Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:28][C@@H:29]1[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]1>CCOC(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:28][C@@H:29]2[CH2:33][CH2:32][C@H:31]([CH2:34][OH:35])[CH2:30]2)=[N:6][CH:7]=1
Reactant: N[C@@H]1CC[C@H](CO)C1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OC[C@H]1CC[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)C1
Yield: 78.7 %

Procedure:
To 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (100 mg, 0.301 mmol) was added DMSO (1 ml), ((1S,3R)-3-aminocyclopentyl)methanol (104 mg, 0.903 mmol) and TEA (0.21 ml, 1.51 mmol). The crude mixture was stirred at 100° C. for 20 hours, followed by LCMS. The crude reaction mixture was cooled, was diluted with EtOAc (60 mL), washed H2O (60 mL×2), brine (60 mL), dried over Na2SO4, and reduced. The crude was adsorbed onto silica gel, and purified by silica gel chromatography, 40-80% EtOAc/Heptane, 12 g ISCO silica column, resulting in ((1S,3R)-3-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclopentyl)methanol (101 mg, 0.237 mmol). LCMS (m/z): 427.1 (MH+). retention time=0.69 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=1)(=O)=O.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC.[Cl-].[Li+]>O1CCOCC1.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>[CH:20]([C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=1)=[CH2:21]
Reactant: O=C1CCCc2nc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(n1)CCCC2=O
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl trifluoromethanesulfonate (Preparation 54B, 2.21 g, 7.49 mmol) in dioxane (12 mL) in a sealed tube was added sequentially tributyl(vinyl)stannane (2.418 mL, 8.23 mmol) and lithium chloride (0.952 g, 22.46 mmol). The mixture was degassed under reduced pressure and charged with nitrogen (3×). To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.865 g, 0.749 mmol), and the mixture was stirred under a strong stream of nitrogen for 5 min. The reaction mixture was sealed, immersed in an oil bath at 100° C., and stirred overnight. The reaction mixture was filtered and the solid was rinsed with ethyl acetate (150 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was diluted with ether (150 mL). The resulting solid was removed by vacuum filtration and rinsed with ether (150 mL). The filtrate was concentrated under reduced pressure and purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (5%-12.5%-20%) to give 2-vinyl-7,8-dihydroquinolin-5(6H)-one (1.09 g, 6.29 mmol, 84% yield) as a pale yellow solid. The compound had an HPLC ret. time=0.738 min. (condition A); LC/MS M+1=273.8; 1H NMR (500 MHz, CDCl3) δ ppm 2.21 (quin, 2H), 2.67-2.73 (m, 2H), 3.15 (t, J=6.10 Hz, 2H), 5.65 (d, J=10.82 Hz, 1H), 6.35 (d, J=17.48 Hz, 1H), 6.86 (dd, J=17.48, 10.54 Hz, 1H), 7.34 (d, J=8.05 Hz, 1H), and 8.25 (d, J=8.05 Hz, 1H).
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH2:7].[OH-].[Na+].[CH:13](Cl)(Cl)[Cl:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O.CCOCC>[ClH:14].[ClH:1].[CH3:13][NH:7][CH2:6][C:5]([N:4]([CH3:10])[CH3:3])([CH3:9])[CH3:8]
Reactant: CN(C)C(C)(C)CN
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CNCC(C)(C)N(C)C

Procedure:
2-Dimethylamino-2-methyl-propylamine dihydrochloride (2 g.) was dissolved in water (2 ml.) and the solution made alkaline with 5N sodium hydroxide. Chloroform (100 ml.) was added and the mixture was dried (anhyd. Na2SO4) and filtered. A solution of chloral (1.45 g.) in chloroform (50 ml.) was added to the stirred and cooled chloroform solution. The mixture was heated under reflux for 40 hrs., and the excess chloroform evaporated under reduced pressure to give an oily residue (0.9 g.). This was dissolved in ether (50ml.), the solution was added dropwise to a cooled and stirred suspension, of lithium aluminum hydride (0.43 g.) in ether (100 ml) and the mixture was heated under reflux for 16 hrs. On cooling, the excess lithium aluminum hydride was decomposed by the addition of water, and the mixture dried (anhydrous Na2SO4), and extracted with ether. The ether extracts were extracted with 2N HCl (2 × 20 ml. and 40 ml.), the excess water was evaporated under reduced pressure and the liquid residue dried by re-evaporation with ethanol/benzene mixture to give a solid residue. This was crystallised from ethanol to give N-methyl-2-dimethylamino-2-methyl propylamine dihydrochloride (0.9 g.)
