Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]C(C)(C)C.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CCCCC>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(I)cc(OC)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(OC)cc(OC)c1
Temperature: -20 °C
Yield: 70.9 %

Procedure:
To a solution of 5.28 g (20 mmol) of 1-iodo-3,5-dimethoxybenzene (W. Riedhl, F. Imhof, Justus Liebigs Ann. Chem., 1955;597:153–157) in 100 mL of THF at −78° C. is added 12.3 mL (21 mmol) of 1.7 M tert-BuLi in pentane, and after a further 5 minutes 4.4 g (30 mmol) of diethyl oxalate is added. After being allowed to warm to −20° C., the mixture is quenched with aqueous NH4Cl, and the THF is removed under vacuum. Work-up in EtOAc, followed by chromatography on silica, eluting with hexane/EtOAc (9:1) gives 3.38 g (71%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C>C(#N)C>[C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][CH2:23][CH2:22][NH:21][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(NCCCNC(=O)OC(C)(C)C)nc2ccccc12
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A solution of 1,1,1-trifluoromethanesulfonic acid 4-methoxyquinolin-2-yl ester (4.51 g, 14.7 mmol), tert-butyl N-(3-aminopropyl)carbamate (3.07 g, 17.6 mmol), and diisopropylethylamine (3.84 ml, 22.0 mmol) in anhydrous acetonitrile (35 ml) was heated at reflux for 6 days. The solution was cooled to ambient temperature then evaporated under reduced pressure to an oil. It was taken into water (35 ml) then extracted into ethyl acetate. The extracts were dried (sodium sulfate) then concentrated to an oil. Column chromatography on silica (1:1 ethyl acetate/hexanes) gave [3-(4-methoxyquinolin-2-ylamino)propyl]carbamic acid tert-butyl ester (3.10 g, 64%) as a colorless oil that solidified on standing. [M+H]+ 332.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[CH2:34](O)[CH2:35][OH:36].Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:34][CH2:35][OH:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: OCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCCO)c[nH]4)c3)cc2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 5-{4-[4 ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (50 mg, 0.11 mmol), ethylene glycol (1 ml), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 25 mg, 0.13 mmol) and 4-dimethylaminopyridine (DMAP, 5 mg, 0.04 mmol) in anhydrous THF (10 ml) was stirred at 60° C. for 16 hours. The mixture was poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography with a gradient of 3˜5% MeOH/CHCl3 to give 2-hydroxyethyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 36 mg, 67%.
Reaction SMILES: [NH2:1][C@@H:2]([C:47](=[O:82])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C@@H:53]([C:75]([O:77]C(C)(C)C)=[O:76])[NH:54][C:55](=[O:74])[NH:56][C@H:57]([C:67]([O:69]C(C)(C)C)=[O:68])[CH2:58][CH2:59][C:60]([O:62]C(C)(C)C)=[O:61])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:46])[CH2:9][N:10]1[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:29])[O:24]C(C)(C)C)[CH2:18][CH2:17][N:16]([CH2:30][C:31](=[O:37])[O:32]C(C)(C)C)[CH2:15][CH2:14][N:13]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:12][CH2:11]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:47](=[O:82])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C@@H:53]([C:75]([OH:77])=[O:76])[NH:54][C:55](=[O:74])[NH:56][C@H:57]([C:67]([OH:69])=[O:68])[CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:46])[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH2:38][C:39]([OH:41])=[O:40])[CH2:14][CH2:15][N:16]([CH2:30][C:31]([OH:37])=[O:32])[CH2:17][CH2:18][N:19]([CH2:22][C:23]([OH:29])=[O:24])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](N)CCCCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCCCNC(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1)C(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O
Yield: 5.9 %

Procedure:
A solution of ((8R,15S,19S)-tri-tert-butyl 8-amino-2,9,17-trioxo-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,10,16,18-tetraazahenicosane-15,19,21-tricarboxylate (64 mg) in TFA (1.0 mL) and DCM (1.0 mL) was stirred at rt for overnight. The solvent was removed under a stream of nitrogen to give crude (8S,15S,19S)-8-amino-2,9,17-trioxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,10,16,18-tetraazahenicosane-15,19,21-tricarboxylic acid (57.9 mg). A small amount (9 mg) crude product was purified by HPLC to give pure (8S,15S,19S)-8-amino-2,9,17-trioxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,10,16,18-tetraazahenicosane-15,19,21-tricarboxylic acid (MIP-1457, (2.7 mg)) as a white solid. MS (ESI), 832.2 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[OH:24][CH2:25][C@H:26]1[NH:30][C:29](=[O:31])[CH2:28][CH2:27]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[C@H:26]([CH2:25][OH:24])[CH2:27][CH2:28][C:29]3=[O:31])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3)CC2)c(C)c1
Yield: 50.8 %

