Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)n1
Yield: 40.7 %

Procedure:
A solution of 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared in Example 28(B)(a), 94.5 mg, 0.23 mmol) in methanol (15 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 40 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (36.8 mg, 40.3%) as a white solid: mp 95-98° C.; EI-HRMS m/e calcd for C19H21ClN2O3S (M+) 392.0961, found 392.0989.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[C@@H:14]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O-:30][N+:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[N:13]3[C@@H:14]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=2[CH:5]=1
Reactant: CC(C)(O)[C@H]1COCc2nc3cnc4ccccc4c3n21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 1.25 h
Yield: 99.9 %

Procedure:
2-[(11R)-10,11-Dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (755 mg, 2.67 mmol) was dissolved in 30 mL of CH2Cl2 and treated with MCPBA (57-86%, 806 mg). After stirring for 75 minutes, the reaction was treated with 50 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with 10% methanol/CHCl3 (10×10 mL). The combined organic layers were washed with 10 mL of brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced to give 2-[(11R)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (798 mg) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=O>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2,6-Difluorobenzoyl chloride (1.28 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 2 days. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)OCc3ccc(Cl)cc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccc(Cl)cc3)cc2)cc1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
36.5 g (0.1 mol) of p-chlorobenzyl 4'-acetyl-4-biphenylcarboxylate, 150 ml of chloroform and 50 ml of ethanol were supplied into a four-necked flask equipped with a stirrer and a thermometer. Then 3.8 g (0.1 mol) of sodium borohydride was added at 15°-25° C. over a period of 10 minutes. The mixture was maintained at the same temperature for 2 hours. The reaction mixture was poured into ice-water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain 36.5 g (99.5% yield) of p-chlorobenzyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate (III-27).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.CCN(CC)CC.[CH3:49][S:50](Cl)(=[O:52])=[O:51].[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:37][CH2:38][N:39]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:40][CH2:41]2)[CH3:35])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNCC4)cnc3F)nc(C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)nc(C)n2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of 6-(2-fluoro-5-((1R)-1-(1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.448 g, 0.805 mmol) in CH2Cl2 (4 mL) at −20° C. was treated with NEt3 (1.122 mL, 8.05 mmol) followed by methanesulfonyl chloride (0.190 mL, 2.414 mmol). The mixture stirred at −20° C. for 30 minutes and then 1 M NaOH (aq.) and CH2Cl2 were added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 75% to 100% EtOAc in hexane, to provide 6-(2-fluoro-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.317 g, 0.499 mmol, 62.1% yield) as a white foam. m/z (ESI, +ve) 635.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=9.00 Hz, 1H); 8.18 (s, 1H); 7.17 (d, J=7.63 Hz, 4H); 6.83-6.89 (m, 5H); 4.74 (br. s., 4H); 3.80 (s, 6H); 3.65 (m, 1H); 3.18-3.30 (m, 4H); 2.77 (s, 3H); 2.64 (s, 5H); 2.50-2.58 (m, 2H); 1.44 (d, J=6.65 Hz, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:11][O:12][C:13]([F:23])([F:22])[C:14]([F:21])([F:20])[CH2:15][C:16]([F:19])([F:18])[F:17])([CH3:10])[CH2:6][N:7]=[N+]=[N-])=[N+]=[N-].NN>>[NH2:1][CH2:4][C:5]([CH2:11][O:12][C:13]([F:22])([F:23])[C:14]([F:20])([F:21])[CH2:15][C:16]([F:17])([F:18])[F:19])([CH3:10])[CH2:6][NH2:7]
Reactant: CC(CN=[N+]=[N-])(CN=[N+]=[N-])COC(F)(F)C(F)(F)CC(F)(F)F
Agent: NN
Product: CC(CN)(CN)COC(F)(F)C(F)(F)CC(F)(F)F
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
