Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(CC)C.[CH3:6][C:7]([CH3:18])([O:9][C:10]([NH:12][C@H:13]1[CH2:16][NH:15][C:14]1=[O:17])=[O:11])[CH3:8].[CH3:19][S:20]([N:23]=[C:24]=[S:25])(=[O:22])=[O:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:8][C:7]([CH3:18])([O:9][C:10]([NH:12][C@H:13]1[CH2:16][N:15]([C:24](=[S:25])[NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[C:14]1=[O:17])=[O:11])[CH3:6]
Reactant: CS(=O)(=O)N=C=S
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=S)NS(C)(=O)=O)C1=O
Reaction time: 0.03 h

Procedure:
Sec-Butyl lithium (9.25 ml of 1.35 M solution in cyclohexane) was added to a stirred solution of (S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-oxoazetidine (2.33 g) in 250 ml of dry tetrahydrofuran at -75° C. under nitrogen. After stirring for 2 minutes, (methylsulfonyl)-isothiocyanate (1.75 ml) was added, and the solution was stirred for 25 minutes at -75° C. and poured into 125 ml of 0.5 M pH 5.5 monobasic potassium phosphate buffer. Ethyl acetate and water were added, and the pH was adjusted to 2.5 (3N hydrochloric acid). The ethyl acetate layer was washed with water, dried with sodium sulfate, and evaporated to a residue (3.69 g), which was recrystallized from ethyl acetate to give 2.04 g of the title compound. Recrystallization of a portion from ethyl acetate gave crystals, melting point 181° C.,dec.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[C:4]([NH:8][C:9]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])=S)[CH:5]=[CH:6][CH:7]=1>C(#N)C.C(OCC)(=O)C.[Hg](Cl)Cl>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[NH:11][C:9]1[N:21]([CH3:22])[C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1
Reactant: CNc1c(N)cccc1NC(=S)Nc1c(C)cc(C)cc1C
Agent: Cl[Hg]Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(C)c(Nc2nc3cccc(N)c3n2C)c(C)c1
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution containing 0.25 g (0.79 mmol) of 1-(3-amino-2-methylaminophenyl)-3-mesitylthiourea in acetonitrile was added 0.52 g (1.6 mmol) of mercury (II) chloride, and the mixture stirred for 1 h. The reaction mixture was diluted with ethyl acetate (2 ml) and filtered through a prepacked celite column. The filtrate was concentrated under reduced pressure and the residue purified via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane to afford 0.12 g (55%) of product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2([OH:15])[C:12]([CH3:14])([CH3:13])[CH:5]3[CH:6]=[CH:7][C:8]2([CH3:16])[CH:3]1[CH2:4]3>O=[Pt]=O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2([OH:15])[C:12]([CH3:14])([CH3:13])[CH:5]3[CH2:6][CH2:7][C:8]2([CH3:16])[CH:3]1[CH2:4]3
Reactant: CC1CCC2(O)C(C)(C)C3C=CC2(C)C1C3
Agent: O=[Pt]=O
Product: CC1CCC2(O)C(C)(C)C3CCC2(C)C1C3

Procedure:
4,8,11,11-Tetramethyltricyclo[5.3.1.03,8 ]undec-9-en-7-ol, prepared according to the process described in Example 1, was catalytically hydrogenated in the presence of PtO2, in accordance with the process described by G. Buchi et al, J. Am. Chem. Soc., 83, 927 (1961). The product obtained was in all respects identical to that prepared by the cited authors.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1>CCO>[NH2:28][C:29]1[N:30]=[CH:31][C:32]([C:33]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:34])=[CH:36][CH:37]=1
Reactant: C1COCCN1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCOCC2)cn1
Reaction time: 18 h
Yield: 30 %

Procedure:
To a solution of morpholine (9.00 g, 103 mmol) in EtOH (400 mL) was added EDCI (10.0 g, 52.2 mmol), HOBt (7.00 g 51.8 mmol), and 6-aminonicotinic acid (6.00 g, 43.4 mmol). After stirring for 18 h, the resulting suspension was filtered. The solid was triturated with a mixture of MeOH (100 mL) and methylene chloride (100 mL) to afford 111a as a white solid (2.7 g, 30%). LCMS: (M+H)+ 208
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:8][N:9]([C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=O.C(O)C>C(O)(=O)C>[Cl:22][C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:3](=[O:2])[C:5]3([CH2:7][CH2:6]3)[CH2:8][N:9]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:15]=2[N:16]=1
Reactant: COC(=O)C1(CN(c2nc(Cl)ncc2N)C2CCCC2)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CC2
Yield: 98 %

