Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:19])=[C:9]([CH:11]3[CH2:13][CH:12]3[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:7]=1.[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][NH:30][C:29](=[O:33])[CH:28]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][N:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH3:19])=[C:9]([CH:11]5[CH2:13][CH:12]5[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=4)[CH:7]=3)[C:29](=[O:33])[CH:28]=2)=[CH:23][CH:22]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: CCOC(=O)C1CC1c1nc2ccc(I)cn2c1C
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cn2c1C
Temperature: 110 °C
Yield: 88.1 %

Procedure:
To a mixture of ethyl 2-(6-iodo-3-methylimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxylate (280 mg), 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (140 mg), potassium carbonate (243 mg) and dioxane (2 ml) were added CuI (57 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (43 mg), and the mixture was heated at 110° C. for 12 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was diluted with DCM, washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (250 mg) as a white solid.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]#[N:32])=[CH:21][CH:20]=2)=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:33]([O-])([O-])([O-])[O:34][CH2:35][CH2:36][CH3:37]>>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:7]3[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=[CH:16][C:6]=3[N:5]=[C:33]2[O:34][CH2:35][CH2:36][CH3:37])=[CH:20][CH:21]=1)#[N:32]
Reactant: CCCOC([O-])([O-])[O-]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CC(=O)O
Product: CCCOc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.2 g) was added to a solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (0.9 g) in propyl orthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate. The solvent was evaporated to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.72 g, 68%), m.p. 90°-92° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.[O:15]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][C:28]=1[O:35][CH3:36])[C@H:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18].N1CCCCC1>CO>[C@@H:16]1([O:15][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[C:11]3[S:10][C:9](=[S:14])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)[C:12]3=[O:13])=[CH:29][C:28]=2[O:35][CH3:36])[O:24][C@H:23]([CH2:25][OH:26])[C@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: O=C1CSC(=S)N1c1ccc(O)cc1
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1cc(C=C2SC(=S)N(c3ccc(O)cc3)C2=O)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
3-(4-Hydroxyphenyl)-2-thioxothiazolidin-4-one (0.23 g, 1.0 mmol) was added to a suspension of 4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.32 g, 1.0 mmol) in methanol (20 ml) containing a drop of piperidine. The mixture, which rapidly turned yellow, was gently heated under reflux and deposited a thick precipitate after 30 min. The mixture was then cooled and filtered to give the required product (5c){0.12 g, 23%, m.p. decomp.>230° C., [α]D -34.4° (c 0.6, DMOS)}(Found: C, 53.04; H, 4.55; N, 2.81. C23H23NO9S2 requires C, 52.96; H, 4.44; N, 2.68%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>O.C1(C)C=CC=CC=1.C(OCC)C>[C:12]1([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]=[C:2]([B:29]([OH:34])[OH:30])[CH:11]=[CH:10]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc2cc(-c3ccccc3)ccc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OB(O)c1ccc2cc(-c3ccccc3)ccc2c1
Temperature: -10 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
In an atmosphere of argon, 360 g (1.27 mol) of 2-bromo-6-phenylnaphthalene, 2 L of dehydrated diethyl ether and 2 L of dehydrated toluene were charged and cooled to −10° C. Then, 1 L (1.58 mol) of a hexane solution of 1.58M n-butyl lithium was added dropwise, and stirred at −10° C. for 5 hours. The reaction solution was cooled to −60° C., and after adding 718 g (3.81 mol) of triisopropyl borate, the mixture was stirred at room temperature for 17 hours. After adding 1 L of toluene and 1 L of water, the resulting mixture was stirred for an hour. Then, an aqueous layer was removed. An organic layer was washed with water, and dried with magnesium sulfate. The organic layer was concentrated, and heat-washed with toluene, whereby 276 g of 6-phenylnaphthalene-2-boronic acid was obtained (yield: 87%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:36])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OCC2C=CC=CC=2)=O)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.ClCCl.[OH-].[OH-].[Pd+2]>[CH2:10]([O:11][C:12](=[O:36])[CH3:13])[CH3:9].[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:36])[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCN)cc1
Yield: 137.5 %

Procedure:
A solution of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid 2-tert-butoxycarbonylaminoethyl ester 44a (162 mg, 0.32 mmol) and acetic acid (3 drops) in ethyl acetate (3 mL) and dichloromethane (6 mL) was stirred at room temperature for 16 h under hydrogen atmosphere in the presence of palladium hydroxide on activated charcoal (80 mg, 60% wet). The catalyst was removed by suction filtration and the liquid filtrate was concentrated in vacuo to give [4-(4-aminobutyl)phenoxy]acetic acid 2-tert-butoxycarbonylaminoethyl ester ethyl acetate 45a as an off-white solid (100 mg, 84% yield) which was used directly without purification. m/z (ESI) 367 [C19H30N2O5+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:13][C:12]2=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:13][C:12]2=1
Reactant: Fc1ccc(CCNC2CCc3[nH]c4ccc(OCc5ccccc5)cc4c3C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc2[nH]c3c(c2c1)CC(NCCc1ccc(F)cc1)CC3
Yield: 44.7 %