1,3-Diazido-2-heptafluorobutoxymethyl-2-methyl-propane (50.0 g, 0.142 mole) was weighed into a 1-L, 3-neck flask fitted with a magnetic stir bar, reflux condenser, drying tube and a thermocouple probe. Pearlman's catalyst (4.2 g, 10% Pd on carbon) was slurried in methanol (50 ml) and added to the flask. The mixture was stirred, and additional methanol (200 ml) was added. After heating to 60° C., anhydrous hydrazine (5.0 g, 0.16 mole) was added with a syringe at a rate such that the temperature did not exceed 63° C. Evolution of gas was observed during the addition, and the addition was complete after 20 minutes. 1H NMR analysis indicated that the reaction was 80% complete. A second portion of anhydrous hydrazine (1.27 g, 0.04 mole) was added, and the mixture was stirred overnight at 60° C. The progress of the reaction was also monitored by GC and by following the disappearance of the N3 stretching band in the infrared spectrum. The mixture was cooled to room temperature, filtered, and stripped of solvent on a rotary evaporator. Short path distillation of the crude product (bp 45°-47° C., high vacuum) gave 36.1 g (84.7%) of 1,3-diamino-2-heptafluorobutoxymethyl-2-methyl-propane (9), a clear oil: IR 3400-3370 (NH2), 2925, 2875, 1330, 1225, and 1120 cm-1 ; 1H NMR (CDCl3) 0.84 (s, 3H), 1.20 (s, 4H), 2.63 (s, 4H), 3,46 (s, 2H) and 3.92 (t, J=13.8 Hz, 2H); 13C NMR (CDCl3) 18.36, 40.27, 46.85 68.38 (t, J=25.92 Hz), and 77.72. Anal. Calcd for C9H15F7N2 : C, 36.00; H, 5.05; N, 9.33; Found: C, 34.99; H, 5.08; N, 7.98.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][N:7]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: COC(=O)c1ccnc(-c2ccc(Cl)c(Cl)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccnc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=252.0 ([M-H]−) was obtained as a light yellow solid (53% yield) by the reaction of 2-(3,4-dichloro-phenyl)-isonicotinic acid methyl ester with lithium aluminum hydride in THF at 20° C. for 1 h followed by chromatography [silica, elution with CH2Cl2/(2M NH3 MeOH)=19:1]
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].C[O:22][C:23](=[O:39])[C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:38])[CH2:34][CH2:35][CH2:36]Cl)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:36][CH2:35][CH2:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([C:24]([CH3:25])([CH3:26])[C:23]([OH:39])=[O:22])=[CH:28][CH:29]=3)=[O:38])[CH2:19][CH2:20]2)=[CH:7]1)[CH3:2]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: CCOCCn1cc(C2CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOCCn1cc(C2CCN(CCCC(=O)c3ccc(C(C)(C)C(=O)O)cc3)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 152 (parts D and E) starting with 0.1 g (0.37 mmol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-indole, 0.142 g (0.48 mmol) of 2-[4-(4-chlorobutyryl)-phenyl]-2-methyl-propionic acid methyl ester, 0.07 g (0.48 mmol) of potassium carbonate and 0.04 g (0.24 mmol) of potassium iodide.
Reaction SMILES: CN1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:18]=[C:17]([C:28](=[NH:31])[NH:29][OH:30])[C:16]=2[CH3:32])=[CH:11][CH:10]=1.[CH:33]1([C:39](O)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:18]=[C:17]([C:28](=[NH:31])[NH:29][O:30][C:39]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:40])[C:16]=2[CH3:32])=[CH:13][CH:14]=1
Reactant: Cc1c(C(=N)NO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1c(C(=N)NOC(=O)C2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NMM (0.42 mL, 3.77 mmol) was added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-hydroxy-4-methyl-1H-pyrazole-3-carboxamid amide (0.30 g, 0.75 mmol) obtained in Step 3, cyclohexylcarboxylic acid (97 mg, 0.75 mmol), HOBt (194 mg, 1.43 mmol) and EDCI (220 mg, 1.13 mmol) dissolved in DCM (7 mL). The mixture was stirred overnight at room temperature. After adding thereto EtOAc (30 mL), the mixture was successively washed with water, saturated NaHCO3 solution (20 mL) and brine (20 mL). The organic layer was isolated, dried over MgSO4, filtered, and concentrated under a vacuum, to obtain 5-(4-chlorophenyl)-N-(cyclohexanecarbonyloxy)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximidamide as a white solid, which was used in the next step without further purification. The crude material was dissolved in pyridine (4 mL), and was subjected to microwave irradiation at 180° C. for 20 min., to remove volatile components under a vacuum. The residue was further purified by reverse phase preparative HPLC, to obtain the title compound as white solid (67 mg, 0.137 mmol, 18% via two steps).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]/[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18](OCC)(OCC)(OCC)[CH3:19]>>[CH3:18][C:19]1[N:8]2[C:9](=[O:15])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:16][N:17]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Temperature: 100 °C
Yield: 91.6 %

