Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:13])=[CH:5][CH:4]=1.[CH:14](OCC)(OCC)OCC>O1CCCC1.C(OCC)(=O)C>[O:12]1[C:11]2[C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=[CH:14]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2c(c1O)C(=O)CC2
Agent: Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCc2ccc3ncoc3c21
Yield: 61.7 %

Procedure:
6-Amino-7-hydroxyindan-1-one hydrobromide (50 mg, 0.205 mmol) and triethyl orthoformate (128 μL, 0.769 mmol) were heated under reflux in tetrahydrofuran (2.5 mL) for 0.5 hr. The mixture was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (21.9 mg, yield from Reference Example 3 62%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][CH3:11])[C:7]([CH:12]([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)O)=[C:6]([CH2:19][CH3:20])[CH:5]=1)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:19][CH3:20])[C:7]([CH2:12][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[C:8]([CH2:10][CH3:11])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(CC)c(C(O)c2ncc[nH]2)c(CC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CC)c(Cc2ncc[nH]2)c(CC)c1

Procedure:
2-(4-Ethoxy-2,6-diethyl-benzyl)-1H-imidazole was prepared from rac-(4-ethoxy-2,6-diethyl-phenyl)-(1H-imidazol-2-yl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): light yellow crystals; MS (ISP): 259.4 ([M+H]+, 100%).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:13][N:14]1[C:22]2[C:18]([N:19]=[C:20]([C:23]([O:26]CC3C=CC=CC=3)([CH3:25])[CH3:24])[N:21]=2)=[C:17]([NH:34][CH2:35][CH3:36])[N:16]=[CH:15]1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[ClH:1].[CH2:35]([NH:34][C:17]1[N:16]=[CH:15][N:14]([CH2:13][C:12]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:10]([OH:9])[CH:11]=2)[C:22]2[C:18]=1[N:19]=[C:20]([C:23]([OH:26])([CH3:25])[CH3:24])[N:21]=2)[CH3:36]
Reactant: CCNc1ncn(Cc2ccc(OC)c(OCc3ccccc3)c2)c2nc(C(C)(C)OCc3ccccc3)nc1-2
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1ncn(Cc2ccc(OC)c(O)c2)c2nc(C(C)(C)O)nc1-2
Yield: 80.2 %

Procedure:
The above crude 3-(3-benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-6-ethylamino-3H-purine hydrochloride (3.28 g, 5.7 mmole) was hydrogenated at room temperature and pressure in a mixture of THF:methanol 1:1 (60 ml) with 10% Pd-C (0.66 g). The catalyst was filtered off, the solvents evaporated in vacuo and the residue crystallized from acetone to give 6-ethylamino-3-(3-hydroxy-4-methoxy-benzyl)-8-(1-hydroxy-1-methyl-ethyl)-3H-purine hydrochloride (1.80 g, 80.0%), mp 184-185° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(OC(C)C)(C)C.N>C(OCC)(=O)C.CO>[N:20]1([CH2:26][CH2:27][CH:28]2[O:33][CH2:32][CH2:31][N:30]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCN(CCC2CNCCO2)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Agent: N
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1Nc2ccccc2N(C(=O)N2CCOC(CCN3CCCCC3)C2)c2ncccc21
Yield: 78 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-(1-piperidinyl)ethyl]morpholine in a yield of 78% of theory. Colourless crystals, m.p. 136°-138° C. (diisopropylether), Rf 0.46 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: ethyl acetate/methanol/conc. ammonia 100/30/3, v/v/v).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=3[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:10](=[O:29])[NH:9]2)=[C:4]([O:30][CH3:31])[CH:3]=1.[Cu][C:33]#[N:34]>CN(C)C=O.CO.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:29]=[C:10]1[NH:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]#[N:34])=[CH:3][C:4]=2[O:30][CH3:31])[C:17]2[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=1
Reactant: N#C[Cu]
Reactant: COc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 140 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromo-2-methoxyphenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (intermediate 50, 21 mg, 42 μmol), copper(I) cyanide (10 mg, 0.11 mmol) and tetrakis(triphenylphosphine)-palladium(O) (5 mg, 4 μmol) in N,N-dimethylformamide (1 mL) is heated at 140° C. over it) night. The mixture is cooled at room temperature, diluted with methanol and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 4 mg; ESI mass spectrum [M+H]+=442; Retention time HPLC: 0.87 min (Z011_S03).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH2:23][CH2:22][F:21])[CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(OCCF)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OCCF)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(2-fluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.82 min.; [M+H]+: 388.02 g/mol.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33]C)[CH:28]=3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=C(B(O)O)C=CC=1.B(O)O>>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=3)[CH:26]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cncc(-c3cc(NCc4ccccc4)nc(-c4ccccn4)c3)c2)c1
Agent: COc1cccc(B(O)O)c1
Agent: OBO
Product: Oc1cccc(-c2cncc(-c3cc(NCc4ccccc4)nc(-c4ccccn4)c3)c2)c1

