Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12]([CH2:15][OH:16])=[N:13][S:14][C:10]=2[CH:9]=1.C(=O)([O-])[O-:20].[K+].[K+]>O>[Cl:7][C:8]1[CH:18]=[CH:17][C:11]2[C:12]([C:15]([OH:20])=[O:16])=[N:13][S:14][C:10]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: OCc1nsc2cc(Cl)ccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1nsc2cc(Cl)ccc12
Temperature: 25 °C
Yield: 15 %

Procedure:
Potassium permanganate (1.69 mmol) was added in several batches a solution of (6-chlorobenzo[d]isothiazol-3-yl)methanol (2.50 mmol) in water (3 mL). Potassium carbonate (2.90 mmol) was added and the reaction mixture was maintained for 30 min at 25° C. The insoluble materials were removed by filtration and the aqueous layer was extracted with ethyl acetate (3×10 mL). The pH of the aqueous layer was adjusted to 3-4 by the addition of 1 N hydrochloric acid and the reaction mixture was maintained for 10 min. The solids were collected by filtration to provide 6-chlorobenzo[d]isothiazole-3-carboxylic acid in 15% yield as a white solid.
Reaction SMILES: C(C1C(C)=C(Cl)C=C(C(C)C)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:35]=[C:36]([CH:46]([CH3:48])[CH3:47])[C:37]2[O:41][CH:40]([CH2:42][OH:43])[CH2:39][C:38]=2[C:44]=1[CH3:45].[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>>[CH3:59][C:49]1[CH:54]=[CH:53][C:52]([S:55]([O:43][CH2:42][CH:40]2[CH2:39][C:38]3[C:44]([CH3:45])=[C:34]([Cl:33])[CH:35]=[C:36]([CH:46]([CH3:48])[CH3:47])[C:37]=3[O:41]2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(Cl)cc(C(C)C)c2c1CC(CO)O2
Agent: C=CCc1c(C)c(Cl)cc(C(C)C)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(C)c(Cl)cc(C(C)C)c3O2)cc1
Yield: 69 %

Procedure:
Treatment of 2-allyl-4-chloro-6-isopropyl-3-methylphenol (8.88 g, 0.04 mmol) with 3-chloroperoxybenzoic acid (13.63 g, 0.079 mol, 77%)) followed by potassium carbonate (10.92 g, 0.079 mol) generally according to the procedure described for Intermediate 9 provided (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (5.95 g, 0.025 mol) with p-toluenesulfonyl chloride (5.66 g, 0.03 mol) generally according to the procedure described for Intermediate 10 afforded 6.71 g (69%) (±)-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 103-105° C.; Anal. calcd. for C20H23ClO4S C, 60.83; H, 5.87. Found C, 60.67; H, 5.88.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)#[N:8].O>C1COCC1>[NH2:8][CH2:7][C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: N#Cc1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.4 %