Reaction SMILES: C([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:38]=[CH:37][C:29]([C:30]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:13]=2)[C@@H:6]([CH3:39])[CH2:5]1)C=C.C(O)(=O)C1C(=CC=CC=1)S>O1CCCC1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:39][C@H:6]1[CH2:5][NH:4][C@H:9]([CH3:10])[CH2:8][N:7]1[C@H:11]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:31])=[CH:37][CH:38]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][S:19]([C:22]([F:23])([F:24])[F:25])(=[O:20])=[O:21])[CH:13]=1
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(OS(=O)(=O)C(F)(F)F)c2)C[C@H]1C
Agent: O=C(O)c1ccccc1S
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OS(=O)(=O)C(F)(F)F)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Yield: 92.9 %

Procedure:
A solution of 4-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide (4.03 g, 7.20 mmol) and thiosalicylic acid (1.32 g, 8.52 mmol) in anhydrous tetrahydrofuran (25 mL) was stirred under nitrogen for 3 h at room temperature with a catalyst solution prepared by dissolution of bis(dibenzylidineacetone)palladium (204 mg, 0.355 mmol) and 1,4-bis(diphenylphosphino)butane (151 mg, 0.355 mmol) in tetrahydrofuran (3 mL). The reaction mixture was evaporated to dryness, the residue dissolved in a mixture of ethyl acetate/ether (1:3, 125 mL) and extracted with 5% sodium carbonate solution (2×75 mL). The organic layer was diluted with two volumes of pentane and extracted with 3M-hydrochloric acid (5×25 mL). The aqueous solution was adjusted to pH 9–10 with concentrated ammonia solution and extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to yield 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide as a brittle pale yellow foam (3.53 g). The product showed a single spot on thin layer chromatography (silica gel, EM60F264, 2% NH4OH in ethyl acetate, Rf=0.33). 1H NMR (CDCl3, 500 MHz); δ 0.95 (d, J=6 Hz, 3H); 1.13 (br m, 3H); 1.20 (d, J=6.1 Hz, 3H); 1.26 (br m, 3H); 1.50 (t, J=9.7 Hz, 1H); 2.31 (m, 1H); 2.64 (dd J=11.3, 2.5, 1H); 2.71 (m, 1H); 2.95 (m, 1H); 3.29 (br m, 2H); 3.56 (br m, 2H); 5.43 (s, 1H); 7.04 (m, 1H); 7.21 (d, J=7.7, 1H); 7.24 (dd, J=8.2, 2.2 Hz, 1H); 7.34 (d, J=8.2 Hz, 2H); 7.42 (d, J=8.1 Hz, 2H); 7.48 (t, J=8 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[CH2:18][N:19]2C(=O)CS[C:20]2=[O:25])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(O)C>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:26][C:20](=[O:25])[NH:19][CH:18]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=C(CN1C(=O)CSC1=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1[nH]cc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
2.8 ml (20.1 mmol, 2.5 eq.) of triethylamine were added to a solution of 2.3 g (8.0 mmol) of 3-[2-(4-nitrophenyl)-2-oxoethyl]-1,3-thiazolidine-2,4-dione in 80 ml of ethanol, and the mixture was stirred under reflux for 14 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water/ethyl acetate. After phase separation, the organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The residue was stirred in dichloromethane and the precipitate was filtered off and dried under reduced pressure. Yield: 1.1 g (67% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][N:3]=1.C([Mg]Cl)CCC.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:45]OS(O)(=O)=O>O1CCCC1.O>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:45])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cn1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
To a clear solution of Example 33 (2.4 g, 6.3 mmol) in tetrahydrofuran (60 ml) at 0° C., n-BuMgCl (2M solution in THF, 15.7 ml, 31.5 mmol) was added over 10 minutes. After stirring for additional 20 minutes, the ice bath was removed and the solution was stirred for 2 hours. The reaction mixture was recooled to 0° C. and triethylborane (1M solution in THF, 38 ml, 38 mmol) was added. After stirring for 1 hour, the reaction was heated to reflux for 72 hours. The reaction mixture was cooled to room temperature and treated with aqueous sodium acetate (5.5 g in 22 ml water). After stirring for 5 minutes, solid hydroxylamine-O-sulfonic acid (5.5 g) was added and the mixture stirred for 24 hours. The reaction mixture was diluted with water and extracted with ether. The ethereal layer was dried over sodium sulfate, filtered and concentrated. The crude solid (13.3 g) was chromatographed (silica gel, hexane/isopropanol, 7/3) to give 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (298 mg, 12%): mp (DSC) 203° C. Anal. Calc'd. for C16H13N4SO2F3 0.25H2O: C, 49.68, H, 3.52 N, 14.48, S, 8.29. Found: C, 49.88, H, 3.39, N, 13.94, S, 8.47.
