Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH2:2][N:3]=C=NCCCN(C)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.NC>CN(C=O)C.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH:3][CH3:2])=[O:23])=[CH:15][CH:14]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: CN
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)CCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
EDAC (1.56 g, 8.1 mmol) was added in one portion to 3-(4-bromophenyl)propanoic acid (2.5 g, 7.4 mmol) and HOBt (1.1 g, 8.1 mmol) in DMF (6 mL) and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to 0° C. and NH2Me (2.0 M in MeOH, 29 mL, 58 mmol) was added dropwise. The solution was stirred at 0° C. for 30 min and 10 h at ambient temperature. The reaction mixture was diluted with water (25 mL), extracted with diethyl either (3×50 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 22A (1.7 g, 67%) as an off-white solid. MS (ESI) m/z 242.22/244.22 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:13])=[CH:5][C:6]=1[C:7](N(OC)C)=[O:8].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[C:7]([C:6]1[CH:5]=[C:4]([Cl:13])[S:3][C:2]=1[Cl:1])(=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(Cl)sc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(Cl)sc1Cl
Temperature: -30 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a stirred solution of 2,5-dichloro-N-methoxy-N-methyl-3-thiophenecarboxamide (350 mg, 1.46 mmol) in THF (5 mL) was added 3M solution of phenylmagnesium bromide in diethyl ether (1.2 mL, 3.6 mmol) at −78° C., and the mixture was stirred for 4 hours at −30° C. Saturated ammonium chloride solution was added, and the whole was extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with hexane-ethyl acetate (12:1) to provide the title product as a yellow oil. (212 mg, 56% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.F[C:24]1[C:29]([C:30](=O)[CH2:31][CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[N:25]=1>ClCCl>[CH2:31]([C:30]1[C:29]2[C:24](=[N:25][C:26]([F:34])=[CH:27][CH:28]=2)[N:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:8]=1)[CH3:32]
Reactant: CC(C)(C)OC(=O)NNC1CCOCC1
Reactant: CCC(=O)c1ccc(F)nc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(C2CCOCC2)c2nc(F)ccc12
Temperature: 75 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
A mixture of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate (3.8 g, 0.018 mol) and trifluoroacetic acid (20 mL, 0.3 mol) were stirred in dichloromethane (20 mL) for 90 minutes. The mixture was concentrated, and the residue was taken up in acetonitrile (30 mL). 1-(2,6-difluoropyridin-3-yl)propan-1-one (2.34 g, 0.0137 mol) was then added, and the resulting mixture was stirred at 75° C. for 72 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel using a 10-50% hexane:ethyl acetate gradient (flow rate 20 mL/min). The organics were combined and the crude product was then extracted with ethyl acetate. The combined extracts were washed with saturated sodium bicarbonate and then concentrated to afford 2.86 g (83.9%) of 3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine as a white solid. LC/MS (EI) tR 3.5 (Method E), m/z 250 (M++1).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].C(=O)([O-])[O-].[Ca+2].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: OC1CCNCC1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Yield: 69.6 %

Procedure:
Proceeding as indicated in example 2, with 0.0506 mole (15 g) of 2,4'-dichloro-5-nitro-benzophenone, 0.076 mole (10.5 g) of calcium carbonate and 0.076 mole (76.8 g) of 4-hydroxypiperidine, in 100 cm3 of ethanol, 12.7 g (Yield: 70%) of the expected product are obtained after re-crystallization in ethyl acetate. M.P. 142° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].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(O)C>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:8]3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: Brc1ccc(CN2CCOC(c3ccccc3)C2)cc1
Reactant: Cc1ccc(B(O)O)cc1
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: Cc1ccc(-c2ccc(CN3CCOC(c4ccccc4)C3)cc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
