then 70 g 4-chloro-2,6-dimethylpyridine in 50 ml DME was added over a 1.5 hour period while keeping the temperature at 0°-10° C. The reaction mixture was stirred at the latter temperature for 1 hour and then allowed to stand at room temperature overnight. The mixture was filtered and concentrated, and the residue treated with ether and again filtered and concentrated. The resulting orange liquid was distilled, collecting the material boiling at 130° C. (20 mm) to give 80 g 2,6-dimethyl-4-(trimethylstannyl)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:50][C:51]1[C:56](C)=[CH:55][C:54](O)=[CH:53][C:52]=1C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:17][C:54]2[CH:55]=[CH:56][C:51]([Br:50])=[CH:52][CH:53]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCCCCCC(O)c1ccc(C(=O)OC)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-heptyl)-benzoic acid methyl ester (1000 mg, 4.0 mmol) in toluene (40 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 1514 mg, 6.0 mmol) at 0° C., followed by the additions of tributylphosphine (1.49 mL, 6.0 mmol) and 4-bromo-3,5-dimethyl-phenol (965 mg, 4.8 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid methyl ester. The ester product (1800 mg) is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 5 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (5 mL), extract with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid (1790 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:16]=1>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(C#CCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1c(C(=O)c2cccc(CCCN3CCOCC3)c2)cnn1-c1ccc(F)cc1
Reaction time: 16 h

Procedure:
A mixture of 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylprop-1-ynyl)-benzoyl]pyrazole (0.45 g, 1.0 mmol) [prepared as described in Example 1] and 5% Pd/C (0.07 g) in ethanol (20 ml) was stirred under hydrogen atmosphere. After 16 h, the reaction mixture was filtered through CELITE® and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (elution gradient, EtOAc-15% MeOH/EtOAc with 0.2% NH4OH). The product was converted to the hydrochloride salt and recrystallized from a mixture of methanol/ethyl acetate to give 5-amino-1-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl]pyrazole.HCl (0.3 g, mpt. 211.9-212.6° C.) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH:17]([CH3:19])[CH3:18])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: CC(C)Br
Reactant: Oc1ccc(I)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(I)nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 2-chloro-6-iodo-pyridin-3-ol (5.00 g, 19.57 mmol) in DMF was added finely ground potassium carbonate (5.409 g, 39.14 mmol) followed by 2-bromopropane (4.814 g, 3.675 mL, 39.14 mmol). The reaction mixture was allowed to stir at 70° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved/suspended in EtOAc (75 mL) and washed with water (1×75 mL). The aqueous layer was further extracted with EtOAc (1×75 mL). Both organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a yellow oil which was purified by silica gel column chromatography: 0-30% EtOAc/hexane gradient to provide 2-chloro-6-iodo-3-isopropoxy-pyridine (5.68 g, 97. %) as a clear colourless thin oil. ESI-MS m/z calc. 296.9, found 298.4 (M+1)+; Retention time: 1.74 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.3 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 4.53 (dt, J=12.1, 6.1 Hz, 1H), 1.39 (d, J=6.1 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[S:11][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2ccccn2)s1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-c4ccccn4)s3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-(2-pyridinyl)-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 420.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=O)=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.CO.C[O-].[Li+].C(Cl)[Cl:25]>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([Cl:25])=[N:16][OH:18])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(Cc2ccc(CC[N+](=O)[O-])cc2)o1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Cc2ccc(CC(Cl)=NO)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a mixture of 2-methyl-5-(4-(2-nitro-ethyl)-benzyl)-furan (87 mg, 0.36 mmol) described in Manufacturing Example 46-1-5 and methanol (2 mL) was added lithium methoxide (27 mg, 0.71 mmol) at room temperature, which was stirred for 15 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure. Titanium (IV) chloride (86 μL, 0.78 mmol) was added at −78° C. to a mixture of the resulting residue, methylene chloride (2 mL) and tetrahydrofuran (1 mL), which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., water (5 mL) was added, and the temperature was gradually raised to room temperature. The reaction mixture was extracted by addition of ethyl acetate and water. The organic layer was washed with water until the pH became about 5. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Thereafter, the organic layer was filtered and the filtrate was concentrated under a reduced pressure to obtain the title compound (79 mg, 84%).