Procedure:
LAH (42 mL, 1M solution in THF) was added dropwise through a syringe to a solution of 2-cyanoindole (2.0 g, 14.1 mmol) in anhydrous THF (20 mL) with cooling, and the resulting solution was stirred at RT under argon for 5 h. H2O was added dropwise with cooling to destroy excess LAH, and the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K2CO3) and concentrated to afford the title compound (2.11 g, quantitative) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, 1H), 7.29 (d, 1H), 6.97 (t, 1H), 6.91 (t, 1H), 6.20 (s, 1H), 3.82 (s, 2H), 2. 18 (br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:40][C:41]([O:43][CH3:44])=[O:42])=[C:6]([C:8]#[C:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:13]=[C:12]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]4[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[N:11]=2)[CH:7]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:40][C:41]([O:43][CH3:44])=[O:42])=[C:6]([CH:7]=1)[CH2:8][CH2:9][C:10]1[C:15]([C:16]([F:18])([F:19])[F:17])=[CH:14][N:13]=[C:12]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)[N:11]=1
Reactant: COC(=O)Cc1ccc(F)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(F)cc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of Pd/C 10% (0.100 g) and tert-butyl 4-(4-((4-((5-fluoro-2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A51) (0.158 g, 0.258 mmol) in EtOAc (20 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The resulting mixture was filtered through a Celite plug, washing with EtOAc (100 mL) then the combined organic washings were evaporated in vacuo to yield the title compound A52 as a yellow oil (0.092 g, 58%); 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.48 (d, J=8.5 Hz, 2H), 7.17-7.10 (m, 3H), 6.91-6.78 (m, 2H), 4.18 (s, 2H), 3.62 (s, 2H), 3.60 (s, 3H), 3.01 (s, 4H), 2.73 (t, J=11.9 Hz, 2H), 2.57 (tt, J=12.0, 3.4 Hz, 1H), 1.75 (d, J=12.8 Hz, 2H), 1.54 (qd, J=12.8, 4.2 Hz, 2H), 1.41 (s, 9H). LCMS-A: rt 6.727/6.998 min; m/z 617 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:29])([F:28])[C:9]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][CH2:26][CH3:27])[CH:19]=1)([O:14][CH2:15][O:16][CH3:17])[C:10]([F:13])([F:12])[F:11].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.O>CN(C)C=O>[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]([O:14][CH2:15][O:16][CH3:17])([C:10]([F:12])([F:11])[F:13])[C:8]([F:28])([F:29])[F:7])=[CH:19][C:20]=1[CH2:25][CH2:26][CH3:27]
Reactant: BrCCCCBr
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCCCCBr
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Potassium carbonate (132.4 mg, 0.96 mmol) was added to a mixed solution of 4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-propylphenol (221.1 mg, 0.64 mmol) and 1,4-dibromobutane (1.38 g, 6.39 mmol) in N,N-dimethylformamide (20 mL), followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin-layer chromatography (hexane:ethyl acetate=10:1) to obtain 219.5 mg of the title compound (yield: 71%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:14](Cl)(=[O:23])[C:15]1[C:16]([O:21][CH3:22])=[CH:17][CH:18]=[CH:19][CH:20]=1>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCCCc1cc2ccccc2o1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccccc1OC

Procedure:
Acylation of 9.4 g. (0.054 mol.) of 2-n-butylbenzofuran with 9.9 g. (0.058 mol.) of o-anisoyl chloride according to the procedure described in Example 10 gave 2-n-butyl-3-(2'-methoxybenzoyl)benzofuran which was demethylated with pyridine hydrochloride as previously described to give 2-n-butyl-3-(2'-hydroxybenzoyl)benzofuran.
Reaction SMILES: C([C:6]1[C:7](=[O:18])[NH:8][C:9]2[CH2:10][CH:11]([CH3:17])[CH2:12][CH2:13][C:14]=2[C:15]=1[OH:16])(OCC)=O>Cl>[OH:16][C:15]1[C:14]2[CH2:13][CH2:12][CH:11]([CH3:17])[CH2:10][C:9]=2[NH:8][C:7](=[O:18])[CH:6]=1
Reactant: CCOC(=O)c1c(O)c2c([nH]c1=O)CC(C)CC2
Agent: Cl
Product: CC1CCc2c(O)cc(=O)[nH]c2C1

Procedure:
A suspension of 3-carboethoxy-4-hydroxy-7-methyl-5,6,7,8-tetrahydrocarbostyril (7.48 g; 0.03 mole) in 2N hydrochloric acid (50 ml) was refluxed 48 hrs. and the clear solution evaporated to dryness. After resolution in water and adjusting to pH 4.0 the precipitated white solid was filtered, washed well with water and recrystallised from acetic, m.p. >360°.
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH2:11][OH:12])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.N1C=CN=C1.[Cl-].[C:19]([SiH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].[Cl-].[NH4+]>CN(C)C=O>[Br:1][CH2:2][C:3]1([CH2:11][O:12][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:4][O:5][C:6]([CH3:9])([CH3:10])[O:7][CH2:8]1
Reactant: CC(C)(C)[SiH](c1ccccc1)c1ccccc1
Reactant: CC1(C)OCC(CO)(CBr)CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1(C)OCC(CBr)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.4 %

