Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[CH3:12][S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14]>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:17][CH2:16][S:13]([CH3:12])(=[O:15])=[O:14])[CH2:7]2
Reactant: Brc1cccc2c1CCNC2
Reactant: C=CS(C)(=O)=O
Solvent: ClCCl
Product: CS(=O)(=O)CCN1CCc2c(Br)cccc2C1
Temperature: 35 °C
Reaction time: 14 h

Procedure:
A mixture containing 5-bromo-1,2,3,4-tetrahydroisoquinoline (212 mg, 1 mmol) and methylsulfonylethene (106 mg, 1 mmol) in dichloromethane is stirred at 35° C. for 14 hours. The solution is concentrated to afford 5-bromo-2-(2-(methylsulfonyl)ethyl)-1,2,3,4-tetrahydroisoquinoline as a brown oil (LC-MS m/z: 318.1 (M+1)) which is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH2:12][O:13][N+]([O-])=O)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH2:12][OH:13])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(CO[N+](=O)[O-])(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(CO)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
Prepared analogously to Example 1i from 2-(4-chloro-3-nitro-phenyl)-3-nitroxy-2-methyl-propionic acid and 6N hydrochloric acid in dioxane.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH:11]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1CCCCC1>[CH:11]([NH:24][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCCCBr
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: C1CCCCC1
Product: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1

Procedure:
25.1 g of ethyl 5-bromovalerate, 66 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 15 days. Processing analogously to Example 19 yields 23.4 (62.6%) of ethyl 5-benzhydrylaminovalerate [B.P. 158° to 163° (0.01 mm Hg)].
Reaction SMILES: [ClH:1].[C:2]1([O:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[C:17]([C:20](=[O:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[CH:15][C:14]=3[OH:28])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1>[ClH:1].[C:2]1([O:8][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[C:17]([CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[OH:28])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c2[nH]c(C(=O)Oc3ccccc3)cc12
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NCC(O)c1ccc(O)c2[nH]c(C(=O)Oc3ccccc3)cc12
Yield: 89.6 %

Procedure:
Under the conditions of Example 14(E), 1.5 g of 4-tert-butylaminoacetyl-7-hydroxyindole-2-carboxylic acid phenyl ester hydrochloride is hydrogenated in a mixture of 40 ml of methanol and 40 ml of tetrahydrofuran and worked up, thus producing 1.35 g of 4-(2-tert-butylamino-1-hydroxy-ethyl)-7-hydroxyindole-2-carboxylic acid phenyl ester hydrochloride, decomposition point 165°-166° C.
Reaction SMILES: CS(O[CH:6]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)(=O)=O.O.[CH3:31][NH2:32]>>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([CH2:7][CH:6]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[NH:32][CH3:31])[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CN
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccc(F)cc2)CCN(C)C1
Solvent: O
Product: CNC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethyl methane sulfonate (250 mg, 0.6 mmol) in methyl amine (40% solution in water, 5 mL) was heated at 100° C. for 4 h. The progress of the reaction was monitored by TLC and LCMS. 10 mL of water was added to the reaction mixture and then extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase HPLC to obtain 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)-N-methyl ethanamine (30 mg) as the TFA salt. 1H NMR (CDCl3, freebase): δ (ppm): 7.32 (t, 2H), 7.24 (m, 1H), 7.21 (s, 1H), 7.01 (m, 3H), 3.91 (m, 2H), 3.65 (dd, 2H), 2.80 (m, 3H), 2.62 (m, 1H), 2.54 (s, 3H), 2.45 (s, 3H), 2.14 (s, 3H). Chiral HPLC separated the racemate into enantiomers II-12a-b.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:19][C:20]1[CH:31]=[CH:30][C:23]([CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(CCN(C)C)C.[C:40]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.O>[CH2:12]([O:19][C:20]1[CH:31]=[CH:30][C:23]([CH:24]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[OH:47])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(COc2ccc(Cn3ccnc3)cc2)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccccc1)(c1ccccc1)C(c1ccc(OCc2ccccc2)cc1)n1ccnc1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 9.4 %

