Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[CH:49]=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[CH:49]([OH:50])[CH3:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To the solution of aldehyde 101 (390 mg, 0.55 mmol) in THF (5.5 mL) was added methyl magnesiumbromide (3.0 M in ether, 0.28 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was poured into a saturated NH4Cl solution and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography provided the desired secondary alcohol 103 (300 mg, 75%) as a solid. MH+723.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:42][C:39]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=2
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 641.9 (M+H)+.
Reaction SMILES: [OH-].[Na+].O.Cl.[NH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8].[C:12](=S)=[S:13].Cl>O>[C:9]([CH:6]1[CH2:7][S:8][C:12](=[S:13])[NH:5]1)([OH:11])=[O:10]
Reactant: N[C@@H](CS)C(=O)O
Reactant: S=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CSC(=S)N1
Reaction time: 24 h
Yield: 26.2 %

Procedure:
Sodium hydroxide (40 g, 1.0 mol), cysteine hydrochloride hydrate (50 g, 0.285 mol) and carbon disulfide (30 g, 0.4 mol) were added in that order to 200 ml water at room temperature. This mixture was stirred for 24 hours. At the end of this period, the reaction mixture was acidified to pH 6 with hydrochloric acid and evaporated to yield a yellow foam. Trituration of this foam with concentrated hydrochloric acid caused crystallization to occur. The white solid thus obtained was recrystallized from 6 N hydrochloric acid to yield 12.2 g (21.2%) of 4-carboxythiazolidine-2-thione, m.p. 183°-184°C with decomposition.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[N+:9]([O-])([OH:11])=[O:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1

Procedure:
Forthly, 4-Nitroimidazole is dissolved in acetic acid and then a nitric acid having a high concentration as much as 80 mass % or more and acetic anhydride are added thereto to produce 1,4-dinitroimidazole in any of the processes described in the documents mentioned above.
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.O.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C.C1COCC1>[NH2:8][CH:12]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:21])=[CH:17][CH:18]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)COC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC(CO)c1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 80 °C
Yield: 133.7 %

Procedure:
To a solution of (RS)-4-{4-[3-(4-chloro-phenyl)-ureido]-phenyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.24 g) in acetonitrile (3 ml) were added water (9 ml) and trifluoroacetic acid (0.33 ml). The mixture was heated overnight at 80° C. The mixture was then cooled to room temperature and diluted with ethyl acetate/THF (1:1). The resulting mixture was washed sequentially with 1 N aq. sodium hydroxide solution and saturated brine, the phases were then separated and the organic phase was dried over sodium sulphate and concentrated in vacuo to afford (RS)-1-[4-(1-amino-2-hydroxy-ethyl)-phenyl]-3-(4-chloro-phenyl)-urea (0.22 g, quant.) an off-white solid. MS (ISP): 291.1 ([{37Cl}M+H—OH]+), 289.1 ([{35Cl}M+H—OH]+).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[C:7]1([N:13]2[C:21](=[O:22])[C:20]3[C@@H:19]4[C:23]([CH3:25])([CH3:24])[C@@:16]([CH3:26])([CH2:17][CH2:18]4)[C:15]=3[NH:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl.O>[CH:3]1([CH2:2][N:14]2[C:15]3[C@:16]4([CH3:26])[C:23]([CH3:25])([CH3:24])[C@@H:19]([CH2:18][CH2:17]4)[C:20]=3[C:21](=[O:22])[N:13]2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2)n1CC1CCC1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
A mixture of (bromomethyl)cyclobutane (1.7 mL, 15.1 mmol), (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 393 mg, 1.46 mmol) and tetra-n-butylammonium iodide (400 mg, 1.08 mmol) in N,N-dimethylformamide (7 mL) was heated in an oil-bath at 100° C. for 16 h. Additional quantities of (bromomethyl)cyclobutane (1.7 mL, 8.9 mmol) and tetra-n-butylammonium iodide (400 mg, 1.08 mmol) were added and the mixture was heated in an oil-bath at 135° C. for 6 days. The reaction mixture was allowed to cool and it was then diluted with dichloromethane (75 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with water (5×30 mL), sodium thiosulfate solution (30 mL) and brine (30 mL). The organic extract was dried (magnesium sulfate), filtered, evaporated, and the residue purified on an Isco 40 g column, eluting with 15-75% ethyl acetate/hexanes and then held under high vacuum to give (4R,7S)-1-(cyclobutyl)methyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (52 mg, 11%) as a yellow gum. ES(+)-MS (M+H) 337.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1>[CH3:24][O:23][C:21]([NH:1][C@@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4])=[O:22]
Reactant: COC(=O)Cl
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
(S)-2-amino-4-phenylbutanoic acid (0.50 g, 2.8 mmol) was suspended in 1M Na2CO3 (8.4 mL, 8.4 mmol) and then a solution of methyl chloroformate (0.32 mL, 4.2 mmol) in THF (4.0 mL) was added and the mixture was stirred vigorously at room temperature for 4 hours. The mixture was then concentrated under reduced pressure and the residue was dissolved in water and made acidic with 0.1N HCl. The mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (0.64 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[C:10]([C:20]([O:22]CC)=[O:21])[C:9]=2[O:25][CH3:26])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[C:10]([C:20]([OH:22])=[O:21])[C:9]=2[O:25][CH3:26])=[O:7])=[CH:27][CH:28]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(OC)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C(=O)O)c(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 109.8 %