Procedure:
This compound is prepared analogously to Benzyl-[5″-(3-methoxy-phenyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.43) by 3-methoxyphenylboronic acid with the appropriate boronic acid.
Reaction SMILES: [CH2:1]([C:4]1[CH:24]=[C:23]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH3:3].N12CCCN=C1CCCC[CH2:30]2.IC.CO>C1COCC1.CCOC(C)=O>[CH2:1]([C:4]1[CH:24]=[C:23]([S:25]([NH:28][CH3:30])(=[O:26])=[O:27])[CH:22]=[CH:21][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH3:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCCc1cc(S(N)(=O)=O)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Solvent: CI
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1cc(S(=O)(=O)NC)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 7.2 %

Procedure:
To a solution of 2.19 g (5.38 mmol) of the product of Step C dissolved in 20 mL of anhydrous THF was added 2.41 mL (16.1 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and the reaction mixture was magnetically stirred under a nitrogen atmosphere for 25 minutes at room temperature. Iodomethane (1.00 mL; 16.1 mmol) was added and the reaction mixture was stirred an additional 15 hours at room temperature. The reaction mixture was diluted with EtOAc and a precipitate formed which was redissolved by addition of methanol. The mixture was further diluted with warm EtOAc (150 mL total), refridgerated overnight and a solid separated which was removed by filtration. The filtrate was evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 5% EtOAc-CHCl3. Combination of the purified fractions and evaporation in vacuo afforded 0.164 g of the title compound and a number of impure fractions which were reserved for repurification. 1H-NMR (400 MHz, CD3OD, ppm): δ 0.97 (t, J=7.20 Hz, 3H), 1.65-1.77 (m, 2H), 2.48 (s, 3H), 2.74 (t, J=7.20 Hz, 2H), 3.71 (s, 3H), 5.87 (s, 1H), 5.98 (s, 2H), 6.85 (d, J=8.00 Hz, 1H), 6.96 (d, J=8.80 Hz, 1H), 7.04 (d, J=1.60 Hz, 1H), 7.07 (dd, J=1.60, 8.00 Hz, 1H), 7.58-7.61 (m, 2H). ESI-MS m/e=421 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([CH2:14][C:15](OC)=[O:16])(=O)[CH2:10][CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCO>[CH3:8][C:7]1[C:2]2=[N:1][C:9]([CH2:10][CH2:11][CH3:12])=[CH:14][C:15](=[O:16])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1N
Reactant: CCCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: CCCc1cc(=O)n2cccc(C)c2n1
Temperature: -30 °C

Procedure:
A solution of 54.0g of 2-amino-3-methylpyridine, 144.0g of methyl butyrylacetate, 5.0g of p-toluenesulfonic acid, and 750ml of ethylene glycol monomethyl ether is heated in a nitrogen atmosphere, under reflux, for 60 hours. The solution is concentrated to dryness in vacuo, and the residual oil extracted with two 250ml portions of pentane. The pentane solution is concentrated to a volume of 250ml and cooled at -30°C to yield the title compound, melting point 59°-60°C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[CH3:47][NH:48][CH2:49][C:50]([NH2:52])=[O:51].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[CH3:47][N:48]([CH2:49][C:50](=[O:51])[NH2:52])[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11]([S:13][C:14]3[C@H:15]([CH3:45])[C@@H:16]4[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:41])([CH3:43])[CH3:42])([CH3:38])[CH3:39])[CH3:35])[C:32](=[O:44])[N:17]4[C:18]=3[C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])[CH2:10]2)[S:7][CH:8]=1)=[O:3]
Reactant: CNCC(N)=O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)O)cs4)C3)[C@H](C)[C@H]12
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N(C)CC(N)=O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.9 %

