Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[N:6][CH:7]=1.[H-].[Na+].IC.[C:20]([O-])(O)=O.[Na+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([CH3:20])[C:9]2=[O:15])=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC1(C)CN(c2ncc(I)cn2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ncc(I)cn2)CC1(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
(55 mg, 173 μmol) 1-(5-Iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 122, step 1) was dissolved in DMF (1 ml) and cooled to 0-5° C. NaH (55%) (9 mg, 225 μmol, 1.3 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (13 μl, 200 mmol, 1.2 equiv.) was added and the mixture was stirred for 30 min without cooling bath. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (31 mg, 54% yield) was obtained as a white solid, MS: m/e=333.1 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]3[S:23][CH:24]=[C:25]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[N:26]=3)[CH:15]=2)=[O:12])=[C:6]([O:31][CH3:32])[CH:5]=1.O1CCCC1.O.[OH-].[Li+]>CO>[CH:27]1([C:25]2[N:26]=[C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[CH:5][C:6]=4[O:31][CH3:32])[CH:19]=[CH:18][CH:17]=3)[S:23][CH:24]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1

Procedure:
A solution of 0.57 g of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]-3-methoxybenzoic acid methyl ester, 25 ml of tetrahydrofuran, 8 ml of methanol and 0.28 g of lithium hydroxide monohydrate was stored at 25° C. for 20 hr. The solvents were removed by rotary evaporation and the residual materials solubilized in 50 ml of water. Acetic acid was added and the precipitate of (E)-4-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]-3-methoxybenzoic acid was isolated by filtration, m.p. 242°-243° C. after trituration with hot acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:3]=1.[NH2:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:29][N:28]([CH3:30])[C:26](=[O:27])[CH2:25][NH:24][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:3]=1
Reactant: FC(F)(F)c1ccc(-c2nc(Cl)cc(-c3ccccc3)n2)cc1
Reactant: CN(C)C(=O)CN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)CNc1cc(-c2ccccc2)nc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 150 °C
Yield: 89.2 %

Procedure:
A mixture of 4-chloro-6-phenyl-2-(4-trifluoromethylphenyl)-pyrimidine (15 g), 2-amino-N,N-dimethylacetamide (8.2 g) and triethyl-amine (5.4 g) is heated at 150° C. under reflux for 2 hours. To the reaction mixture are added water and chloroform, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform), and recrystallized from ethanol to give the desired compound (16 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][OH:45]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][CH2:43][CH2:44][OH:45])=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCO

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 3-amino-1-propanol (18 ul) according to Method A to give material was re-purified by reversed phase HPLC in absence of trifluoroacetic acid to give the title compound (11 mg). 1H-NMR (400 MHz, CD3OD) d 7.84 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.27-7.17 (m, 5H), 7.04 (d, J=8.5 Hz, 1H), 4.79 (s, 2H), 4.51 (m, 1H), 4.23 (dd, J=5.2 Hz, J=9.3 Hz, 1H), 3.25 (m, 1H), 3.15 (m, 1H), 2.75 (m, 1H), 1.62 (m, 2H), 1.36 (s, 9H); HRMS m/z 587.2493 (calc. of monoisotopic mass for C29H37N3O10 gives 587.2479).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:21]=[C:20]([I:22])[C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.O>ClCCl>[CH3:23][N:17]1[CH2:16][CH2:15][C:14]2[C:20]([I:22])=[CH:21][C:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:12][C:13]=2[CH2:19][CH2:18]1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(I)c2c(c1)CCNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCc2cc(S(=O)(=O)c3ccc(F)cc3)cc(I)c2CC1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 7-(4-fluorophenylsulfonyl)-9-iodo-1,2,4,5-tetrahydro-3-benzazepine (2.4 g, 5.5 mmol) in dichloromethane (20 ml) were added sodium triacetoxyborohydride (1.8 g, 8.5 mmol) and formalin (1 ml, 37%, 12 mmol). The mixture was stirred for 2 h without cooling then poured into water (100 ml) and extracted with more dichloromethane (100 ml). The resulting organic layer was washed with brine (100 ml), dried (MgSO4), and evaporated to give the subtitle compound as a white foam (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][SH:5].Br[C:11]1[N:12]=[C:13]([O:37][CH3:38])[C:14]([N:17](COCC[Si](C)(C)C)[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:15][CH:16]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:14]1[C:13]([O:37][CH3:38])=[N:12][C:11]([S:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:16][N:15]=1)(=[O:20])=[O:19]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: SCc1ccccc1Cl
Product: COc1nc(SCc2ccccc2Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 82 using 2-chlorobenzylmercaptan (0.15 g) and N-(5-bromo -3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.4 g). Yield 0.18 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]3[CH:11]=[C:12]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:13]=[C:14]([O:16]CC4C=CC(OC)=CC=4)[CH:15]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([C:10]3[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc(COc2cc(Nc3cccnc3)cc(-c3cccc4sccc34)c2)cc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(Nc2cccnc2)cc(-c2cccc3sccc23)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 66.7 %