91 mg of 4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 56 mg of 4-Methylphenyl boronic acid, 16 mg of tetrakis(triphenylphosphine)palladium(0), 0.92 mL of 2M sodium carbonate solution, 2.5 mL toluene and 1.23 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with 4 mL DCM and 130 mg of MP-TsOH resin (4.2 mmol/g loading) was added and the mixture agitated at room temperature overnight. The solution is filtered and the resin is then washed with 2M N3 in methanol to liberate product. The resin is washed several times with methylene chloride, concentrated in vacuo and purified by reverse phase HPLC. 18.5 mg of product was obtained as oil. ES MS m/z 344, 20% yield
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: NCCCCc1ccccc1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Yield: 83.8 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.521 mmol), TEA (0.079 g, 0.782 mmol) and 4-phenylbutylamine (0.117 g, 0.782 mmol) in MeCN (3 mL) was heated in a microwave reactor at 120° C. for 5 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using a 75:25 mixture of heptane and EtOAc as eluant, to give the title compound (0.174 g, 84%); 1H NMR (500 MHz, CDCl3): δ 7.52-7.48 (m, 2H), 7.45-7.41 (m, 3H), 7.30-7.26 (m, 2H), 7.22-7.17 (m, 1H), 7.10-7.06 (m, 2H), 5.28-5.23 (m, 1H), 4.45-4.38 (m, 1H), δ 2.89-2.84 (m, 2H), 2.49-2.44 (m, 2H), 1.59 (d, 6H), 1.43-1.38 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 158.8, 141.8, 135.6, 131.8, 129.8, 128.8, 128.6, 128.5, 126.2, 125.3, 106.8, 47.7, 44.2, 35.4, 29.2, 28.3, 20.4; Mass Spectrum: M−H+ 399.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].Cl.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]Cl.[I-].[Na+].C(N(CC)CC)C>C(#N)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(CCCN(C)C)CC2)cc1
Yield: 25.2 %

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.29 g, 0.793 mmole) in 25 mL of acetonitrile was added 3-(dimethylamino)propyl chloride hydrochloride (0.013 g, 0.793 mmol), sodium iodide (0.02 g, 0.119 mmol), and triethylamine (0.32 g, 3.18 mmol). The reaction mixture was refluxed for 20 hours under Argon and then was cooled and concentrated in vacuo. To the residue was added, aqueous sodium hydroxide (1 N) solution (30 mL), and the resulting solution was extracted three times with chloroform (25 mL). The organic extracts were combined, washed with sodium carbonate solution, dried (Na2SO4), and concentrated to provide a brown oil. This material was purified on a flash silica gel column (10% methanol-chloroform to 17.5% methanol-chloroform) to provide 0.09 g (25%) of N,N-diethyl-4-[benzyl(1-(3-dimethylaminopropyl)piperidin-4-yl)amino]benzamide as a pale rose glass. MS (ES), m/z 451 (MH+). 300 MHz 1H NMR (CDCl3) δ1.17 (t, J=7.0 Hz, 6H), 1.69-1.89 (m, 4H), 2.14 (br t, 2H), 2.18-2.38 (br m, 2H), 2.42 (s, 4H), 2.47 (t, J=7.1 Hz, 2H), 2.59 (t, J=6.9 Hz, 2H), 3.06 (br d, J=11.6 Hz, 2H), 3.30-3.49 (m, 4H), 3.72-3.90 (br m, 1H), 4.52 (s, 2H), 6.65 (d, J=8.7 Hz, 2H), 7.10-7.30 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)[CH:5]=[C:4]([C:28]2[C:33]([OH:34])=[CH:32][CH:31]=[CH:30][C:29]=2[O:35][CH2:36][CH:37]2[CH2:39][CH2:38]2)[N:3]=1.C(N(CC)CC)C.Cl[C:48](Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([C:6]2[C:7]3[CH2:8][N:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:48](=[O:50])[NH:1][C:2]=3[N:3]=[C:4]([C:28]3[C:33]([OH:34])=[CH:32][CH:31]=[CH:30][C:29]=3[O:35][CH2:36][CH:37]3[CH2:38][CH2:39]3)[CH:5]=2)[CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)NCc1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1Cc2c(C3CCCN(C(=O)OC(C)(C)C)C3)cc(-c3c(O)cccc3OCC3CC3)nc2NC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 595.3 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-{[(ethoxycarbonyl)amino]methyl}-4-pyridinyl)-1-piperidine-carboxylate (0.145 g, 0.268 mmol), which was obtained in the step (1) of Example 23-2, and triethylamine (0.226 mL, 1.609 mmol) in tetrahydrofuran(30 mL) was added triphosgene (0.079 g, 0.268 mmol) in tetrahydrofuran (10 mL) under an argon atmosphere. The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with water and brine successively, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give ethyl 5-[1-(tert-butoxycarbonyl)-3-piperidinyl]-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidine-3(2H)-carboxylate as a white solid (0.904 g, yield; 60%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:35]N(C=O)C.CI>>[CH3:35][O:12][CH2:11][CH2:10][CH:9]([N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CCO)c4ccccc4)c3)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCCC(c1ccccc1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