Procedure:
A mixture of 0.2224 g (0.00068 mole) of 1-{[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclopropanecarboxylic acid methyl ester (V-53), 12 mL of ethanol and 0.3 mL of acetic acid was heated at reflux for 18 hours, and then concentrated under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed successively twice with 15 mL of aqueous sodium bicarbonate, twice with 15 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.195 g of 2-chloro-9-cyclopentyl-8,9-dihydro-spiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VI-53), as a light yellow solid.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:11][P:12]([CH2:23][C:24]([N:26]1[CH2:40][CH2:39][CH2:38][C@H:27]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:25])([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[C:1]([NH:9][CH:10]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:11][P:12]([CH2:23][C:24]([N:26]1[CH2:40][CH2:39][CH2:38][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)CC(Cc1ccccc1)NC(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)OCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)O)CC(Cc1ccccc1)NC(=O)c1ccccc1

Procedure:
A solution of the diester product from part (a) in methanol is added to a 10% palladium on carbon catalyst and the resulting mixture is shaken in a Parr hydrogenation apparatus for several hours. The catalyst is filtered off and the methanol is stripped from the filtrate. The crude product is chromatographed on silica gel to yield (S)-1-[[[2-(benzoylamino)-3-phenylpropyl][(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]acetyl]-L-proline.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]#[N:28])[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:30][CH2:31][CH2:32][CH2:33]Br.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][C:26]2([C:27]#[N:28])[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2CCC#N)c1
Reactant: BrCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2CC2(C#N)CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-(2-fluoro-5-methoxyphenyl)pyridin-3-yl)propanenitrile (514 mg) and 1,4-dibromobutane (0.30 mL) in THF (10 mL) was added a THF solution (1 M, 3.9 mL) of lithium bis(trimethylsilyl)amide, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was 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) to give the title compound (514 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: O=C(O)c1ccc(CBr)cc1Br
Reaction time: 1 h
Yield: 51.9 %

Procedure:
2-Bromo-4-methylbenzoic acid (33.5 g, 156 mmol, 1 eq) and N-Bromosuccinimide (40.7 g, 233 mmol, 1.5 eq) were dissolved in refluxing 1,2-dichloroethane (600 ml) and a catalytic amount of AIBN was added. The mixture was left stirring under a lamp and under nitrogen for 1 hour. The solvent was removed and the mixture was partitioned between 600 ml of water and 600 ml EtOAc. The organic layer was washed twice with water (600 ml), washed once with brine (600 ml) and then dried with sodium sulfate. The solvent was removed and the crude mixture was triturated with 10% EtOAc/Hexane for 2 hours to give 23.8 g (52%) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:45]4[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=4[N:43]=3)=[CH:38][CH:37]=2)=[CH:32][CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.O1CCOCC1>[C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[C:31]([C:36]5[CH:41]=[CH:40][C:39]([C:42]6[N:46]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)[C:45]7[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=7[N:43]=6)=[CH:38][CH:37]=5)=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Brc1ccccc1-c1ccccc1-c1ccc(-c2nc3ccccc3n2-c2ccccc2)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: O
Solvent: C1COCCO1
Product: c1ccc(-n2c(-c3ccc(-c4ccccc4-c4ccccc4-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)nc3ccccc32)cc1