Procedure:
1.1 g (4.6 mmol equivalents) of 5-bromomethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane was dissolved in 23 mL of dimethylformamide, 626 mg (9.2 mmol equivalents) of imidazole and 1.43 mL (5.5 mmol equivalents) of t-butyldiphenylsilane chloride were added thereto, and the mixture was stirred at room temperature (25° C.) for 5 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added dropwise, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=20/1) to give 1.70 g (3.56 mmol equivalents) of 5-bromomethyl-5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH:13][NH:14][C:15]([NH2:17])=[S:16])=O)[C:5]=2[CH:4]=[N:3][N:2]=1.S(=O)(=O)(O)O.N>>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[S:16][C:15]([NH2:17])=[N:14][N:13]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1
Reactant: NC(=S)NNC(=O)c1cccc2cnncc12
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1nnc(-c2cccc3cnncc23)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 100 mL round bottom flask was added 1-(phthalazine-5-carbonyl)thiosemicarbazide (0.20 g, 0.81 mmol) and concentrated sulfuric acid (10 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was poured into a mixture of 10 mL 33% aqueous ammonia and 10 mL ice with stirring. The resulting solution was adjusted to pH 8 with additional ammonia solution. The product was obtained as a yellow solid via filtration and washing with water. The solid was dried in a vacuum oven for 24 hours at 50° C. to provide 5-(phthalazine-5yl)-1,3,4-thiadiazol-2-amine. LCMS (M+H) 230.1 calc. C10H8N5S for 230.0. 1H NMR (400 MHz, CDCl3): δ ppm 8.23 (m, J=8.41 Hz, 1H) 8.46 (d, 1H) 8.53 (d, 1H) 9.63 (d, J=16.24 Hz, 2H). NH2 not detected.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[Sn](Cl)[Cl:13].C([O-])(O)=O.[Na+]>C(O)C>[Cl:13][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9]
Reactant: Cl[Sn]Cl
Reactant: O=[N+]([O-])c1cccc(F)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 119.5 %