Sodium hydride (9.6 mg, 0.00040 mol) was added to a solution of 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propan-1-ol (120 mg, 0.00027 mol) in DMF (3 mL, 0.04 mol) and the mixture was cooled to 0° C. The reaction was stirred for 20 min and methyl iodide (22 mL, 0.00035 mol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give 4-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 88%) as a semisolid. m/z=464 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:22]([NH2:25])=[N:23][OH:24])[CH2:9][C@@H:8]1[CH2:41][CH3:42])=[O:6])([CH3:3])[CH3:2].[C:43](OC(=O)C)(=O)[CH3:44]>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C@H:10]([N:21]([CH2:26][C:27]2[CH:28]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=2)[C:22]2[N:25]=[C:43]([CH3:44])[O:24][N:23]=2)[CH2:9][C@@H:8]1[CH2:41][CH3:42])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(N)=NO)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2noc(C)n2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 80 °C

Procedure:
To (+/−)-cis-4-[N-(3,5-bis-trifluoromethyl-benzyl)-hydroxyguanidino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (80 mg, 0.13 mmol), add acetic anhydride (0.5 mL). Seal the tube and heat the reaction mixture at 80° C. overnight. Cool down the mixture and remove the solvents under reduced pressure. Add 2 N NaOH (2 mL) and ether to the crude material. Separate the layers, and extract the aqueous phase with ether. Dry the combined organic phase, filter, and concentrate in vacuo. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (32 mg, %). MS (ES+): 640 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][N:8]2[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:31]([O-:33])=[O:32].[CH:34]([C:36]1[CH:44]=[CH:43][C:39]2[O:40][CH2:41][O:42][C:38]=2[CH:37]=1)=[CH2:35].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:40]1[C:39]2[CH:43]=[CH:44][C:36](/[CH:34]=[CH:35]/[C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[C:3]([N+:31]([O-:33])=[O:32])[CH:4]=4)[N:8]([C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:7]=3)=[CH:37][C:38]=2[O:42][CH2:41]1
Reactant: C=Cc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc2c(/C=C/c3ccc4c(c3)OCO4)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F
Temperature: 100 °C
Reaction time: 5 h
Yield: 13.8 %

Procedure:
Under nitrogen atmosphere, 1 g of 6-fluoro-3-iodo-5-nitro-1-trityl-1H-indazole was dissolved in 10 mL of acetonitrile, added successively with 1.35 g of 5-vinyl-benzo[1,3]dioxole, 81.7 mg of palladium acetate (II), 162 mg of 2-(di-tert-butylphosphino)biphenyl and 2 mL of triethylamine, and stirred at 100° C. for 5 hours. After cooling to room temperature, 5 g of silica gel was added, and the solvent was evaporated, and purified by silica gel column chromatography, to obtain 468 mg of the crude product as yellow crystal. This crude product was washed with 50% diethylether solution in hexane, and the solvent was evaporated, to afford 143 mg of the title compound as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[C:11]1([CH:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:3]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CNCCN1
Reactant: CC(Oc1cncc(Cl)n1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(Oc1cncc(N2CCNCC2)n1)c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of the product from step 1 above (1.53 g, 6.5 mmol), piperazine (1.62 g, 18.9 mmol) and K2CO3 (0.90 g, 6.5 mmol) in acetonitrile (6 mL) was heated in a sealed pyrex flask at 90° C. for 3.5 h. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (13×4 cm) using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated off and the remaining oil was redissolved in CHCl3, filtered through a short plug of alumina and concentrated in vacuo. This gave 1.34 g (72%) of the title compound as an oil that solidified when refrigerated. HRMS m/z calcd for C16H20N4O (M)+ 284.1637, found 284.1650. Anal. (C16H20N4O.C4H4O4) C, H, N.