Reaction SMILES: [CH:1]1([N:5]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([OH:28])[CH:22]=3)[CH:16]=2)[C:6]([C:8]2[N:9]=[CH:10][N:11]([CH3:13])[CH:12]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.[Cl:29][C:30]([F:35])([F:34])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[ClH:43].[OH-].[Na+]>O.CN(C)C=O>[ClH:29].[ClH:43].[CH:1]1([N:5]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([O:28][CH:30]([F:35])[F:34])[CH:22]=3)[CH:16]=2)[C:6]([C:8]2[N:9]=[CH:10][N:11]([CH3:13])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1cnc(C(=O)N(Cc2ccnc(-c3ccc(F)c(O)c3)c2)C2CCC2)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc(C(=O)N(Cc2ccnc(-c3ccc(F)c(OC(F)F)c3)c2)C2CCC2)c1
Temperature: 100 °C

Procedure:
A mixture of N-cyclobutyl-N-{[2-(4-fluoro-3-hydroxyphenyl)pyridin-4-yl]methyl}-1-methyl-1H-imidazole-4-carboxamide (200 mg), sodium chlorodifluoroacetate (190 mg), cesium carbonate (241 mg), dimethylformamide (1.5 mL) and water (0.15 mL) was stirred while heating at 100° C. for 5 hr. After the reaction mixture was cooled in ice, concentrated hydrochloric acid (0.2 mL) was added thereto, and the resulting mixture was stirred for 1 hr. After addition of an aqueous solution of 2M sodium hydroxide, the mixture was extracted with ethyl acetate. The organic phase was separated out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by HPLC. The resulting residue was dissolved in acetonitrile, and 4N hydrochloric acid/ethyl acetate was added thereto, followed by concentration to afford the title compound (30 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl.C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCC(=O)CC2)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Iron powder (16.4 g, 294 mmol) was slowly added to an ice-cold solution of 1-(2-fluoro-4-nitro-phenyl)-piperidin-4-one (7 g, 29.4 mmol), obtained in Preparation 5, in ethanolic HCl (50 ml) at 0° C. and stirred at the same temperature for 2 h. The reaction mixture was basified by the addition of sodium carbonate and pH of the solution was brought to 8. It was then diluted with ethyl acetate (100 ml) and the aqueous layer was separated. The aqueous layer was further extracted with ethyl acetate (100 ml×2). Combined organic extract was washed with water followed by brine and dried over sodium sulfate. Removal of volatiles left a pasty mass (7 g), which was used for the next step.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.C1([Si](C2C=CC=CC=2)(C)C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:42])[CH3:41])=[CH:36][CH:35]=1.[C:43]([C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH:48]=O)#[N:44].C(=O)(O)[O-].[Na+]>ClCCl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:42])[CH:41]=[CH:48][C:47]2[CH:46]=[C:45]([CH:52]=[CH:51][CH:50]=2)[C:43]#[N:44])=[CH:36][CH:35]=1
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: C[Si](C)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C=CC(=O)c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Triflic acid (3.2 g, 21 mmol) is added portionwise to diphenyldimethylsilane (2.22 g, 10.5 mmol) in 20 mL of dichloromethane and stirred for 1 hour. After cooling to -78° C., diisopropylethylamine (1.42 g, 11 mmol) and 4'-fluoroacetophenone (1.38 g, 10 mmol) are added and the reaction mixture stirred for another hour before adding 3-cyanobenzaldehyde (1.0 g, 7.62 mmol). After the reaction mixture is stirred 18 hours, it is diluted with 100 mL of dichloromethane and stirred 1 hour with a saturated solution of sodium bicarbonate. The organic layer is separated, dried (MgSO4), concentrated and columned over SiO2 eluting with dichloromethane to provide 0.8 g of the title compound; mp 170°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11](I)[N:10]=[C:9]2[CH3:14])=[CH:4][N:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[N:10]=[C:9]2[CH3:14])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(I)cn1-c1ccc(Cl)nc1