Procedure:
Crude ethyl 5-(p-chlorobenzoyl)-3-ethoxycarbonyl-4-methoxy-1-methylpyrrole-2-acetate (505 mg) is suspended in 1 ml ethanol and heated to reflux. After all the solids dissolve, 5 ml of 2.5 N aqueous sodium hydroxide is added dropwise, causing an oil to separate at the end of the addition. However, the reaction mixture becomes homogeneous again after stirring vigorously at 100° for about 5 min. The reaction is then cooled, diluted with 5 ml water and acidified with 5.5 ml 2.5 N hydrochloric acid. The resulting precipitate is filtered, dried in vacuo to afford 478 mg of crude 5-(p-chlorobenzoyl)-3-hydroxycarbonyl-4-methoxy-1-methylpyrrole-2-acetic acid.
Reaction SMILES: I[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[C-:15]#[N:16].[K+].C(=O)([O-])O.[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][CH2:4][CH:3]([CH2:2][C:15]#[N:16])[O:8][C:7]=2[CH:9]=1
Reactant: COc1ccc2c(c1)OC(CI)CO2
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc2c(c1)OC(CC#N)CO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.35 g (4.43 mmol) of the iodinated compound obtained in Step C and 1.37 g (26.6 mmol) of potassium cyanide are dissolved in 15 ml of anhydrous hexamethylphosphoric triamide; the reaction mixture is then stirred for 2 days under argon and at ambient temperature. The solution is then hydrolysed with a solution of sodium hydrogen carbonate; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The title nitrile is obtained pure in the form of a clear oil after chromatography on silica gel (eluant: PE then AcOEt/PE: 15/85).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=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>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:29]1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccoc4)n3)cnc2n1
Temperature: 90 °C
Yield: 95.1 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (from Example 34) (200 mg, 0.49 mmol), 3-furanboronic acid (111 mg, 0.98 mmol), K3PO4 (457 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 9 mol %) in DMA (6 ml) was heated at 90° C. for 45 min under N2. The reaction was concentrated under reduced pressure while azeotroping with xylene (3×30 ml). EtOAc (50 ml) and H2O (50 ml) were added and the organics separated and concentrated under reduced pressure while loading onto MgSO4. Purification by column chromatography on silica using 3% MeOH/CH2Cl2 as the eluent gave 3-[2-(furan-3-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (203 mg, 94%): m/z (ES+) 435 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[O:30][CH3:29])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1ccccc1C=O
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: COc1ccccc1CNCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (63.9 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (1.3 ml) and then added with 2-methoxybenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0350 ml) and trimethyl orthoformate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0560 ml), followed by stirring at room temperature for 30 minutes. The solution was added with sodium borohydride (19.3 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. Then, the residue was added with water and extracted with chloroform, and the extract was washed with saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and treated with hydrochloric acid. The residue was purified through a solid-phase extraction column (Sep-Pack®, tC18, manufactured by Waters Corporation), thereby obtaining hydrochloride (6.80 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:20](=[O:61])[CH2:21][CH2:22][C:23](=[O:60])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:31](=[O:51])[CH2:32][CH2:33][C:34](=[O:50])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:62](Cl)(=[O:72])[CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69][O:70][CH3:71]>>[CH2:1]([O:8][N:9]([C:20](=[O:61])[CH2:21][CH2:22][C:23](=[O:60])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:31](=[O:51])[CH2:32][CH2:33][C:34](=[O:50])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][N:41]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:62](=[O:72])[CH2:63][O:64][CH2:65][CH2:66][O:67][CH2:68][CH2:69][O:70][CH3:71])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Reactant: COCCOCCOCC(=O)Cl
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)COCCOCCOC
Yield: 78 %

Procedure:
11,22,33-Tris(benzyloxy)-12,15,23,26,34-pentaoxo-11,16,22,27,33-pentaaza-2,5,8,36,39,42-hexaoxatritetracontane (23) was synthesized by reacting compound (21) (3.91 g, 4.60 mmol) with 3,6,9-trioxadecanoyl chloride [Helmann, supra] (NEt3 /CH2C12) to give 4.0 g (78%) of (23): NMR δ 1.17-1.78 (m, 12 H), 2.3-2.9 (m, 8 H), 3.04-3.37 (m, 10 H), 3.4-3.8 (m, 24 H), 4.21 (s, 2 H), 4.76 (s, 2 H), 4.81 (s, 2 H), 4.88 (s, 2 H), 6.17-6.37 (m, 2 H), 7.34 (s, 15 H). Analysis: (C53H79N5O14) C, H, N.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:35](O)(=O)[CH3:36]>>[CH3:35][C:36]1[N:13]([C:11]2[N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]3[S:23][C:22]([CH2:24][N:25]4[CH2:28][CH:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[CH2:26]4)=[CH:21][C:9]=3[N:10]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=1
Reactant: Nc1ccccc1Nc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Reactant: CC(=O)O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Temperature: 120 °C
Yield: 43 %