Procedure:
To the solution of 2-bromo-3-fluoronitrobenzene (100 mg, 0.46 mmol) in ethanol (5 ml), Tin (II) chloride (520 mg, 2.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The NaHCO3 (aq) was added to pH=7. Then was extracted with ethyl acetate (3x). The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give desired product (80 mg, 93%). EI-MS m/z 191 (M+).
Reaction SMILES: C1([N:7]=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:19][CH:18]=1.[N+](C1C=CC(O)=CC=1)([O-])=O>C(OCC)(=O)C>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([NH2:7])=[O:27])=[CH:19][CH:18]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: NC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
N,N′-dicyclohexylcarbodiimide (2.48 g, 0.012 mol) was added to chilled (0° C.) 3-(4-hydroxyphenyl)propanoic acid solution (2 g, 0.012 mol) and 4-nitrophenol (1.95 g, 0.014 mol) in ethyl acetate (25 cm3) and mixed magnetically at 0° C. for 30 min. The reaction mixture was then stirred magnetically for 2 h at room temperature. Thereafter, the precipitated N,N′-dicyclohexylureaa was filtered out, washed using ethyl acetate (5 cm3) and the combined filtrates were evaporated until dry. Anhydrous methanol saturated with ammonia (10 cm3) was added and the reaction mixture was stirred magnetically for 2 hrs, thereafter the mixture was evaporated until dry, and the remainder was loaded onto a chromatography column packed with Merck 60H silica gel (5-40 μm). The column was eluted with chloroform-methanol (50:1, v/v). The chromatographically purified product was crystallized out of the methanol and then vacuum desiccated over phosphorus pentocide yielding 1.45 g 3-(4-hydroxyphenyl)propanoic acid amide (75% efficiency) (FIG. 1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].Cl[C:7]1[C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[NH:12][C:11]=2[C:10]([N+]([O-])=O)=[CH:9][CH:8]=1>CO.C1COCC1>[CH3:23][O:22][C:16]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:20]4=[C:7]([N:4]([CH2:3][CH2:2][OH:1])[N:5]=[C:19]4[C:18]=2[CH:17]=1)[CH:8]=[CH:9][CH:10]=3
Reactant: NNCCO
Reactant: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)-c1nn(CCO)c3cccc(c13)N2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.6 g of 2-hydroxyethyl hydrazine in 5 ml of methanol and 20 ml of THF was added over 1.5 hours to a mixture of 6.09 g of 1-chloro-7-methoxy-4-nitro-9(10H)-acridinone in 75 ml of methanol and 55 ml of THF, and the resulting suspension was stirred 20 hours at room temperature. The precipitate was collected and recrystallized from DMSO-methanol, providing 9-methoxypyrazolo[3,4,5-kl]acridine-2(6H)-ethanol, mp 275°-276° C.
Reaction SMILES: [C:1]([S:4][C@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH:25][C:26](=[O:29])[CH2:27]Cl)[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31].C(=S)(SC)[NH2:33].[Na]>O>[C:1]([S:4][C@H:5]1[N:8]([S:9]([O-:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[NH:14][C:15](=[O:30])[C:16]([C:20]1[N:21]=[C:22]([NH:25][C:26](=[O:29])[CH2:27][NH2:33])[S:23][CH:24]=1)=[N:17][O:18][CH3:19])(=[O:3])[CH3:2].[Na+:31]
Reactant: CSC(N)=S
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1SC(C)=O)c1csc(NC(=O)CCl)n1
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1SC(C)=O)c1csc(NC(=O)CN)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
To a solution of 0.10 g of sodium (3R,4R)-4-acetylthio-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate in 5 ml of water is added under ice-cooling 0.030 g of sodium monomethyl dithiocarbamate, and the mixture is stirred for 3 hours at room temperature. The same procedure as Example 3B yields 0.016 g of sodium (3R,4R)-4-acetylthio-3-[2-(2-aminoacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C:28]=2[CH:27]=[N:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][C:35](=[O:38])[CH2:36][CH3:37])[C:28]=2[CH:27]=[N:26][CH:25]=1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)NC1CCCc2c(-c3cc4c(cc3F)N(C)C(=O)CC4)cncc21
Temperature: 100 °C
Yield: 62.9 %

Procedure:
A mixture of 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-9, 168 mg, 0.55 mmol) and (rac)-N-(4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-propionamide (intermediate B-1) (142 mg, 0.5 mmol) in DMF (3 mL) was purged with argon for 1 min before bis(triphenylphosphine)palladium (II)chloride (38 mg, 0.054 mmol) and 1 N aq. Na2CO3 (2.5 mL) were added. The resulting reaction mixture was purged with argon for 2 min, and heated at 100° C. for 45 min in a microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc (5 mL) before it was poured into a satd. aq. solution of NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×5 mL) and the combined organic layers were washed with water and brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (120 mg, 63% yield) as a white solid. MS: 382.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1([CH2:25][OH:26])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2([CH2:25][OH:26])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: NC1(CO)CC1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OCC1(Nc2nc(Cl)nc3c2SCC3)CC1
Temperature: 160 °C