Procedure:
[3-benzo[b]thiophen-4-yl-5-(4-methoxy-benzyloxy)-phenyl]-pyridin-3-yl-amine (35 mg, 0.08 mmol) was dissolved in CH2Cl2 (1 mL) and thioanisole (188 μL, 1.60 mmol) was added. The solution was cooled to 0° C. and trifluoroacetic acid (0.1 mL) was added. The reaction mixture was stirred at room temperature for 5 h and was then quenched with water (3 mL). Sat. NaHCO3 solution was added until pH 7 and the mixture was extracted with CH2Cl2 (4×10 mL). The combined organics were washed with brine (5 mL), dried (Na2SO4) and concentrated. Flash chromatography (SiO2, CH2Cl2/MeOH 95:5) provided 3-benzo[b]thiophen-4-yl-5-(pyridin-3-ylamino)-phenol (17 mg, 58%). 3-Benzo[b]thiophen-4-yl-2-(4-methoxy-benzyl)-5-(pyridin-3-ylamino)-phenol was also isolated from this reaction. 3-Benzo[b]thiophen-4-yl-5-(pyridin-3-ylamino)-phenol 1H NMR (300 MHz, methanol-d4): δ 8.2 (d, 1H), 7.8 (d, 1H), 7.7 (d, 1H), 7.45 (d, 1H), 7.4 (two d, 2H), 7.2 (m, 2H), 7.1 (dd, 1H), 6.4 (s, 1H), 6.35 (s, 1H), 6.3 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:24]1([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2CCC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OCC2CCNCC2)c(CCC2CCCCC2)c1
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
1.138 g of 1-(tert-butoxycarbonyl)-4-[[(2-cyclohexylethyl)phenoxy]methyl]piperidine was dissolved in 3 ml of dichloromethane, 3 ml of trifluoroacetic acid was added thereto, and the mixture was left at room temperature for one hour 30 minutes. An aqueous sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and to the residue was added n-hexane, to give 899 mg of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].CI.[CH3:16]C(C)([O-])C.[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH3:16])[CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)NS(=O)(=O)c1cc[nH]c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of N-(1,1-dimethylethyl)-1H-pyrrole-3 -sulfonamide 9 g (0.044 mol) in 90 mL N,N-dimethylforamide was cooled to 15° C. under a nitrogen atmosphere. To this was added 3.2 mL (0.053 mol) of methyl iodide followed by 5.43 g (0.048 mol) of potassium t-butoxide. The mixture was warmed at ca. 60° C. for 2 hours then allowed to cool to room temperature and stirred for ca. 2 hours. The reaction mixture was diluted with ethyl acetate, washed three times with 1N HCl, once with brine, dried (MgSO4) and evaporated to an oily solid which was triturated with 5% diethyl ether/95% hexanes affording 6 g of the title compound as a beige solid, m.p. 134°-135° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.CN(C)C=O>O>[O:19]=[C:20]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][C:11]=3[C:2]2=[N:1][CH:27]=[C:21]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc2ncnc(N)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Temperature: 155 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A mixture of 4-amino-6-methanesulfonamidoquinazoline (6.89 g), diethyl ethoxymethylenepropanediate (15.5 g) and N,N-dimethylformamide (55 ml) was stirred at 155° C. for 2.5 hours. The reaction mixture was cooled to ambient temperature. To the mixture was added water to give precipitates, which were separated by filtration and washed with water. To the crystals was added a mixture of methanol and chloroform (1:4) (400 ml). After stirring under heating, insoluble materials (6.95 g) were filtered off and recrystallized from N,N-dimethylformamide to give crystalline ethyl 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (5.76 g).
Reaction SMILES: C1(NS([C:8]2[CH:13]=[C:12]([O:14][C:15]3[C:20]([Cl:21])=[CH:19][C:18]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:17][C:16]=3[Cl:30])[CH:11]=[CH:10][C:9]=2[OH:31])(=O)=O)CC1.[H][H].[C:34](OCC)(=O)C.CO>[Pd]>[Cl:30][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([Cl:21])[C:15]=1[O:14][C:12]1[CH:11]=[CH:10][C:9]([O:31][CH3:34])=[CH:8][CH:13]=1)[CH2:22][CH:23]1[S:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]
Reactant: [H][H]
Reactant: O=C1NC(=O)C(Cc2cc(Cl)c(Oc3ccc(O)c(S(=O)(=O)NC4CC4)c3)c(Cl)c2)S1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1