Product: Cc1nc(C#C[Si](C)(C)C)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=290.6 (M+H+), was prepared in accordance with the general method of example B, step 1, from 2-chloro-5-(4-iodo-2-methyl-imidazol-1-yl)-pyridine and trimethylsilylacetylen.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([NH2:11])=[S:10].[C:12]([CH2:14][C:15](OCC)=[O:16])#[N:13].[O-]CC.[Na+].[Na].S(=O)(=O)(O)O>C(O)C.O>[NH2:13][C:12]1[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:9](=[S:10])[NH:11][C:15](=[O:16])[CH:14]=1
Reactant: CCOC(=O)CC#N
Reactant: NC(=S)NCc1ccccn1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(=O)[nH]c(=S)n1Cc1ccccn1
Temperature: 90 °C
Yield: 95 %

Procedure:
N-(Pyridin-2-ylmethyl)thiourea (1.35 g, 8.09 mmol, obtained from Example 1(a)) and ethyl cyanoacetate (1.1 g, 9.71 mmol) was added to sodium ethoxide (freshly made from sodium 0.20 g, 8.9 mmol in ethanol (16 mL)). The reaction mixture was stirred under reflux at 90° C. for 16 h. The mixture was then diluted with water (20 mL) and neutralized with 2M sulfuric acid. The precipitated solid was collected by filtration, washed with water and dried, giving the title compound (1.8 g, 96%) as a solid. The crude product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[CH3:10][Zn]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.CN(C=O)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([CH3:10])[CH:7]=1
Reactant: C[Zn]C
Reactant: Nc1nnc(Cl)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nnc1N
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A 100 mL flask was charged with 4-bromo-6-chloropyridazin-3-amine (1 g, 4.80 mmol), dimethylzinc (9.59 mL, 9.59 mmol), Pd(PPh3)4 (0.277 g, 0.240 mmol) and DMF (10 mL). The reaction mixture was stirred at RT. Then the reaction mixture was quenched with MeOH and concentrated. The crude product was loaded onto a 10 g SCX SPE, and 3 volumes of MeOH followed by 3 volumes of 2N ammonia in MeOH were added. The fractions were combined and concentrated to afford 6-chloro-4-methylpyridazin-3-amine (693 mg, 80% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[H-].[Na+].[I-].[Na+].Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>CN(C)C=O.C(OCC)(=O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][CH2:21][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:8]2)[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc2c(Cc3ncc[nH]3)c[nH]c2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCn1cc(Cc2ncc[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-(1-Imidazolylmethyl)indole (3.94 g) was dissolved in N,N-dimethylformamide (50 ml) and the solution was treated with sodium hydride (1.00 g of 50% dispersion in oil) as described in Example 44. To the solution of the anion at 0° C. was added sodium iodide (3.0 g) and N-(3-bromopropyl)phthalimide (5.36 g) over 10 minutes. The mixture was then stirred at room temperature for 20 hours and evaporated to dryness. The residue was chromatographed on silica gel. The column was first eluted with petrol (b.p. 40°-60° C.) to remove mineral oil and then with chloroform to remove the product. The chloroform eluate was evaporated to give a viscous gum which was pure enough for further reaction. A portion was dissolved in ethyl acetate and the solution was treated with an excess of fumaric acid in ethyl acetate. The solid was filtered off and crystallised from ethyl acetate containing a trace of ethanol to give 1-(3-phthalimidopropyl)-3-(1-imidazolylmethyl)indole fumarate, m.p. 166°-167° C. Found: C, 64.56; H, 4.78; N, 11.09. C23H20N4O2.C4H4O4 requires: C, 64.79; H, 4.83; N, 11.20.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH:22]=[O:23].[NH4+].[Cl-]>C1COCC1.O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:22]([OH:23])[CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CCCBr)cc1OC