Procedure:
1.4 g (II) are placed in 10 ml dioxane, then 3.6 ml diisopropylethylamine followed by 1 g of 1-aminocyclopropanemethanol (see 4.2) are added. The reaction mixture is heated at 160° C. until there is no further reaction, and after cooling evaporated down. The residue is treated with cyclohexane/ethyl acetate (8:2) in the ultrasound bath and the solid is suction filtered and dried. 1.24 g (III-4) are obtained as a solid.
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:17]2([OH:16])[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]2)=[CH:11][CH:10]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: Clc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C1CC(O)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
While under argon, isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 160 mL, 0.208 mol) was added dropwise over 15 minutes to a solution of p-chloroiodobenzene (54.3 g, 0.227 mol) in 100 mL of dry THF at −78° C. After 1 h, 3-oxocyclobutanecarboxylic acid (7.42 g, 0.065 mol) in 40 mL of dry THF was added and the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction was quenched with 1 M HCl to pH-3, and stirred 2 h. Diethyl ether was added, the solution was stirred vigorously and the phases separated. The product was leached from organic layer with 1 M NaOH, reacidified to pH-3 with 6 M HCl and extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4 filtered and concentrated to give the crude product as an off-white solid. Recrystallization from diethyl ether and n-heptane afforded the subject compound as a white solid 4.03 g (27.3%). 1H NMR (DMSO-d6, 600 MHz) δ 12.25 (bs, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 5.86 (bs, 1H), 2.74-2.80 (m, 1H), 2.62-2.65 (m, 2H), 2.53-2.57 (m, 2H). ESI MS found for C11H11ClO3 m/z [225.1/227.1 (M−1)].
Reaction SMILES: CN(C=[O:5])C.[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][CH:27]=[CH2:28])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>[Pd](Cl)Cl.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][C:27](=[O:5])[CH3:28])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: C=CCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Product: CC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
Palladium chloride (100 mg) and cupric chloride dihydrate (50 mg) were added to DMF solution (30 ml) of 2-t-butoxycarbonyl-9-allyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.90 g, 6.1 mmol) and stirred at room temperature for 18 hours. The reaction solution was mixed with ethyl acetate, washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure, the thus obtained residue was mixed with diisopropyl ether (20 ml) and the thus precipitated crystals were collected by filtration to obtain 1.17 g of the title compound (59% in yield).
Reaction SMILES: [CH3:1][S-:2].[Na+].[C:4]1([CH2:10][CH2:11][CH2:12]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:4]1([CH2:10][CH2:11][CH2:12][S:2][CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[S-]
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: CSCCCc1ccccc1

Procedure:
Sodium methanethiolate (6 mmol, 0.42 g) and 3-phenylpropyl bromide (5 mmol, 1 g) in methanol were refluxed overnight. After removal of solvent, diethyl ether was added, washed with H2O and evaporated to give 3-phenylpropylmethyl sulfide. It was then reacted with equivalent amount of bromoacetic acid in acetonitrile (5 mL) at room temperature under N2 overnight, affording S-methyl-3-phenylpropylsulfoniumylacetic acid bromide as a white powder. It was then subjected to the general procedure 1 to give compound 585 as a white powder (0.75 g, 36% overall yield). Anal. (C12H19NaO7P2S.0.5 C2H5OH) C, H.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Product: COc1ccc(N)c(NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (5-methoxy-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A12) (12.234 g, 45.6 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a purple solid (7.185 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([OH:14])=O)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>O.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:11]([C:12](=[O:14])[NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1C(=O)O
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc2cccnc2c1C(=O)Nc1nnn[nH]1

Procedure:
To a solution of 4.7 g. (0.026 mole) of 7-methyl-8-quinolinecarboxylic acid, 3.9 g. (0.037 mole) of 5-aminotetrazole hydrate in 30 ml. of pyridine and 50 ml. of chloroform is added dropwise with stirring 5.6 ml. of thionyl chloride. The mixture is stirred at 70° C. for about one hour. The reaction mixture is evaporated to provide a residue which is diluted with water. The precipitate is separated by filtration and recrystallized from acetic acid. The product is again recrystallized from ethanol to provide 7-methyl-8-(1H-tetrazole-5-ylcarbamoyl)-quinoline, m.p. 285°-287° C.