Procedure:
The title compound of Step C (93 mg) was dissolved in ethyl acetate/methanol (4 ml/2 ml) and then 10% palladium on carbon (70 mg) was added. The reaction mixture was placed on Parr shaker for four hours under 50 psi hydrogen at room temperature. The solution was filtered through diatomaceous earth, and concentrated. The residue was purified by preparative TLC (3% methanol in dichloromethane) to afford the title compound (52 mg) as a solid. MS (APCl−) Calc: 397.0, Found: 396.0 (M−1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO[C:29](=[O:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]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>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:35]4[CH:34]=[CH:33][C:32]([O:31][CH2:30][C:29]([N:59]5[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]5)=[O:39])=[CH:37][CH:36]=4)[CH2:20][CH2:19][C:18]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)COc1ccc(I)cc1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Reactant: C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C2(C#Cc3ccc(OCC(=O)N4CCCCC4)cc3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Yield: 96 %

Procedure:
A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.150 g, 0.42 mmol) and 4-iodophenoxyacetic acid methyl ester (0.123 g, 0.42 mmol) in dry piperidine (2 mL) was treated at 80° C. for 1.5 hr by the procedure of Example 11 with a mixture of tetrakis(triphenylphosphine)palladium (0.027 g, 0.023 mmol), cuprous iodide (0.0048 g, 0.025 mmol), and triphenylphosphine (crystal). The crude product was chromatographed (silica 50 to 75% ethyl acetate in petroleum ether) and was stripped in vacuo to afford the titled intermediate as a viscous yellow oil (0.232 g, 96%). 1H-NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.7 Hz, 2H), 7.24 (d, J=2.3 Hz, 1H), 7.13 (d-d, J=8.4 Hz, J=2.3 Hz, 1H), 6.89 (d, J=8.9, 1H), 6.84 (d, J=8.4, 1H),4.81 (p, 1H), 4.69 (s, 2H), 4.00 (s, 4H), 3.84 (s, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.49 (t, J=5.5 Hz, 2H), 2.3 to 1.5 (m, 32H with H2O).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1)[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:12])=[CH:17][CH:16]=1)[CH3:14]
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CCc1ccc(CCN)cc1
Product: CCc1ccc(CCNC(=O)c2ccc3c(c2)OCO3)cc1