Procedure:
Following the procedure for Host-1, (9-phenyl-9H-carbazol-3-yl)boronic acid (0.458 g, 1.60 mmol), Compound 3 (0.800 g, 1.60 mmol), tetrakis(triphenylphosphine)palladium(0) (73.7 mg, 63.8 μmol), Na2CO3 (0.530 g, 5.00 mmol), H2O (5 mL) and 1,4-dioxane (25 mL) provided Host-2 (0.78 g, 74%) as an off-white solid after flash chromatography (SiO2, 17:3-hexanes: acetone) and recrystallization from methanol (CH3OH): confirmed by LCMS (APCI): calculated for C49H33N3 (M+): 664; Found: 664.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[S:30][C:18]2[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20](=[O:23])[CH:21]=[CH:22][C:17]=2[C:16]=1[C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1)(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:14][C:15]1[S:30][C:18]2[N:19]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20](=[O:23])[CH:21]=[CH:22][C:17]=2[C:16]=1[C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1
Reactant: Cc1cccc(C(=O)c2c(NC(=O)OC(C)(C)C)sc3c2ccc(=O)n3-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2c(N)sc3c2ccc(=O)n3-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of Example 3 (5.4 g, 11.0 mmol) in DCM (20 ml) and stirred at r.t. for 5 h. NaHCO3(aq) (200 ml) was added to the reaction, and the mixture extracted with DCM (3×100 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography (silica, 10% THF in DCM) to give the title compound as a yellow solid (3.0 g, 76%). δH (CDCl3) 7.52-7.45 (3H, m), 7.33-7.30 (6H, m), 6.72 (1H, d, J 9.6 Hz), 6.33 (1H, d, J 9.6 Hz), 2.35 (3H, s). LCMS (ES+) RT 3.11 minutes, 361 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:25][NH:26][C:27](=[O:28])[O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=2)[CH:17]=1
Reactant: CN=C=O
Reactant: O=C(NCCN1CCCC1c1cccc(O)c1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2CCNC(=O)c2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 94 %

Procedure:
The 4-chloro-N-{2-[2-(3-hydroxyphenyl)-1-pyrrolidinyl]ethyl}benzamide (0.29 g) was dissolved in tetrahydrofuran (20 ml), and methyl isocyanate (50.0 μl) and milled potassium carbonate (0.17 g) at ambient temperature were added, under nitrogen. The reaction mixture was stirred for 2 hrs and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the combined filtrates were concentrated. Crystallization of the residue with ether/petroleum ether gave 0.32 g (94%) of product. Recrystallization from ether gave the analytical sample, mp 103°-106° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2.[F:22][C@@H:23]1[CH2:27][N:26]([C:28](=[O:40])[CH2:29]OS(C2C=CC=CC=2)(=O)=O)[C@H:25]([C:41]([NH2:43])=[O:42])[CH2:24]1.O>CN(C)C=O>[CH2:20]([O:19][C:17]([C:12]12[CH2:11][CH2:10][C:9]([NH:8][CH2:29][C:28]([N:26]3[CH2:27][C@@H:23]([F:22])[CH2:24][C@H:25]3[C:41]([NH2:43])=[O:42])=[O:40])([CH2:16][CH2:15]1)[CH2:14][CH2:13]2)=[O:18])[CH3:21]
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
Potassium carbonate (277 mg) was added to a solution of ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (319 mg) in N,N-dimethylformamide (1.8 mL), followed by stirring at an inner temperature of 40° C. for 30 minutes. (2S,4S)-4-Fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carboxamide (295 mg) was added thereto, followed by stirring at the same temperature for 1 hour. Water (5.4 mL) was added to the reaction solution, followed by stirring at an inner temperature of from 5 to 10° C. for 30 minutes. The precipitate were collected by filtration, washed with cold water (4 mL) and then blast-dried at an outer temperature of 40° C., thereby obtaining white crystals of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (obtained amount: 247 mg, yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(O)CO>O>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:17]3[CH2:16][CH2:15][N:14]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=4)[CH2:19][CH2:18]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)cc(Cl)c2n1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)cc(Cl)c4n3)CC2)cc1
Temperature: 82.5 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A mixture of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 19, Step 1; 0.301 g), 4-(piperazin-1-yl)benzamide (Example 3, Step 1; 0.2916 g), triethylamine (Aldrich; 0.21 mL), and ethylene glycol (2 mL) is stirred for 1 h at 80-85° C. The mixture is then allowed to cool and water is added. The solids are collected, washed with water and hexane, and dried under reduced pressure. The solid is then adsorbed onto silica gel and chromatographed using methanol/dichloromethane (8/92). The appropriate fractions are combined and concentrated and the residue is crystallized from dichloromethane/methanol to give 0.2938 g of the title compound; mp 234-235° C.; MS m/z 403,405; IR (mineral oil) 1606, 1668, 1392, 1522, 1241 cm-1 ; 1H NMR (CDCl3) δ2.74, 3.35, 3.83, 6.89, 7.27, 7.63, 7.72, 8.10.
Reaction SMILES: C([O:8][C:9](=[O:35])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:34])[C@H:16]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H].Cl>CO.[C].[Pd].O>[C:21]1([S:18]([NH:17][C@H:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:35])=[O:8])=[O:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1
Yield: 70.5 %