Procedure:
Subsequently, to a suspension of p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carboxy-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.00 g, 1.51 mmol) (obtained as described in Reference Example 41(7)) and 2-methylamino-acetamide hydrochloride (282 mg, 2.26 mmol) (obtained as described above) in dimethylformamide (30 ml) were added diethylphosphoryl cyanide (0.37 ml, 2.26 mmol) and triethylamine (0.95 ml, 6.80 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred at room temperature for 3.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed successively with 0.5M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate ethyl acetate:methanol (10:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[N-methyl-N-(carbamoyl)methyl-carbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate (932 mg, yield 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:22])[N:10]([CH3:21])[C:11](O)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:25].C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:22])[N:10]([CH3:21])[C:11]([Cl:25])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(O)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Cl)nc(-c2ccncc2)c(-c2cccc(Br)c2)c1=O
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To a 250 mL RBF, was added 5-(3-bromo-phenyl)-2-hydroxy-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (5.76 g, 16.1 mmol), 50 mL POCl3. The mixture was warmed up to 85° C. and stirred for 15 h under nitrogen. The mixture was cooled down to rt and vacuumed down all volatile composites. The black cake obtained was dissolved in dichloromethane, neutralized with sat. NaHCO3. After purified by flash chromatography, the 5-(3-Bromo-phenyl)-2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one was obtained in 4.72 g as white powder. MS (ES+): 376 (M+H)+; (ES−): 374 (M−H).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([NH:18][C:6](=[O:8])[CH2:5][C:4](=[O:3])[CH3:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)NCc1ccccc1

Procedure:
9 ml (0.05 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene-acetone adduct) were added dropwise to a solution of 5.5 ml (0.05 mol) of benzylamine in 20 ml of toluene and the temperature was allowed to rise 70° C. The solution was refluxed for 2 h then the solvent was removed in vacuo. The crude product was triturated with ether obtaining 7.5 g of the title compound. M.p.=84°-86° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2)=O.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][C:13]([NH:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:1][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:36])(=[O:24])=[O:25]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc2c(c1)CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCc2cc(CN3CCCCC3)ccc21

Procedure:
The title compound was prepared from N-(5-formyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 5, Step F) and piperidine yielding a white solid. MS (ESI) m/z 568 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1csc(CO)c1
Solvent: ClCCl
Product: COC(=O)c1csc(CCl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4.86 g of methyl 5-(hydroxymethyl)thiophene-3-carboxylate was dissolved in 50.0 mL of dichloromethane, and 4.12 mL of thionyl chloride was added thereto under ice-cooling, followed by stirring at room temperature for 15 hours. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added ethyl acetate, and then washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine. It was dried over anhydrous magnesium sulfate, and then the solvent was evaporated to obtain 4.90 g of methyl 5-(chloromethyl)thiophene-3-carboxylate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]([C:25]#[N:26])([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[OH-].[Na+]>C1COCC1>[CH2:5]([N:12]1[CH2:13][CH2:14][C:15]([C:25]2[NH:26][N:3]=[N:2][N:1]=2)([NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(Nc3ccccc3)(c3nnn[nH]3)CC2)cc1
Reaction time: 8 h
Yield: 47 %

Procedure:
Sodium azide (5.85 g, 90 mmol) and 1-benzyl-4-cyano-4-anilinopiperidine (2.91 g, 10 mmol) were added slowly to a solution of AlCl3 (2.67 g, 20 mmole) in dry THF (100 ml). The resulting mixture was refluxed overnight. The reaction was quenched with water (50 ml). After separating the THF layer, the aqueous layer was extracted with additional THF (4×50 ml). The combined THF layers were dried over MgSO4 and concentrated in vacuo. The solid obtained was dissolved in 1N.HCl solution and the pH was adjusted to 6.0 with 1N NaOH solution. The resulting mixture was left overnight and filtered to give the product (1.58 g, 4.7 mmol) as white crystalline solid: mp 205°-206° C. (decomposed); IR (nujol) 3300 cm-1 ; NMR (270 MHz, DMSO-d6) δ2.2 to 2.7 (m, 8H, piperidine CH2), 3.53 (s, 2H, benzyl CH2), 6.35, 6.63 and 7.01 (3 m, 5H, anilinophenyl H's), 7.25 (m, 5H, benzylphenyl H's). Anal. Calcd. for C19H22N6 : C, 68.24; H,6.63; N,25.13. Found: C, 68.79; H,6.76; N,24.81. ##STR20##
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:9][CH:10]=1)=[O:5])C.O1CCCC1.[OH-].[Na+]>CO>[N:15]1[CH:16]=[CH:17][C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1csc(Nc2ccncc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1csc(Nc2ccncc2)n1