Reactant: COc1ccc(C=O)cc1OC
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCCC(O)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 0 °C

Procedure:
Under N2, Mg powder (21.15 g, 0.87 gram-atom) was added to a 5 1, 3-neck flask fitted with a mechanical stirrer, condenser, and septum inlet. The Mg was covered with dry THF (200 cc), stirring was begun and a trace of iodine was added followed by about 20 cc then dropwise addition of a solution of 1-bromo,3-(3,4-dimethoxyphenyl)propane (222 g, 0.857 mole) from which all traces of water had been removed in dry THF (1150 cc) at a rate to maintain gentle reflux over a period of 2.5 hours. The resulting dark grey solution was stirred and refluxed for 45 minutes and then cooled to 0° C. With stirring a solution of dried 3,4-dimethoxybenzaldehyde (149.5 g, 0.899 mole) in dry THF (150 cc) was added dropwise over 1 hour at 0° C.-3° C. The resulting mixture was stirred overnight at room temperature, cooled to 0° C., and treated over 1/2 hour at 0°-5° C. with saturated NH4Cl solution (100 cc). The nitrogen atmosphere was discontinued at this point. After standing at room temperature for several hours, the mixture was filtered and the solids were air-dried overnight. The filtrate was evaporated in vacuo to a syrup. The solids were extracted with CH2Cl2 (500 cc) by stirring for a few hours and filtering. The filtrate was combined with the syrup from above and the mixture was diluted with CH2Cl2 (1:1) The organic solution was washed with H2O (3 ×500 cc), dried (Na ), and evaporated in vacuo to a light orange syrup; yield: 300 g (>100%).
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH2:1]([CH:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CC2CCC3(CC2)OCCO3)cc1
Yield: 99.1 %

Procedure:
A solution of 28 g of 8-benzylidene-1,4-dioxa-spiro[4.5]decane and 1 g of 5% palladium on carbon in 250 mL of ethanol was allowed to stir overnight under 1 atm of hydrogen. The catalyst was filtered off and the solution concentrated to give 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane as an oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:30]([OH:32])=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:33]I.C>O1CCCC1.O.C(OCC)(=O)C>[CH2:3]([O:10][C:11]([N:13]([CH3:33])[C@H:14]([C:30]([OH:32])=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of sodium hydride (50%, 9.64 g., prewashed with tetrahydrofuran to remove mineral oil) and tetrahydrofuran (120 ml.) were added dropwise with stirring first a filtered solution of N-benzyloxycarbonyl-O-benzyl-L-tyrosine (16.22 g.) in tetrahydrofuran (50 ml.), then methyl iodide (20 ml.), then tetrahydrofuran (10 ml.). The resulting mixture was stirred overnight at room temperature. Ethyl acetate (200 ml.) was added, then water (6 ml.) dropwise, and stirring was continued for one hour. Charcoal was added and the mixture was filtered. Water (70 ml.) and ether were added, affording a pale yellow solid which melted upon drying at 65° C. and resolidified upon cooling (15.72 g., m.r. 88°-90° C.). Recrystallization of the solid from ethyl acetate (12 ml., 5 ml. used for washing) afforded N-benzyloxycarbonyl-N-methyl-O-benzyl-L-tyrosine (14.13 g.; m.r. 90°-91.5° C.).