Procedure:
N-benzenesulfonyl-L-phenylalanyl-L-proline benzylester (2.14 g, 4.3 mmole) was dissolved in methanol (40 ml), and water (5 ml) solution of sodium bicarbonate (0.42 g, 5 mmole) was added thereto. Hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 3 hours. The catalyst was removed by filtration and the solution was concentrated under reduced pressure. The residue thus obtained was dissolved in water (20 ml), and 1N aqueous hydrochloric acid (10 ml) was added thereto to give white crystals. They were recrystallized from ethyl acetate and petroleum ether to obtain N-benzenesulfonyl-L-phenylalanyl-L-proline (yield: 1.22 g, 69.8%).
Reaction SMILES: [OH-].[Na+].S(OC)(O[CH3:7])(=O)=O.[OH:10][C@H:11]1[CH2:16][O:15][CH2:14][C@@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:7][O:10][C@H:11]1[CH2:16][O:15][CH2:14][C@@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1
Reactant: COC(=O)[C@@H]1COC[C@H](O)C1
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1COC[C@H](OC)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
15 ml of 50% NaOH, 367 mg of benzyltriethylammonium bromide and 0.95 ml of dimethyl sulphate are added to a solution of 1.05 g of methyl (cis)-5-hydroxytetrahydropyran-3-carboxylate in 30 ml of toluene. The two-phase mixture is stirred at room temperature for 18 hours. A further 1 ml of dimethyl sulphate is added. The mixture is stirred at room temperature for a further 6 hours, then diluted with water and ethyl acetate, and stirred at room temperature for 20 minutes. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The crude title compound is identified. by means of the Rf from the residue.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:18][C:8]2=1)=O.[NH2:28][C:29]([NH2:31])=[S:30]>>[NH2:31][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:14])[C:9]2[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:18][C:8]3=2)[N:28]=1
Reactant: NC(N)=S
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(N)n4)ccc3n(C)c21

Procedure:
The process is carried out as for Example 21 above, using compound A, 6-(2-bromoacetyl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and thiourea.
Reaction SMILES: [N:1]([CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([OH:7])=O)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[N:1]([CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([NH:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:7])=[N+:2]=[N-:3]
Reactant: NCc1ccccc1
Reactant: [N-]=[N+]=NC(Cc1ccccc1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: [N-]=[N+]=NC(Cc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
2-Azido-3-phenylpropanoic acid (J. T. Lundquist IV, J. C. Pelletier, Org. Lett. 2001, 3, 781-783) (112 mg, 0.588 mmol) and HOBt (108 mg, 0.705 mmol) were suspended in CH2Cl2 (2 mL), and the mixture was cooled to 0° C. under Ar(g). DIC (107 μL, 0.705 mmol) was added, and the resulting mixture was stirred for 30 min. Benzyl amine (122 μL, 1.06 mmol) was then added, and the mixture was allowed to warm to room temperature and then stirred overnight under Ar(g). The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 15% EtOAc/hexanes, to give the required amide 2b as a white solid (117 mg, 0.418 mmol, 71% yield).
Reaction SMILES: ClC1C=CC(CSCC2[C:18]3[C:13](=[CH:14][CH:15]=[C:16](C4C=CC=CC=4OC)[CH:17]=3)[NH:12]C(C)(C)C=2)=CC=1.Br[CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])[CH:41]=2)[NH:36][C:35]([CH3:52])([CH3:51])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CC(CS)=CC=1>>[CH3:50][O:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:52])([CH3:51])[CH:34]=[C:33]2[CH2:32][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSCc1ccc(Cl)cc1)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: SCc1ccc(Cl)cc1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-(4-Chlorobenzylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 76 μL of 4-chloro-α-toluenethiol reacted to give 8 mg of the title compound as an oil.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:36][C:37]([Cl:41])=[C:38]([NH2:40])[CH:39]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[Cl:41][C:37]1[S:36][C:35]([S:32](=[O:34])(=[O:33])[NH:31][C:28]([CH3:30])([CH3:29])[CH2:27][OH:26])=[CH:39][C:38]=1[NH:40][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Light yellow solid. MS (ISP) 622.2 [(M−H)−]; mp 233° C.