Procedure:
2-(Pyridin-4-ylamino)-thiazole-4-carboxylic acid (160 mg) was prepared according to General Procedure C using 2-(pyridin-4-ylamino)-thiazole-4-carboxylic acid ethyl ester in methanol:tetrahydrofuran:2N NaOH (1:1:1, 1.5 mL). The solvents were evaporated and the compound was dried. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][CH:8]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[Br:25][C:5]1[C:6]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl ((1S,2S)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclopentyl)carbamate (3.49 g, 10.08 mmol) in dry DCM (67 ml) at 0° C. was added 1-bromopyrrolidine-2,5-dione (CAS number 128-08-5; 2.15 g, 12.09 mmol). The reaction was allowed to warm to room temperature overnight. A further portion of portion of 1-bromopyrrolidine-2,5-dione (CAS number 128-08-5; 1.70 g, 9.56 mmol) was added and the reaction stirred for an additional 24 hours. The reaction was concentrated in vacuo and then purified by column chromatography (silica, 0-30% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:18]=2)[NH:13][CH:12]=1)[CH2:9][NH2:10].O=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.O1CCOCC1>O1CCOCC1.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:18]=3)[NH:13][C:12]=2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:10][CH:9]=1
Reactant: Cc1cc2[nH]cc(C(CN)c3ccccc3F)c2cc1Oc1cncnc1
Reactant: CCOC(=O)C=O
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C)c(Oc3cncnc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(6-methyl-5-(pyrimidin-5-yloxy)-1H-indol-3-yl)ethanamine (0.262 g, 0.724 mmol) and 50% ethyl 2-oxoacetate in toluene (0.316 mL, 1.593 mmol) in 1,4-dioxane (18.10 mL) under nitrogen was added 4 N HCl/1,4-dioxane (0.543 mL, 2.172 mmol). After stirring overnight, the reaction was concentrated in vacuo and dissolved in water. Saturated aqueous NaHCO3 was added until pH ˜12 by litmus paper. The solution was extracted with EtOAc (2×). After separation of the layers, the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give crude product which was used in subsequent step. This was added to 10% Pd/C (0.770 g, 0.724 mmol) in toluene (10.34 mL), and the reaction was refluxed for 45 min. After cooling to room temperature, the reaction was filtered through a pad of CELITE® and rinsed with EtOAc. The filtrate was concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 40 g column eluting with 0-2% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0716 g, 0.162 mmol, 22.4% yield) as a tan solid.
Reaction SMILES: [CH:1]1([CH:4]([NH:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]O)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:1]1[CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)NC(=O)NC(CCO)C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)NC(=O)NC(CCBr)C1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
The 1-(1-cyclopropyl-3-hydroxy-propyl)-3-isopropyl-urea (0.189 g, 0.950 mmol) was then dissolved in CH2Cl2 (10 mL) and CBr4 (0.477 g, 1.40 mmol) was added and the mixture was cooled to 0° C. To the mixture was added PPh3-polymer-bound resin (0.889 g, 1.40 mmol; 1.6 mmol/g) in portionwise. After stirring for at rt for 3 h, the mixture was diluted with CH2Cl2 (50 mL), filtered, and washed with CH2Cl2/MeOH/Acetone. The combined filtrates were concentrated in vacuo to give 1-(3-Bromo-1-cyclopropyl-propyl)-3-isopropyl-urea (0.212 g). GC-MS m/z 262.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:1]([C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)=[O:12])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc4c(c3)OCO4)nc12

Procedure:
From piperonylic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. []D20=+25.7° (c=0.86, CHCl3), ES-MS m/e (%): 415 (M+H+, 100).