Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.Cl.[CH3:55][C:56]1([OH:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C)C=O.C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:59]1[CH2:60][CH2:61][C:56]([OH:62])([CH3:55])[CH2:57][CH2:58]1)=[O:30]
Reactant: CC1(O)CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(O)CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (572 mg, 1.51 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (300 mg, 1.01 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (3 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 10 minutes. A solution of 4-methylpiperidin-4-ol hydrochloride (154 mg, 1.02 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution stirred at 25° C. for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (3×50 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a gum (94 mg, 23.63% yield); 1H NMR (400.132 MHz, DMSO) δ 1.13 (3H, s), 1.29-1.47 (4H, m), 3.20-3.28 (4H, m), 4.32 (2H, s), 4.41 (1H, s), 7.19 (1H, d), 7.31 (1H, dd), 7.38-7.42 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.45 (M+H 396.4).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C3CCCCO3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(OC3CCCCO3)cc2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1

Procedure:
To a solution of 4-octyloxy-4′-tetrahydropyranyloxybiphenyl 9E (R=octyl) (5 g) in methanol (39 ml) is added toluenesulfonic acid (25 mg). The reaction mixture is stirred at room temperature overnight, at which time potassium carbonate (1 g) is added. The reaction mixture is stirred an additional hour, and is then filtered. The solvent is removed in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[CH:23][CH:22]=1)=[O:19].C(NC(C)C)(C)C>>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:18]([N:14]3[CH2:15][CH2:16][CH:11]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:12][CH2:13]3)=[O:19])=[CH:22][CH:23]=2)=[N:29][CH:30]=1
Reactant: CN(CCc1ccccn1)C1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CC(C)NC(C)C
Product: CN(CCc1ccccn1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title product was prepared from methyl-piperidin-4-yl-(2-pyridin-2-yl-ethyl)-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 5 equivalent of diisopropylamine was added, preparative HPLC (method C) (48%, colourless oil). HPLC-MS m/z=501.1 (M+1), Rt: 2.77 min.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:27][OH:28])=[CH:9][N:10]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[C:8]([CH:27]=[O:28])=[CH:9][N:10]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(CO)c(-c2ccccc2)c1-c1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 71.4 %

Procedure:
Using [4,5-diphenyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (352 mg), tetra-n-propylammonium perruthenate (13.8 mg), N-methylmorpholine N-oxide (159 mg) and molecular sieves 4A powder (177 mg), a procedure as in Reference Example 6 was performed to give the title compound as white crystals (yield 250 mg, 72%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35](CO)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35]([CH2:20][Cl:24])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc2cc(CCl)cc(OCc3ccccc3)c2c1
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
To a solution of triphenylphosphine (37.2 g, 142 mmol) in dry THF (160 mL) was added CCl4 (50 mL). The reaction mixture was stirred for 10 minutes and (4-benzyloxy-6-fluoro-naphthalen-2-yl)-methanol (20.0 g, 70.8 mmol) was introduced as a solid at room temperature under nitrogen. The resulting solution was refluxed for 2 hours. THF was distilled off under reduced pressure, and the remaining material diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained crude product was purified over silica gel column chromatography (100-200 mesh, 5% ethyl acetate in hexanes) to yield compound 1-benzyloxy-3-chloromethyl-7-fluoro-naphthalene (19.3 g, 90.6%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](Br)=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:24]2=[O:35])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:26]2[C:25]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)([C:24](=[O:35])[N:23]([C:20]3[CH:21]=[CH:22][C:17]([I:16])=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:5]=1)=[O:15]
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Reactant: COC(=O)C(Br)=NNc1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C1=NN(c2ccc(Cl)cc2)C2(N3CCOCC3)C(=O)N(c3ccc(I)cc3)CCC12
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of bromo[(4-chlorophenyl)hydrazono]acetic acid methyl ester (31, 582 mg, 2.0 mmol) in toluene (6 mL) was treated with 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 768 mg, 2.0 mmol, 1.0 equiv) at 0-5° C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 404 mg, 0.56 mL, 4.0 mmol, 2.0 equiv) at 0-5° C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to 70° C. for an additional 3 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (10 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15-30% EtOAc/hexane gradient elution) to afford the desired 1-(4-chloro-phenyl)-6-(4-iodo-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester (52, 1.13 g, 1.19 g theoretical, 95%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 52, CIMS m/z 595/597 (M++H, C24H24ClIN4O4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.FC1C=CC2N(CC#C)C(=O)COC=2C=1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Agent: C#CCN1C(=O)COc2cc(F)ccc21
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sccc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one under the conditions used in Example 37. The product was isolated by chromatography over the 50 fold amount of silica gel using 4 % (v/v) of ethanol in methylene chloride. The good fractions were combined and evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 4-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin.2.2-propynyl}-7-fluoro-2H-1,4-benzoxazin-3(4H)-one with m.p. 215°-217°.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:19][CH:18]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].Cl>C(O)C.[OH-].[Na+]>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(C(=N)N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)c1ccc(S(=O)(=O)NCCc2ccc(OCC(=O)O)cc2)cc1
Yield: 96.4 %