Procedure:
34 ml (53 mmol) of 1,55 molar n-butyllithium/hexane solution were added dropwise to a solution of 6.87 g (26 mmol) of N-(4-benzyloxybenzyl)-imidazole and 3.03 g (26 mmol) of TMEDA in 100 ml of absolute THF at about -70° C., the mixture was stirred for 20 minutes at -70° C., a solution of 4.74 g of benzophenone in 40 ml of absolute THF was then added dropwise at -70° C., stirring was continued for 30 minutes at about -70° C. and for 1.5 hours at -70° C. to room temperature, and 350 ml of water were added, while cooling. The mixture was extracted with CH2Cl2. The residue (12 g) from the CH2Cl2 extract was chromatographed over a silica gel S/CH2Cl2 column (diameter 2.1 cm, height 55 cm) as described in Example 102. Fractions which were shown by thin layer chromatography to have a high concentration of the desired substance were combined and recrystallized from ethyl acetate/diisopropyl ether. 1.09 g (=16.4% yield) of pure 2-(4-benzyloxyphenyl)-2-(1-imidazolyl)-1,1-diphenylethanol of melting point 204° C. were obtained in this manner.
Reaction SMILES: [P:1]([O:9][C:10]1[CH2:16][S:15][CH2:14][CH2:13][S:12][CH:11]=1)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].S([O-])(O[O-])(=O)=[O:18].[K+].[K+]>O.CO>[P:1]([O:9][C:10]1[CH2:16][S:15](=[O:18])[CH2:14][CH2:13][S:12][CH:11]=1)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOP(=O)(OCC)OC1=CSCCSC1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)OC1=CSCCS(=O)C1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
To a solution of 1.9 g (0.0035 mole) of diethyl 1,4-dithiacyclohept-5-en-6-yl phosphate (Example 17) in a mixture of 10 ml of water and 20 ml of methanol was added portionwise 1.2 g (0.0039 mole) of potassium peroxymonosulfate. During the addition the solution was maintained at 0° C. The mixture was stirred for ten minutes after completion of addition. The reaction mixture was poured into 50 ml of water and was extracted twice with 50 ml of methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was combined with a similar residue from a previous experiment and was subjected to column chromatography on silica gel using acetone as eluant. Evaporation of the solvent yielded 0.90 g of diethyl 1-oxo-1,4-dithiacyclohept-5-en-6-yl phosphate.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[N:12][C:13]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:14]2
Reactant: OCCN1CCCCC1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(OCCN3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-piperidin-1-yl-ethanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [6-methoxy-1-(2-piperidin-1-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([C:7](=[O:17])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH3:6].[H-].[Na+].[CH:21](OC)=[O:22]>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]=[CH:8][C:7]([N:5]([CH3:6])[C:4](=[CH:21][OH:22])[C:3]([O:2][CH3:1])=[O:18])=[O:17]
Reactant: COC=O
Reactant: COC(=O)CN(C)C(=O)C=Cc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(=CO)N(C)C(=O)C=Cc1ccccc1Cl

Procedure:
By a procedure analogous to that described in Example 1, part of the crude N-(o-chlorocinnamoyl)sarcosine methyl ester (6.99 g), methyl formate (30 ml) and sodium hydride (2.35 g) gave methyl N-(o-chlorocinnamoyl)-N-methyl-2-amino-3-hydroxypropenoate (4.56 g) as an off-white solid, m.p. 129°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][Cl:43])[CH:36]=[CH:35][C:31]=2[C:32](=[O:34])[CH:33]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl>C(#N)C>[ClH:43].[CH2:23]([O:25][C:26]([C:28]1[O:29][C:30]2[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][N:13]3[CH2:12][CH2:11][CH:10]([C:8]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[OH:9])[CH2:15][CH2:14]3)[CH:36]=[CH:35][C:31]=2[C:32](=[O:34])[CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cc(=O)c2ccc(OCCCCl)cc2o1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)c1cc(=O)c2ccc(OCCCN3CCC(C(O)(c4ccc(F)cc4)c4ccc(F)cc4)CC3)cc2o1
Yield: 30.9 %

Procedure:
A mixture of 3.0 g (0.01 mole) of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol, 3.1 g (0.01 mol) of 7-(3-chloropropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of acetonitrile heated at reflux for 48 hr gave a gum as residue. The gum was purified by column chromatography on 120 g of Florisil®. The desired fractions eluted with 10% acetone in benzene were combined and concentrated under reduced pressure to give a glass as residue. The glass was dissolved in etherisopropanol and treated with ethereal hydrogen chloride. The solid which precipitated was collected by filtration and recrystallized from absolute ethanol to give 1.9 g (31%) of white solid, m.p. 191° C. with decomposition.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][C:36]=1[OH:37])[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=1)=[O:21].ClC1C=C(C=CC=1O)C(O)=O.S(=O)(=O)(O)O.B(O)(O)O.[Cl:58][CH:59]([CH:63]([CH3:65])[CH3:64])[C:60](O)=[O:61]>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][C:36]=1[O:37][C:60](=[O:61])[CH:59]([Cl:58])[CH:63]([CH3:65])[CH3:64])[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=1)=[O:21]
Reactant: CC(C)C(Cl)C(=O)O
Reactant: CCCCCc1ccc(OC(=O)c2ccc(O)c(Cl)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)C(Cl)C(C)C)c(Cl)c2)cc1