Procedure:
To a solution of 0.700 gm (1.69 mMol) 6-benzyloxy-3-(2-(4-fluorophenyl)eth-1-yl)amino-1,2,3,4-tetrahydro-9H-carbazole in 50 mL methanol were added 1.07 gm (16.90 mMol) ammonium formate followed by 0.190 gm 5% palladium on carbon. The resulting mixture was stirred at reflux for 15 minutes. The reaction mixture was then filtered through a bed of celite and the filter cake washed well with methanol. The combined filtrates were concentrated under reduced pressure and the residue partitioned between water and dichloromethane. The phases were separated and the aqueous was extracted again with 4:1 isopropanol:dichloromethane. The combined extracts were dried over magnesium sulfate, concentrated under reduced pressure, and the residue subjected to silica gel chromatography, eluting with 91:8:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.245 gm (52%) of 6-hydroxy-3-(2-(4-fluorophenyl)eth-1-yl)amino-1,2,3,4-tetrahydro-9H-carbazole. The hydrochloride salt was prepared and crystallized from ethanol/diethyl ether to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>C(O)(C)(C)C>[CH3:1][O:2][C:3]([CH2:20][CH:19]=[CH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(C(=O)c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C=CCBr
Product: C=CCC(OC)(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
Benzoin methyl ether (50 g) and t-butanol (500 g) were added to a 1 liter, 3-neck round bottom flask equipped with magnetic stirrer, and placed in an oil bath at 80° C. To this mixture, 33.7 g of potassium t-butoxide was added and the solution stirred for 15 minutes. Allyl bromide (42.3 g) was added dropwise over a 1 hour period and stirring was continued at 85° C. for 2 more hours followed by cooling to room temperature. After evaporation of t-butanol and filtration of potassium bromide, the product was distilled at 125° C.±2° C. and 0.05 mm Hg to yield 49.2 g of α-allylbenzoin methyl ether which crystallized upon cooling.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[N:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=O)=O.Cl.Cl.[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.C(O)(=O)C>C(O)C>[CH2:21]([N:28]1[C:11](=[O:13])[C:10]2[CH:15]=[CH:16][CH:17]=[N:18][C:9]=2[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)c1cccnc1C(=O)c1ccccn1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2cccnc2c(-c2ccccn2)nn1Cc1ccccc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-picolinoyl nicotinate, compound 6, (130 mg, 0.54 mmol), benzylhydrazine dihydrochloride (146 mg, 0.81 mmol), diisopropylethylamine (104 mg, 0.81 mmol), and ethanol (5 mL) was heated overnight at 75° C. To the reaction mixture was added acetic acid (46 μL, 0.81 mmol). The reaction mixture was heated at 75° C. for 2 h and then 100° C. for 2 h. After cooling the excess solvent was removed under reduced pressure. The residue was partitioned between 15 mL of ethyl acetate and 10% aqueous sodium carbonate. The aqueous fraction was further extracted with 2×15 mL of ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase flash chromatography eluting with 0-5% methanol in dichloromethane over 20 minutes. Like fractions containing product were combined and concentrated under reduced pressure to give 6-benzyl-8-(pyridin-2-yl)pyrido[2,3-d]pyridazin-5(6H)-one, RL-10 (44 mg, 0.13 mmol). 1H NMR (400 MHz, Chloroform-d) δ 9.11 (dd, J=4.5, 1.8 Hz, 2H), 8.89 (d, J=3.9 Hz, 2H), 8.77 (dd, J=8.1, 1.8 Hz, 1H), 7.91 (s, 2H), 7.68 (dd, J=8.1, 4.5 Hz, 1H), 7.49 (dd, J=25.2, 5.7 Hz, 3H), 7.37-7.24 (m, 5H), 5.53 (s, 2H). LCMS: (M+H)+, 316.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cccc(-c2cc(N3CCC[C@H]3CO)nc3c(I)c(C)nn23)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(C)nn3c(-c4cccc(C)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
(S)-(1-(7-(3-Methylphenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (22 mg), 4-methoxyphenylboronic acid (17 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (12 mg).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCO.O.N>[Fe].CC(O)=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Fe]
Agent: N