Procedure:
A mixture of (2Z)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (3.1 g, 0.013 mol) and triethyl orthoacetate (20 mL, 0.1 mol) was heated at 100° C. for 3 h. The suspension was cooled to room temperature and the solid formed was filtered and washed with DCM/Hex (1:1) mixture to provide the desired product (3.1 g, 91% yield). LCMS calculated for C12H17N6O (M+H): 261.1. found: 261.1.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]1.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:3]3[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]3)(=[O:31])=[O:32])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1cc[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
NaH (0.49 mg, 60%, 12.4 mmol) was a solution of 1H-Pyrrole-3-carbaldehyde (0.21 mg, 2.47 mmol) in THF (30 mL) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour at room temperature and cooled down to 0° C. again. 2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.1 g, 20.97 mmol) was added slowly, allowed the reaction to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with NaHCO3 (5 mL), diluted with EtOAc (100 mL), washed with brine (2×15 mL) and dried over Na2SO4. The crude product was purified by MPLC on silica gel using Hexane/EtOAc (1:1) to give 0.44 g (34%) of a white solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.45-1.55 (m, 4 H), 1.56 (s, 9 H), 2.16-2.31 (m, 1 H), 3.25-3.35 (m, 2 H), 3.94-4.02 (m, 2 H), 4.22 (d, J=7.42 Hz, 2 H), 6.67 (dd, J=3.42, 1.66 Hz, 1 H), 7.18-7.22 (m, 1 H), 7.44 (d, J=8.79 Hz, 1 H), 7.76-7.82 (m, 2 H) 8.36 (d, J=1.76 Hz, 1 H) 9.79 (s, 1 H); MS (ESI) (M+H)+=430.00.
Reaction SMILES: I[C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[C@H:4]([CH3:11])[CH2:3]1.[SnH](CCCC)(CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C.C1C=CC=CC=1>[Ni].N1C=CC=CC=1>[CH3:11][C@@H:4]1[CH2:3][CH2:2][C@@H:8]2[CH2:9][C@H:5]1[C:6](=[O:10])[O:7]2
Reactant: C[C@@H]1C[C@H](I)[C@@H]2C[C@H]1C(=O)O2
Agent: [Ni]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C[C@@H]1CC[C@@H]2C[C@H]1C(=O)O2

Procedure:
reacting said (1R,2R,4S,5S)-4-iodo-2-methyl-6-oxabicyclo[3.2.1]octan-7-one (8) with n-Bu3SnH and catalytic AIBN in refluxing benzene, or with Raney Nickel in the presence of pyridine under 50 psi H2, to produce (1R,2R,5R)-2-methyl-6-oxabicyclo[3.2.1]octan-7-one (9),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([C:19](=[O:39])[C:20]1[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:36]=[C:35]([CH3:37])[O:34][N:33]=4)=[CH:28][C:27]=3[CH3:38])=[CH:22][CH:21]=1)[CH2:7][CH2:6]2.CC(C)([O-])C.[K+].CC1C=C(C2N=C(C)ON=2)C=CC=1C1C=CC(C(Cl)=O)=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N:8]([C:19](=[O:39])[C:20]1[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:36]=[C:35]([CH3:37])[O:34][N:33]=4)=[CH:28][C:27]=3[CH3:38])=[CH:22][CH:21]=1)[CH:7]=[CH:6]2
Reactant: COc1cc2c(cc1N1CCN(C)CC1)N(C(=O)c1ccc(-c3ccc(-c4noc(C)n4)cc3C)cc1)CC2
Agent: CC(C)(C)[O-]
Agent: Cc1nc(-c2ccc(-c3ccc(C(=O)Cl)cc3)c(C)c2)no1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc2ccn(C(=O)c3ccc(-c4ccc(-c5noc(C)n5)cc4C)cc3)c2cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A stirred solution of intermediate 2 (300 mg, 0.0012 mole) in dry THF (30 ml) under argon was treated with potassium t-butoxide (140 mg, 0.0012 mole) and kept at room temperature for 20 minutes. The resulting mixture was treated with a solution of 4-[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]benzoyl chloride (0.0014 mole) in dry THF (10 ml) and the mixture stirred at room temperature for 20h. The solution was concentrated in vacuo and the residue treated with 10% Na2CO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 0-3% methanol/dichloromethane. The tide compound was obtained as a yellow solid on crystallisation from ethyl acetate/60-80 petrol (220 mg, 35%) mp 175°-177° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.[OH-].[K+].[CH3:15][N:16]([CH3:20])[C:17](Cl)=[S:18]>O.O1CCCC1>[CH3:15][N:16]([CH3:20])[C:17]([O:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][C:6]([O:12][C:17](=[S:18])[N:16]([CH3:20])[CH3:15])=[CH:5]2)=[CH:10][CH:11]=1)=[S:18]
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=S)Oc1ccc2ccc(OC(=S)N(C)C)cc2c1
Temperature: 10 °C
Yield: 75.1 %