Procedure:
0.012 m of DCC is added to 0.01 m of 4-pentylphenyl 3-chloro-4-hydroxybenzoate (obtainable by esterification of 3-chloro-4-hydroxybenzoic acid with 4-pentylphenyl with the addition of sulfuric acid and boric acid, J. org. Chem. Vol. 40 (1975) 2998), 0.012 m of 2-chloro-3-methylbutyric acid and 100 ml of methylene chloride at room temperature, with stirring. Further working up is carried out analogously to Example 3 to give 4-pentylphenyl 3-chloro-4-(2-chloro-3-methylbutyryloxy)-benzoate (optically active).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8](C)[CH2:9][C:10](O)=[O:11])=S)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[NH:8][CH2:9][C:10](=[O:11])[NH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN(CC(=O)O)C(=S)c1ccc(Cl)cc1
Solvent: O
Solvent: CO
Product: O=C1CNC(c2ccc(Cl)cc2)=NN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorothiobenzoyl methyl glycine (4.87 g, 20 mmol), 2.2 g of hydrazine hydrate (44 mmol) and 20 mL of methanol were combined and stirred at room temperature overnight, then heated to reflux. The reaction mixture was cooled and filtered. The solids were washed, then dried, giving 3-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[S:21])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Solvent: c1ccncc1
Product: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=S)[nH]1
Yield: 130.6 %

Procedure:
A suspension of 2-amino-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidin-4(3H)one (2.56 g) and phosphorus pentasulfide (2.5 g) in pyridine (200 ml) was refluxed for 4 hours. The reaction mixture was cooled down and the precipitate was filtered off, thus providing 2.0 g (yield: 73%) of the pure title compound, which was characterized by its mass spectrum as follows: MS (m/z): 273 ([M+H]+, 100).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH:19]=[CH:20][CH2:21][CH2:22][O:23]CC2C=CC=CC=2)[C:10]=1[CH3:31])C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:11]1[NH:12][C:13]2[C:18]([C:9](=[O:8])[C:10]=1[CH3:31])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Cc1c(C=CCCOCc2ccccc2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1c(CCCCO)[nH]c2ccccc2c1=O
Yield: 75.8 %

Procedure:
To a solution of 4-(benzyloxy)-2-[4-(benzyloxy)-1-buten-1-yl]-3-methylquinoline (2.57 g) in ethanol (26 mL) were added cyclohexene (13 mL) and 20% palladium hydroxide-activated carbon powder (1.5 g), followed by stirring under reflux for 2 hours. The catalyst was removed by filtration, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=93/7) to obtain 2-(4-hydroxybutyl)-3-methylquinolin-4(1H)-one (1.10 g).
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[OH:15][CH2:16][C@@H:17]1[CH2:20][CH2:19][NH:18]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].O>ClCCl>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:18]1[CH2:19][CH2:20][C@H:17]1[CH2:16][OH:15])=[O:25]
Reactant: OC[C@@H]1CCN1
Reactant: O=C(Cl)c1ccccc1F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1F)N1CC[C@H]1CO
Temperature: 5 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
Trifluoroacetic acid (5 ml) in dichloromethane (5 ml) was added to a stirred solution of (S)-N-tert-butoxycarbonyl-azetidin-2-ylmethanol (1.17 g, 6.25 mmol) in dichloromethane (8 ml) cooled to ˜5° C. under nitrogen. The reaction was stirred for 18 h with the temperature being allowed to rise slowly to RT. Solvent and excess acid were removed in vacuo to give the product (S)-2-hydroxymethylazetidine, trifluoroacetate salt as a viscous oil (1.26 g). Triethylamine (0.61 ml, 4.38 mmol) was added slowly to a solution of 0.19 g of (S)-2-hydroxymethylazetidine trifluoroacetate salt (0.94 mmol) and 2-fluorobenzoyl chloride (0.16 ml, 1.30 mmol) in dichloromethane (8 ml) cooled to ˜5° C. and under nitrogen. The reaction was stirred for 18 h with the temperature being allowed to rise slowly to room temperature. Water (15 ml) and dichloromethane (20 ml) were added and the layers were separated. The aqueous layer was washed with more dichloromethane (20 ml) and the combined organic layers were dried (MgSO4), filtered and solvent removed in vacuo. The crude residue was purified by chromatography on silica gel using ethyl acetate:petroleum ether (40/60) 1:1, as eluant giving (S)-N-(2-fluorobenzoyl)-2-hydroxymethylazetidine (0.15 g; 0.72 mmol) as a viscous oil, EIMS: m/z=192 [(M+H)-H2O)]+
Reaction SMILES: [Br-].[F:2][C:3]([F:22])([F:21])[C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[NH:7][C:8]1[CH:17]=[CH:16][N+:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.[OH-].[Na+]>O>[F:22][C:3]([F:2])([F:21])[C:4]1[CH:5]=[C:6]([N:7]=[C:8]2[CH:17]=[CH:16][N:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[CH:9]2)[CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cccc(Nc2cc[n+]3ccccc3c2)c1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1cccc(N=c2ccn3ccccc3c2)c1
Reaction time: 1 h