Procedure:
Using (4-bromophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.87 g) described in Preparation Example 170 and (S)-5-hydroxymethylpyrrolidin-2-one (556 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.00 g) was obtained.
Reaction SMILES: [CH:1]1([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH:1]1([C:7]2([OH:17])[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1(C2CCCCC2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(O)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (5.00 g, 24.0 mmol) in THF (100 mL) was dropwise added cyclohexylmagnesium chloride (2.0 M in diethyl ether, 24.0 mL, 48.0 mmol) at −78° C. over 10 min. The mixture was stirred at 0° C. for 1.5 h, and then quenched with aqueous NH4Cl (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to give crude 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol as a colorless solid. To a solution of crude 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol (<24.0 mmol) in THF (45 mL) was added 3 M HCl (15 mL). The mixture was stirred at room temperature for 4 h, and then poured into EtOAc (50 mL) and aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel hexane to 70:30 hexane/EtOAc) to give the title compound (2.34 g, 37%) as a colorless solid:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH2:8]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21]1[CH:22]=[C:23]([CH:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39](O)=[O:40])[CH:33]=3)[NH:28]2)[CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH2:8]([C@@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21]1[CH:22]=[C:23]([CH:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:40])[CH:33]=3)[NH:28]2)[CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (301 mg, 7.5 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (730 mg, 7.7 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 0.77 mmol) and 1,1′-carbonyldiimidazole (310 mg, 1.9 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-((R)4-Benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (82 mg, 20%) as a white solid: LC/MS m/e calcd for C29H31N3O5S (M+H)+: 534.65, observed: 534.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH3:17][C:18]1[NH:22][C:21]([C:23](O)=[O:24])=[N:20][C:19]=1[C:26]([F:29])([F:28])[F:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH3:17][C:18]1[NH:22][C:21]([C:23]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:24])=[N:20][C:19]=1[C:26]([F:29])([F:27])[F:28]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: Cc1[nH]c(C(=O)O)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(C)[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.22 g, 0.96 mmol), 5-methyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained in Example (36d) (0.10 g, 0.51 mmol), WSC hydrochloride (0.30 g, 1.57 mmol) and HOBT (70 mg, 0.52 mmol), to obtain 0.17 g of the title compound as a white foamy substance (83%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([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)[CH2:13][CH2:12]1)=[O:8].[CH3:34][S-:35].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:34][S:35][C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-:33])=[O:32])=[C:6]([CH:30]=1)[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([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)[CH2:13][CH2:12]1)=[O:8]
Reactant: O=C(NCC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C

Procedure:
Step 1): To a solution of 5-fluoro-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide (2.0 g, 4.46 mmol) in DMF (10 ml) was added dropwise a solution of sodium thiomethoxide (343 mg, 4.9 mmol) in DMF (10 ml) under stirring at room temperature. After the mixture was stirred overnight, an additional sodium thiomethoxide (34 mg, 0.49 mmol) was added to the mixture. The reaction mixture was diluted with AcOEt and washed twice with H2O. The organic layer was dried over MgSO4 and evaporated to give 5-methylthio-2-nitro-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as colorless powders, 1.7 g (80%): mp 179°-181° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2ncc[nH]2)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nccn2CCCCCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-Methyl-2-pyridyl)imidazole (2.16 g) and sodium t-butoxide (1.57 g) in 50 mL dry DMF was added N-(6-bromohexyl)phthalimide (4.72 g). The resulting solution was stirred at room temperature for 3 h and then at 60° C. for 3.5 h. The solution was poured into H2O (80 mL) and then extracted three times with EtOAc (3×100 mL). The combined EtOAc extract was dried with anhydrous Na2SO4, and then evaporated to dryness. The product was purified by a silica gel column using EtOAc as the eluent. Yield: about 4.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[N:13][N:12]=2)[CH2:7][CH2:6]1.[CH3:25][C:26]1([CH3:36])[O:30][C@H:29]([CH2:31][C:32](F)=O)[C:28](=[O:35])[O:27]1>>[Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:17]=[C:32]([CH2:31][C@H:29]4[O:30][C:26]([CH3:36])([CH3:25])[O:27][C:28]4=[O:35])[O:19][N:18]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: NC(=NO)c1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)F)O1
Product: CC1(C)OC(=O)[C@@H](Cc2nc(-c3nnc(N4CCC(Oc5cc(F)ccc5Br)CC4)s3)no2)O1