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(N)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of iron powder (1.4 g, 25.3 mmol, 4 equiv), 1-isopropyl-4-(5-nitro-pyridin-2-yl)piperazine (1.58 g, 6.32 mmol), EtOH (20 mL), H2O (5 mL), and AcOH (2.5 mL) is stirred for 2 h at 90° C., allowed to cool to RT, basified by addition of aqueous ammonia, filtered through a pad of celite and partially concentrated to remove EtOH. The aqueous residue is saturated with sodium chloride and extracted with EtOAc and DCM. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91:8:1) to afford the title compound as a purple solid: ESI-MS: 221.1 [MH]+; TLC: Rf=0.20 (DCM/MeOH/NH3aq, 91:8:1).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].C1(N=C=O)C=CC=CC=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=2[CH2:32][CH2:33][CH2:34][N+:35]([O-])=[O:36])=[CH:20][C:19]=1[CH3:38].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=2[CH2:32][CH2:33][C:34]2[CH2:4][CH:3]([CH2:2][C:1]([O:6][CH3:7])=[O:5])[O:36][N:35]=2)=[CH:20][C:19]=1[CH3:38]
Reactant: C=CCC(=O)OC
Reactant: Cc1cc(C)c(CCC[N+](=O)[O-])c(-c2ccc(F)c(C)c2)c1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CC1CC(CCc2c(C)cc(C)cc2-c2ccc(F)c(C)c2)=NO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A solution of 0.1 g (1.0 mmol) of methyl 3-butenoate and 0.174 ml (1.6 mmol) of phenyl isocyanate in 1 ml of toluene was added with stirring to a solution of 0.240 g (0.8 mmol) of the nitropropyl compound from Step D and 2 drops of triethylamine in 1 ml of toluene. The resulting mixture was stirred at room temperature for 3 hours. Additional quantities of methyl 3-butenoate (0.1 ml), triethylamine (0.1 ml) and phenyl isocyanate (0.15 ml) were added successively and stirring was continued overnight (18 hours). The mixture was filtered and the filtrate was concentrated in vacuo to a residue which was purified by flash chromatography on silica gel (230-400 mesh), first being eluted with methylene chloride to remove the impurities. Continued elution with acetone/methylene chloride (1:50, v/v) gave the desired product (0.218 g, 0.57 mmol, 71%) as a pale viscous oil. nmr (CDCl3) δ: 2.28 (6H, s), 2.32 (3H, s), 2.2-3.0 (6H, m), 3.70 (3H, s), 4.6-5.0 (H, m), 6.85 (H, bs), 7.0-7.2 (4H, m). IR (neat) 1735 cm-1
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N[C@H](C(O)=O)CS.[C:51](O)([CH3:54])([CH3:53])[CH3:52].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:51]([O:21][C:20](=[O:22])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:23][S:24][C:25]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: N[C@@H](CS)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
In one incarnation of the present invention, as illustrated below, the cysteine derivative is 2(R)-(benzhydrylidene-amino)-3-tritylsulfanyl-propionic acid tert-butyl ester. 2(R)-(Benzhydrylidene-amino)-3-tritylsulfanyl-propionic acid tert-butyl ester can be formed by the following process: (1) 2(R)-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid (i.e., (R)-cysteine with Fmoc a protected amino group and with a trityl protected —SH group), is reacted with t-butyl alcohol and dicyclohexyl carbodiimide (DCC) in 4-(dimethylamino)pyridine (DMAP) and tetrahydrofuran (THF) at room temperature to form 2(R)-(9H-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid tert-butyl ester; (2) the Fmoc group is removed from the 2(R)-(9H-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid tert-butyl ester using either diethylamine in dichloromethane or piperidine in dichloromethane to form 2(R)-amino-3-tritylsulfanyl-propionic acid tert-butyl ester; and (3) the 2(R)-amino-3-tritylsulfanyl-propionic acid tert-butyl ester is reacted with benzhydrylideneamine in dichloromethane at room temperature to form 2(R)-(benzhydrylidene-amino)-3-tritylsulfanyl-propionic acid tert-butyl ester.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16](O)[C:17]3[CH:18]=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[N:21][C:22]=3[CH:23]=2)=[CH:10][CH:9]=1>>[Cl:3][C:16]1[N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[N:21]2
Reactant: COc1ccc(-c2cc3nc(C(F)(F)F)ccc3c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3nc(C(F)(F)F)ccc3c(Cl)n2)cc1
Temperature: 100 °C
Yield: 55 %