Procedure:
To a mixture containing 32 grams of 2,7-dihydroxynaphthalene and 26.3 grams of potassium hydroxide in 140 ml of water which had been cooled to 10° C. was slowly added 56.8 grams of dimethylthiocarbamoyl chloride in 88 ml of tetrahydrofuran. The temperature was maintained below 12° C. throughout the addition. The solid which formed was filtered, washed with water, reslurried in methanol and filtered to produce 50.2 grams of dimethyl-thiocarbamic acid O-(7-dimethylthiocarbamoyloxy-naphthalen-2-yl) ester. After drying this was placed in a round bottom flask and heated under a nitrogen atmosphere at 250° C. for 1.5 hours. The mixture was cooled and the solid recrystallized from ethyl acetate to give 17 grams of dimethyl-thiocarbamic acid S-(7-dimethylcarbamolysulfanyl-naphthalene-2-yl) ester. This was added to a mixture of 50 ml of ethanol and a solution of 22.4 grams of potassium in 32 mil of water, and then heated at reflux for 30 minutes. The mixture was cooled, diluted with 300 ml of water and acidified with hydrochloric acid. The solid which formed was filtered and dried yielding 8.5 grams of naphthalene-2,7-dithiol (9).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:40])[CH2:11][C@H:12]([C:17](=[O:39])[NH:18][C@H:19]1[CH2:36][C:35]2=[CH:37][N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=32)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:38])[CH2:13][CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1.C1COCC1>C(O)C.[Pd]>[OH:8][NH:9][C:10](=[O:40])[CH2:11][C@H:12]([C:17](=[O:39])[NH:18][C@H:19]1[CH2:36][C:35]2=[CH:37][N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=32)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:38])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C[C@H](CC(=O)NO)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 4 h
Yield: 91.9 %

Procedure:
Alternatively, (3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide (1.0 g, 1.83 mmol) was taken up in a solution of 20% THF in ethanol (500 mL) and then Pd on activated charcoal (200 mg) was added portionwise. The resulting slurry was stirred as H2 gas was gently bubbled through the solution. After 4 hours, the reaction mixture was suction filtered through a bed of celite (1.5 cm), and the filtrate was concentrated and then taken up in methanol (30 mL) and filtered through a plug of cotton. Recrystallization from methanol/ethyl acetate/ether/petroleum ether gave (3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanamide (768 mg, 92%), MS: 455 (M-H)-.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[C:4]([F:9])[CH:3]=1
Reactant: OC1CCOCC1
Reactant: Oc1ccc(Br)cc1F
Product: Fc1cc(Br)ccc1OC1CCOCC1

Procedure:
The title compound was prepared from 4-bromo-2-fluorophenol and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): MS (EI): 274 and 276 M+.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH:20]=[CH2:21]>>[CH2:21]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH:20]=[CH2:19]
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: C=CCBr
Product: C=CCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-Allylbenzimidazo[2,1-b]quinazolin- 12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and allyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[NH:6].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:6][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)=[N:7][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cccc(Cl)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=378.8 (M+H+), was prepared from 3-chlorobenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([OH:30])[C:26](OC)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([OH:30])[C:26]([NH:11][C:9]2[S:10][C:6]([CH3:5])=[CH:7][N:8]=2)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: Cc1cnc(N)s1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cnc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
Trimethylaluminium (1M in heptane) (3.97 mL, 3.97 mmol) was added to 5-methylthiazol-2-amine (0.434 g, 3.80 mmol) in DCM (40 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-Methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (1 g, 3.45 mmol) in DCM (10 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 2 hours, then left to cool to room temperature overnight. Rochelle solution (20%; 50 mL) was added and the resulting mixture was stirred vigorously for 90 mins. The mixture was diluted with DCM (50 mL) and the layers separated. The organics were dried (MgSO4) and evaporated (733 mg). The residue was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in EtOAc to afford the product (0.300 g, 23.37%).