Procedure:
Prepared in a similar manner to example 4 using benzo[1,3]dioxole-5-carboxylic acid and 2-(4-ethyl-phenyl)-ethylamine. MS (M+H, 298.2).
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(C(C)C)CC)(C)C.Cl[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[F:2][CH2:3][CH2:4][N:5]([CH3:6])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(=O)Cl
Reactant: CNCCF
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(=O)N(C)CCF
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 2-fluoro-N-methylethanamine hydrochloride salt (1 g, 8.81 mmol) in CH2Cl2 (40.0 mL) was added drop-wise diisopropyl-ethylamine (5.59 mL, 32.0 mmol) followed by the drop-wise addition of methyl 2-chloro-2-oxoacetate (0.981 g, 8.01 mmol) and the resulting mixture stirred for 3 h under N2. The solution was concentrated and the residue was taken up in ethyl acetate (20 mL), washed with 1N HCl (2×15 mL) followed by saturated aqueous sodium bicarbonate (15 mL). The organic phase was dried (MgSO4), filtered, and concentrated to give the title compound as a clear oil (1.2 g, 92% yield). 1H NMR (500 MHz, CDCl3) δ: 4.46-4.73 (2 H, m) 3.82-3.93 (3 H, m) 3.60-3.77 (2 H, m) 3.01-3.20 (3 H, m). LCMS (M+H) calcd for C6H11FNO3: 164.07; found: 164.11.
Reaction SMILES: Cl.Cl.[NH2:3][C@@:4]([CH3:16])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].[CH3:17][CH2:18]O>>[NH2:3][C@@:4]([CH3:16])([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: COc1ccc([C@](C)(N)C(=O)O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@](C)(N)c1ccc(OC)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
HCl gas was bubbled through a solution of (S)-α-amino-4-methoxy-α-methyl-benzeneacetic acid, hydrochloride salt (2.0 g, 8.6 mmol) in EtOH (25 mL) at 4° C. The solution was stirred for 1 hour at 20° C. before being refluxed for 5 hours. After cooling, the solution was concentrated in vacuo. The resulting oil was dissolved in CH2Cl2, and washed with aq. NaHCO3 ; the aqueous phase was back-extracted with CH2Cl2. The combined organic fractions were washed with H2O, brine and dried over Na2SO4 prior to concentration to yield the title compound as a yellow oil (1.75 g, 91%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4][N:3]1[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Br:22]Br>C(Cl)Cl>[Br-:22].[O:1]=[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4][NH+:3]1[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)N(C2CCCCC2)CN(C2CCCCC2)C1=O
Reactant: BrBr
Solvent: ClCCl
Product: CN1C(=O)N(C2CCCCC2)C[NH+](C2CCCCC2)C1=O
Product: [Br-]
Yield: 66.8 %

Procedure:
29.3 g (0.1 mol) of 2,4-dioxo-hexahydro-1,5-dicyclohexyl-3-methyl-s-triazine are initially introduced into 40 ml of methylene chloride and 24 g (0.15 mol) of bromine are added dropwise. The temperature is kept at 20° C to 30° C by cooling. The orange-red precipitate which has separated out is filtered off and recrystallised from isopropanol. 25 g (67%) of 2,4-dioxo-1,2,3,4-tetrahydro-1,5-dicyclohexyl-3-methyl-s-triazinium bromide of melting point 250° C are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.[C:22]([C:24]1[O:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1)#[N:23].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd]>[N:16]1([C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[C:4]([NH:1][C:29]([C:27]3[O:28][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)=[O:30])[CH:5]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cc(N2CCOCC2)ccc1N1CCCCC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2cc(N3CCOCC3)ccc2N2CCCCC2)o1
Yield: 45.4 %