Procedure:
A mixture of N-[4-morpholin-4-yl-6-(3-morpholin-4-yl-azetidin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl]benzene-1,2-diamine (100 mg, 0.21 mmol) and glacial acetic acid (0.5 mL) was heated at 120° C. for 3 h. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5) followed by reversed phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 172 as a white solid (45 mg, 43%). LCMS (method A): RT=5.65 min, M+H−=506.1. 1H NMR (CDCl3, 400 MHz) δ 8.08-8.03 (m, 1 H), 7.73-7.68 (m, 1 H), 7.30-7.26 (m, 3 H), 4.05 (t, J=4.8 Hz, 4 H), 3.99 (s, 2 H), 3.88 (t, J=4.8 Hz, 4 H), 3.73 (m, 4 H), 3.65 (s, 2 H), 3.18-2.99 (m, 3 H), 2.93 (s, 3 H), 2.34 (m, 4 H)
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC=C)=[O:26])[CH2:9][C@H:8]1[CH2:31][O:32][CH2:33][CH2:34][Cl:35])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.C(O)C>CC(C)CC(=O)C.[Pd].O>[Cl:35][CH2:34][CH2:33][O:32][CH2:31][C@@H:8]1[CH2:9][C@H:10]([S:12][C:13]2[C@@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([OH:27])=[O:26])[CH2:11][NH:7]1
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCCl)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Solvent: CCO
Solvent: O
Product: C[C@@H]1C(S[C@@H]2CN[C@H](COCCCl)C2)=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Reaction time: 5 h
Yield: 25.7 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-chloroethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.28 g), triphenylphosphine (0.015 g) and dimedone (0.16 g) in a mixture of 4-methyl-2-pentanone (3.36 ml), ethanol (1.68 ml) and water (0.14 ml) was added triphenylphosphine)palladium(0) (30 mg) at ambient temperature in a stream of nitrogen. The mixture was stirred at the same condition for 5 hours to give a solid. The solid was collected by filtration to give (4S,5S,6S)-3-[(2S,4S)-2-(2-chloroethyloxymethyl)pyrrolidine-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.055 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:20])[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:18](=[O:20])[CH3:19])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reacted with 21 μL of acetyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)acetamide.
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[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][N:27]([CH3:26])[C:28]4=[O:32])=[CH:3][C:4]=3[O:24][CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Reactant: CN1CCNC1=O
Product: COc1cc(N2CCN(C)C2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 82 %

Procedure:
Using (4-bromo-2-methoxyphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (404 mg) described in Preparation Example 252 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (347 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C@@H:4]([OH:8])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C@H:4]([OH:8])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: O=C(O)[C@H](O)c1ccccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)c1ccccc1Cl

Procedure:
In a 1 L flask, 120 g (0.643 mole) of (R)-2-chloromandelic acid, 480 ml methanol and 4.8 g concentrated sulfuric acid were added. The solution is then heated to reflux for 2 hours and excess methanol is distilled under vacuum. The oily residue was taken in 650 ml chloroform and washed with 240 gm aqueous solution of 10% potassium carbonate and concentrated under vacuum. 124.4 gm of methyl-(R)-2-hydroxy-2-(2-chlorophenyl)acetate was obtained in the form of a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][C:8]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11]2)[CH2:7][CH2:6]1)=[O:4].[C:20]1([CH:26]([NH2:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C=O)C>[C:27]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:33][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][C:8]3([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12](=[O:19])[O:11]3)[CH2:7][CH2:6]2)=[O:4])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C1OC2(CCN(C(=O)CCl)CC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC2(CCN(C(=O)CNC(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1′-(Chloroacetyl)-3H-spiro[2-benzofuran-1,4′-piperidine]-3-one (50 mg, 0.179 mmol)) and diphenylmethylamine (33 mg, 0.179 mmol) were dissolved in dry DMF (0.8 mL). Then triethylamine (0.074 mL, 0.536 mmol) was added and the reaction mixture was shaken at 25° C. for 2.5 days. Water (0.1 mL) was added and the whole mixture was directly purified by preparative HPLC on YMC-AQ column with a gradient of MeCN in water from 0-90% in 15 min. MS: m/z=427 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1([N:7]([CH3:9])[CH3:8])[CH2:6][CH2:5]1.[C-:10]#[N:11].[Na+].[I-].[K+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CS(C)=O>[CH3:8][N:7]([CH3:9])[C:4]1([CH2:3][C:10]#[N:11])[CH2:6][CH2:5]1
Reactant: CN(C)C1(CCl)CC1
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CS(C)=O
Product: CN(C)C1(CC#N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
30.3 g of the compound obtained in Step 1 are added to a solution of 43 g of sodium cyanide and 3.5 g of potassium iodide in 400 ml of dimethyl sulphoxide. After stirring for 20 hours at ambient temperature, 490 ml of 10% aqueous sodium carbonate solution and then sodium chloride are added. The mixture is extracted with ether. After conventional treatment of the organic phases, chromatography over silica gel allows the expected product to be isolated.