Reaction SMILES: I.CS[C:4](=[N:18][CH3:19])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:20][O:21][CH2:22][CH2:23][NH2:24].C(O)C.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:19][NH:18][C:4]([NH:24][CH2:23][CH2:22][O:21][CH3:20])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COCCN
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CNC(=Nc1ccccc1N1CCOCC1)NCCOC

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210), 2-methoxyethylamine (0.82 g) and ethanol (25 ml) was stored at ambient temperature for three months to yield an oil which was dissolved in methanol and treated with fumaric acid to give 1-methyl-2-(2-morpholinophenyl)-3-(2-methoxyethyl)guanidine monofumarate (m.p. 158°-160° C.) which was recrystallised rom a 1:2 mixture of methanol and ether.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17](O)[CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:12])[CH3:11]>C(Cl)Cl.C(OCC)(=O)C>[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH:17]([F:7])[CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCCC(O)CCCOC(C)=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCCCC(F)CCCOC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of (diethylamino)-sulfur trifluoride (571 mg, 3.54 mmol) in CH2Cl2 was added the solution of acetic acid, 7-acetoxy-4-hydroxy-heptyl ester (403 mg, 1.74 mmol) in CH2Cl2 (10 ml) at −78° C. The resulting mixture was allowed to stir for 15 minutes at −78° C., 30 minutes at room temperature and then diluted with ethyl acetate (300 ml). The organic solution was washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by column chromatography on silica gel, using 15% ethyl acetate in hexanes, gave the title compound (386 mg, 94%) as a colorless oil. 1H NMR (CDCl3) δ 1.55–1.83 (m, 8H), 2.05 (s, 6H), 4.05–4.15 (m, 4H), 4.39–4.63 (m, 1H); 13C NMR (CDCl3) δ 20.97, 24.42, 24.48, 31.51, 31.79, 64.03, 92.22, 94.45, 171.12; 19F NMR (CDCl3) δ −106.44–105.27(m); ES-MS m/z 257.3 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH2:7][OH:8])[N:6]=1.C([OH:17])(C)C>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[S:3][C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([C:7]([OH:17])=[O:8])[N:6]=1
Reactant: CC(C)O
Reactant: CCOC(=O)c1sc(Cl)nc1CO
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of ethyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (Intermediate 8, 2.5 g, 11 mmol) in acetone at 0° C. was slowly added a solution of chromium trioxide (2.26 g, 22 mmol) in 20% conc. Sulfuric acid in water (20 mL). After stirring at room temperature for 2 hrs, isopropanol (1 mL) was added to quench unreacted chromium trioxide. The reaction was diluted with water and the acetone was removed. Partitioning with methylene chloride (×3), drying with MgSO4 and concentrating yielded a white solid (2.3 g, 90%). MS (ES): 236 (M+H+) for C7H6ClNO4S; NMR: 1.26 (t, 3H), 4.31 (q, 2H), 13.99-14.15 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-acetyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C35H42Cl2N5O3 [(M+H)+] 650.2659, observed 650.2662.