Procedure:
The title compound was prepared following the procedure of Example 5, step (b) using 76.7 mg (0.318 mmol) of 4-(3-nitro-4-piperidin-1-yl-phenyl)-morpholine (as prepared in the previous step), 50 mg of 10% palladium on carbon (50% by weight water), 43.6 mg (0.318 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 55.5 μL (0.636 mmol) of oxalyl chloride, and 83.1 μL (0.477 mmol) of DIEA. The resulting residue was chromatographed on a 10-g silica SPE column with 15-25% EtOAc-hexane to afford 54.9 mg (45%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.97 (br s, 1H), 8.17 (d, 1H, J=2.8 Hz), 7.23, 7.26 (AB q, 2H, J=3.7 Hz), 7.13 (d, 1H, J=8.7 Hz), 6.66 (dd, 1H, J=8.7, 2.8 Hz), 3.84-3.87 (m, 4H), 23.17-3.19 (m, 4H), 2.75-2.85 (m, 4H), 1.77-1.82 (m, 4H), and 1.5-1.7 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H24N4O3, 381.2 (M+H), found 381.2.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH:4]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)[N:12]=1)[C:5]([NH2:7])=[NH:6].C(Cl)(Cl)Cl>CS(C)=O>[NH:4]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:1]#[N:2])[N:12]=1)[C:5]([NH2:7])=[NH:6]
Reactant: N=C(N)Nc1nc(CCCCCl)cs1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: N#CCCCCc1csc(NC(=N)N)n1
Temperature: 70 °C
Yield: 80.2 %

Procedure:
In 24 ml of dimethylsulfoxide was added 4.9 g of sodium cyanide, and the obtained mixture was heated at 70° C. Under stirring, 19.5 g of 2-guanidino-4-(4-chlorobutyl)thiazole was added to the solution at 70° to 75° C., and the solution was stirred at the same temperature for 3 hours. The reaction solution was cooled, and 100 ml of chloroform was added to the solution. After filtering off the undissolved material, the residue was purified by a silica gel column chromatography using a mixture of chloroform and methanol as the developing solvent to provide 15 g of 2-guanidino-4-(4-cyanobutyl)thiazole. The product shows a melting point of 104°-105° C. after recrystallization from a mixture of ethyl acetate and n-hexane. ##STR53## 10 g of 2-guanidino-4-(4-cyanobutyl)thiazole was suspended in a mixture of 60 ml of methanol and 110 ml of chloroform, and hydrogen chloride gas was passed through the solution under stirring at -5° to 5° C. for 2 hours. The resulting solution was allowed to stand at 5° C. for 2 days and the solvent was distilled off. The residue was suspended in a mixture of chloroform and methanol, and the suspension was poured into ice water containing 60 g of potasium carbonate. The chloroform layer was separated, and the aqueous layer was extracted further three times each time with 150 ml of chloroform. The extracts were combined, and dried over anhydrous potassium carbonate. The solvent was distilled off to provide 11 g of methyl 5-(2-guanidinothiazol-4-yl)pentanoimidate having a melting point of 143°-145° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.ClCCl.CO.N>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:15](=[O:17])/[CH:14]=[CH:13]/[C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:12][CH:11]=3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)/C=C/c1ccc(CN2CCCC2)cc1
Reactant: COc1ccc(-c2ccc(N)cc2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2ccc(NC(=O)/C=C/c3ccc(CN4CCCC4)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.1.e. from (E)-3-(4-pyrrolidin-1-ylmethylphenyl)acrylic acid and 4′-methoxybiphenyl-4-ylamine. Yield: 74 mg (15.4% of theory); melting point: 199° C.-200° C.; C27H28N2O2 (M=412.53); calc.: molecular ion peak (M+H)+: 413; found: molecular ion peak (M+H)+: 413; Rf value: 0.77 (silica gel, dichloromethane/methanol/ammonia (80:20:1)).