Procedure:
The title compound was prepared in a similar manner as described for Example 13, step 2 from 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-N′-hydroxy-1,3,4-thiadiazole-2-carboximidamide and [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetyl fluoride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=2)[C:7]([O:9][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=2)=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)OCc1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 5-hydroxy-2-methylbenzoic acid (1.0 g, 6.6 mmol) in DMF (50 ml) were added potassium carbonate (1.82 g, 13.14 mmol, 2.0 eq) and 3-chlorobenzyl bromide (1.72 g, 13.14 mmol, 2.0 eq). The mixture was stirred at 70° C. for 2 hours and then left stirring at room temperature overnight. The temperature was increased to 80° C. and heating continued for a further 6 hours. After cooling the mixture was diluted with ethyl acetate (200 ml) and washed with water (2×200 ml). Organic layer was separated, dried over MgSO4, filtered and evaporated to dryness to afford the title compound as a yellow oil, 2.67 g (contains 24% of monoalkylated phenol impurity). No further purification carried out. MS (ES−) m/z 399 [M−H]− (C22H1835Cl2O3). 1H-NMR (400 MHz, CDCl3) δ 2.52 (3H, s), 5.04 (2H, s), 5.29 (2H, s), 7.02 (1H, dd, J 8.4, J 2.8), 7.16 (1H, d, J 8.4), 7.29-7.34 (6H, m), 7.43 (2H, d, J 1.2), 7.54 (1H, d, J 2.8).
Reaction SMILES: [C:1](/[C:3](=[C:7](\OCC)/[CH3:8])/[C:4](=[S:6])[NH2:5])#[N:2].[NH3:12]>CO>[NH2:12]/[C:7](/[CH3:8])=[C:3](\[C:1]#[N:2])/[C:4](=[S:6])[NH2:5]
Reactant: CCO/C(C)=C(\C#N)C(N)=S
Reactant: N
Solvent: CO
Product: C/C(N)=C(/C#N)C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(2E)-2-Cyano-3-ethoxybut-2-enethioamide (method 2) (19.2 g, 0.136 mol) was dissolved in a saturated solution of ammonia in methanol (500 mL) and stirred at r.t. overnight. The reaction mixture was concentrated and the residue was dissolved in hot water (600 mL) and the undissoved solid was filtered and dried to recover 6 g of the starting thiocrotonamide. The aqueous solution on standing overnight provided the pure (2E)-3-amino-2-cyanobut-2-enethioamide (6.85 g, 63%) as off-white crystals. 1H NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), 7.73 (bs, 1H), 8.53 (bs, 1H), 9.01 (bs, 1H), 11.60 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1Cl

Procedure:
A solution of 2-chlorophenylacetic acid (10.0 g) in methanol (100 ml) containing 1 drop of concentrated sulphuric acid was heated at reflux for 2 hours. The reaction mixture was evaporated to half volume and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was dried over magnesium sulphate and evaporated to give the title compound (10.0 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:36][CH2:35][C:34]([NH:33][S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:9][C:10]=23)=[O:21])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31])([CH3:38])[CH3:37]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Pale-yellow solid. MS (ISP) 540.5 [(M+H)+].
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.O.O.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][C:9]=2[C:8]([Br:28])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CC(N1CCCC1)CC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(Br)c2c1CC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-acetamido-7-pyrrolidin-1-yl-5,6,7,8-tetrahydronaphthalene (0.36 g, 1.4 mmol) and sodium acetate trihydrate (0.38 g, 2.8 mmol) in acetic acid (15 mL) was treated with bromine (0.27 g, 1.7 mmol) and stirred at room temperature for 2 h. A precipitate was collected by filtration and the filtrate evaporated. The two solids were combined and dissolved in methylene chloride; water. The mixture was basified with 12.5% NaOH, and the organic phase separated. The aqueous layer was back extracted and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was heated in diethyl ether to form a solid, which was collected and dried (0.31 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]#[N:15])[CH2:10][CH2:9][CH2:8]2)(=O)[CH3:2].[OH:16]O.[OH-].[Na+].O>C(O)C>[CH3:2][C:1]1[NH:15][C:14](=[O:16])[C:13]2[C:5](=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][C:11]=3[CH:12]=2)[N:4]=1
Reactant: CC(=O)Nc1cc2c(cc1C#N)CCC2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)CCC3
Temperature: 50 °C

Procedure:
A mixture of 5-acetamido-6-cyanoindan (104 g), hydrogen peroxide (30% solution in water, 400 ml), sodium hydroxide (35 g), water (200 ml) and ethanol (1 L) was stirred and heated to 50° C. for 1 hour. The mixture was cooled to ambient temperature and evaporated. The residue was dissolved in water (2 L) and the solution was acidified to pH 5 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and dried under vacuum. There was thus obtained 2-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (100 g), m.p. 284° C.
Reaction SMILES: Cl[CH:2]([C:7]1[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[N:9][N:8]=1)[CH2:3][CH:4]1[CH2:6][CH2:5]1.[N-:18]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.O>[CH:4]1([CH2:3][CH:2]([C:7]2[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:9][N:8]=2)[NH2:18])[CH2:6][CH2:5]1
Reactant: Cn1c(SCC2CC2)nnc1C(Cl)CC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(SCC2CC2)nnc1C(N)CC1CC1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a crude solution of the 3-(1-chloro-2-cyclopropylethyl)-5-[(cyclopropylmethyl)thio]-4-methyl-4H-1,2,4-triazole from step d in DMF (3 mL) under nitrogen was added sodium azide (1.0 g, 15 mmol). The mixture was stirred at 65° C. for 20 h, then cooled to room temperature, diluted with water and extracted into ethyl acetate. The organic extract was washed with water and then brine before being dried (MgSO4) and concentrated. The residue was taken up in THF (10 mL), and water (2 mL) was added followed by triphenylphosphine (1.6 g, 6.1 mmol). The reaction mixture was stirred under nitrogen for 5 h, then concentrated in vacuo. The residue was dissolved in methanol and applied to an SCX cartridge. Elution with methanol afforded organophosphorus residues and subsequent elution with 2M ammonia in methanol provided the title amine.