Procedure:
POCl3 (3 mL) was added to 7-(4-methoxyphenyl)-2-trifluoromethyl-[1,6]naphthyridin-5-ol (Example 19) (125 mg, 0.4 mmol). The mixture was heated at 100° C. for 3 hours. The excess POCl3 was concentrated under reduced pressure. The residue was diluted with CH2Cl2, washed with sat. NaHCO3, dried over Na2SO4, and concentrated giving the title compound (73 mg, 55%) as an orange solid.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH2:6][NH:5][N:4]=1)[CH3:2].[CH2:8]([N:10]=[C:11]=[S:12])[CH3:9]>C(O)C>[CH2:8]([NH:10][C:11]([N:5]1[CH2:6][CH2:7][C:3]([CH2:1][CH3:2])=[N:4]1)=[S:12])[CH3:9]
Reactant: CCC1=NNCC1
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)N1CCC(CC)=N1
Yield: 0.8 %

Procedure:
1.25 g (1 mol equiv.) 3-Ethyl-4,5-dihydro-1H-pyrazole (synthesized as described in WO 2008/034863) and 1.45 ml (1.3 mol equiv.) ethyl isothiocyanate were added to 10 mL ethanol. The reaction mixture was refluxed for 5 hours, silica gel was added and volatiles were removed in vacuo. Purification by flash chromatography on silica gel (Et2O:PA=1:1) afforded 1.54 g (65%) 3-ethyl-4,5-dihydro-pyrazole-1-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J=7.5 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 2.38 (q, J=7.5 Hz, 2H), 2.83 (t, J=9.9 Hz, 2H), 3.63-3.72 (m, 2H), 4.19 (t, J=9.9 Hz, 2H), 7.06 (br.s., 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.OCC1C=CNN=1.S(Br)(Br)=O.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH:5]1[CH:6]=[CH:7][C:3]([CH2:2][NH:21][CH2:20][CH2:19][NH2:22])=[N:4]1
Reactant: NCCN
Reactant: BrCc1cc[nH]n1
Agent: O=S(Br)Br
Agent: OCc1cc[nH]n1
Product: NCCNCc1cc[nH]n1

Procedure:
Reaction of 3-bromomethylpyrazole, prepared by treatment of 3-hydroxymethylpyrazole with thionyl bromide, with ethylenediamine by the procedure of Example 34 gives N-(3-pyrazolylmethyl)ethylenediamine.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH2:16]([N:18]([CH2:35][CH3:36])[C:19](=[O:34])[C:20]1[C:25]([O:26][C:27](=[S:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:17].S([N:47]=[N+:48]=[N-:49])(C1C=CC(C)=CC=1)(=O)=O.[NH4+].[Cl-]>C1COCC1>[CH2:35]([N:18]([CH2:16][CH3:17])[C:19](=[O:34])[C:20]1[C:25]([O:26][C:27](=[S:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[C:24]([N:47]=[N+:48]=[N-:49])[CH:23]=[CH:22][N:21]=1)[CH3:36]
Reactant: CCN(CC)C(=O)c1ncccc1OC(=S)N(CC)CC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1nccc(N=[N+]=[N-])c1OC(=S)N(CC)CC
Temperature: -100 °C
Reaction time: 1 h

Procedure:
378 ml of n-butyllithium (1.6M in hexane) are added to a solution of 88.2 g (0.624 mol) of 2,2,6,6-tetramethylpiperidine in 11 of THF at -20° C. under argon and the mixture is stirred at this temperature for 1 hour. The mixture is then cooled to -100° C., and a solution of 104.4 g (0.337 mol) of N,N-diethyl-3-(N',N'-diethylthiocarbamoyloxy)picolinamide in 300 ml of THF is added dropwise in such a way that the temperature does not exceed -90° C. After the mixture has been stirred at -95° C for 1 hour, it is again cooled to -102° C, and a solution of 119.3 g (0.605 mol) of tosyl azide in 200 ml of THF, cooled to -20° C., is added in the course of 30 seconds. After the mixture has been stirred at -80° C. for 15 minutes, 400 ml of a saturated NH4Cl solution are added, the mixture is heated to 0° C., and the aqueous phase is separated off and washed with 500 ml of diethyl ether and the organic phases are washed once with 200 ml of saturated NH4Cl solution and twice with in each case 150 ml of saturated NaCl solution, dried over Na2SO4 and concentrated in vacuo. The brown oil is taken up in 1.2 l of hexane under hot conditions, the mixture is slowly cooled to 0° C., with stirring, and the solid substance is filtered off and dried. Yield: 109.0 g of beige-brown crystals which are employed directly in the subsequent step.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]1([C@H:14]([NH2:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[C:8]1([CH:14]([NH:16][C:5](=[O:7])[CH3:6])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)c1ccccc1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
Acetic anhydride (38.4 g) was dropwise added to a solution (200 ml) of (R)-(+)-1-phenylethylamine (30 g) in chloroform under ice-cooling. After completion of the reaction, ice water was added thereto and the mixture was extracted with chloroform. The extract was washed with 1N aqueous solution of sodium hydroxide and water. After drying, the mixture was concentrated under reduced pressure to give crystals, which were recrystallized from isopropyl ether to give 32.2 g of (+)-N-(1-phenylethyl)acetamide. [α]D =+143.5° (ethanol, c=1)