Procedure:
To a suspension of 2-(3-trifluoromethylanilino)quinolizinium bromide (22 g., 0.060 mole) in H2O (400 ml) was added a solution of NaOH (25 g., 0.62 mole) in H2O (250 ml). The mixture was stirred at about 50° for 1 hour, then chilled and filtered. The yellow product weighed 17 g (97%). The sample was boiled in benzene, filtered and diluted with hexane. Evaporation of the solvent gave yellow crystals which melted at 134°-135°.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C>[I:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[C:9]1=[O:17])[CH2:7]2
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(I)c([N+](=O)[O-])cc1C2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc(I)c([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 525 mg, 13.1 mmol) was added to a solution of (2R)-5-iodo-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (5.14 g, 12.6 mmol) in DMF (40 mL) at 0° C. and the mixture was stirred for 5 min. 2-(Trimethylsilyl)ethoxymethyl chloride (2.23 mL, 12.6 mmol) was then added dropwise, and the reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched with dilute aqueous NaHCO3 (200 mL) and the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc —100:0 to 0:100, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=538 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([S:10]([NH:13][C:28]([NH:27][C:21]2[N:20]=[C:19]([O:18][CH3:17])[CH:24]=[C:23]([O:25][CH3:26])[N:22]=2)=[O:29])(=[O:11])=[O:12])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCOc1ccc(C(C)=O)cc1S(N)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C(C)=O)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a stirred suspension of 0.2 g of the compound from Example 8, 0.23 g of 4,6-dimethoxy-2-pyrimidinylcarbamic acid, phenyl ester in 10 ml of dry acetonitrile was added 127 μl of DBU. After being stirred for 1 hr, the mixture was treated with 40 ml of water and 1N HCl in a dropwise manner until the pH was 3. The precipitate was filtered off and washed with water and ether/hexane (1/1), to give 0.27 g of a solid, m.p. 192°-193° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(#N)C.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]2[S:38][C:37]3[N:39]4[C:30](=[CH:31][N:32]=[C:33]4[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)=[O:27])[CH2:21][CH2:20]1.[I-].[Na+]>C(N(CC)CC)C>[C:9]([C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26]([C:28]3[S:38][C:37]4[N:39]5[C:30](=[CH:31][N:32]=[C:33]5[CH:34]=[CH:35][CH:36]=4)[CH:29]=3)=[O:27])[CH2:23][CH2:24]2)[CH:13]=[CH:12][CH:11]=1)#[N:10]
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: N#Cc1cccc(OCCCCl)c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(OCCCN2CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC2)c1
Yield: 57.4 %

Procedure:
3-(3-Chloropropan-1-yl)oxybenzonitrile (503 mg) was added, at room temperature, to an acetonitrile solution (20 ml) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (800 mg), 1,8b-diazabicyclo[5.4.0]-7-undecene (662 mg), triethylamine (1.09 g) and sodium iodide (285 mg). The mixture was heated under reflux for 6.5 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, which was subjected to extraction with chloroform. The extract solution was washed with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (ethyl acetate/methanol=2/1) to afford the object compound (565 mg, 57%) as reddish purple crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.B([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 94.6 %

Procedure:
1-(Benzo [d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarbox-amide (B-8) (5.1 g, 14 mmol), 4-boronobenzoic acid (3.4 g, 20 mmol), 1 M K2CO3 (54 mL, 54 mmol), Pd-FibreCat 1007 (810 mg, 1.35 mmol), and DMF (135 mL) were combined. The mixture was heated at 80° C. for 3 h. After cooling, the mixture was filtered and DMF was removed in vacuo. The residue was partitioned between dichloromethane (250 mL) and 1N HCl (250 mL). The organics were separated, washed with saturated NaCl solution (250 mL), and dried over Na2SO4. Evaporation of organics yielded 4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]benzoic acid (5.5 g, 98%). ESI-MS m/z calc. 415.1, found 416.5 (M+1)+; Retention time 3.19 minutes. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.83 (s, 1H), 8.06-8.04 (m, 2H), 7.58-7.56 (m, 1H), 7.50-7.48 (m, 3H), 7.27-7.24 (m, 1H), 7.05-7.04 (m, 1H), 6.98-6.94 (m, 2H), 6.07 (s, 2H), 2.22 (s, 3H), 1.46-1.44 (m, 2H), 1.12-1.09 (m, 2H).