Procedure:
A solution of 2.0 g of methyl p-[2-(p-amidinobenzenesulphonamido)ethyl]phenoxyacetate hydrochloride in 100 ml of ethanol and 50 ml of 1 N sodium hydroxide solution was stirred under argon for 90 minutes. For the working up, dilute hydrochloric acid was used to neutralize to pH 6-7, and the mixture was concentrated in vacuo up to 50° C. The crystals which separated out were filtered off with suction and dried over KOH in vacuo at 50° C. 1.70 g of pure p-[2-(p-amidinobenzenesulphonamido)ethyl]phenoxyacetic acid, melting point 292°-293° C., were thus isolated.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15]C>OS(O)(=O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc(OCCCCl)c(O)c1
Temperature: 0 °C
Reaction time: 23 h
Yield: 36.1 %

Procedure:
A mixture of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (10.0 g, 0.0412 mol) and concentrated H2SO4 (50 ml) was stirred at 65° for 23 hours. The cooled reaction was poured into 250 g of ice and was stirred vigorously for 10 minutes. The aqueous mixture was extracted with dichloromethane (CH2Cl2) and the resultant dichloromethane extract was washed well with 5% sodium hydroxide. The basic phases were combined and washed with dichloromethane. The aqueous mixture was cooled in an ice bath and concentrated hydrochloric acid was added until a precipitate formed. The product was isolated by filtration and dried to yield 3.1 of a light brown solid. This was combined with an additional sample (5.0 g total) and two consecutive recrystallizations from toluene provided 3.4 g (22%) of 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone as a beige solid, m.p.=101°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O.N.[CH:17](O)=O>>[CH3:14][N:13]1[C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[N:1]=[CH:17]1
Reactant: O=CO
Reactant: CCOC(=O)c1ccc(NC)c(N)c1
Agent: N
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)ncn2C

Procedure:
Ethyl 3-amino-4-methylaminobenzoate (24.1 g, 124 mmol) in the Step 1-1-3 was dissolved in formic acid (200 ml), and the solution was heated under reflux for 2 hours. After being cooled by ice, the solution was neutralized with a 25% ammonia water. The solution was subjected to extraction with chloroform, and the extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (26.1 g, quantitative) as a light-purple powder.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]2[CH2:11][C:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)([CH2:7]2)[C:5]1=[O:21])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]23[CH2:7][CH:8]([CH2:11]2)[C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:21])=[CH:17][CH:16]=1
Reactant: CC(C)N1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)N1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 2.3 g of 3-isopropyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione are dissolved in 50 ml of ethyl acetate, hydrogenated in the presence of 0.25 g of 5% palladium-on-carbon and worked up. Melting point 191°-201° (from ethyl acetate/hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1.[NH:35]1[CH:39]=[CH:38][CH:37]=[N:36]1.C(=NO)C1C(=CC=CC=1)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.[Cu-]=O>[N:35]1([C:2]2[CH:7]=[C:6]([C:8]([N:10]3[CH2:14][CH2:13][CH:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH2:11]3)=[O:9])[CH:5]=[CH:4][C:3]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH:39]=[CH:38][CH:37]=[N:36]1
Reactant: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Br)c1)N1CCC(c2cccnc2)C1
Reactant: c1cn[nH]c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-n2cccn2)c1)N1CCC(c2cccnc2)C1
Temperature: 25 °C

Procedure:
A solution of 3b (54.0 mg, 0.099 mmol), pyrazole (50.7 mg, 0.745 mmol), salicylaldoxime (19.8 mg, 0.145 mmol), copper(I) oxide (16.6 mg, 0.116 mmol) and cesium carbonate (265 mg, 0.812 mmol) in acetonitrile (1.00 mL) was heated to 120° C. in a sealed microwave vial for a total of 60 min. The reaction mixture was cooled to rt, concentrated in vacuo, and the resulting crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 10a. m/z (ES) 531 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:21]=[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[N:11]3[N:10]=2)=[CH:5][CH:4]=1.[Na].[CH3:23][OH:24]>>[C:19]([C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12]1[CH:21]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:10][N:11]=1)([O:24][CH3:23])=[O:20]
Reactant: COc1ccc(-c2cc3n(n2)C(=O)c2ccccc2-3)cc1
Reactant: CO
Agent: [Na]
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 2-(4-methoxyphenyl)pyrazolo[5,1-a]isoindol-8-one (100 mg), methanol (10 ml), and sodium (0.1 g). was stirred overnight at 25°. Evaporation of the methanol left 120 mg (96%) of colorless gum which was the ester 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole. The crude ester was dissolved in benzene and stirred overnight with 2 g of Florisil. Filtration and evaporation of the benzene solution, followed by recrystallization from hexane-ethyl acetate (1:1), gave 3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole, mp 92-93°.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)(C)(C)C.[NH:34]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:33])=[C:10]2[C:15]=1[N:14]=[C:13]([O:20][CH:21]([F:22])[F:23])[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:37]3[CH:38]=[N:34][NH:35][CH:36]=3)=[CH:27][CH:26]=1)=[C:11]2[CH3:32]
Reactant: OB(O)c1cn[nH]c1
Reactant: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(-c3cn[nH]c3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12

Procedure:
The title compound was prepared by the method of Preparation 22b using [3-(4-bromobenzyl)-8-chloro-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid tert-butyl ester and pyrazole-4-boronic acid.
Reaction SMILES: [OH-].[K+:2].O.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:11](=[S:13])=[S:12]>C1(C)C=CC=CC=1>[C:11](=[S:13])([S-:12])[NH2:5].[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[K+:2]
Reactant: S=C=S
Agent: CN1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=S)[S-]
Temperature: 20 °C

Procedure:
To a 3-necked round bottom flask equipped with a mechanical stirrer, addition funnel and reflux condenser was added 3.12 grams of 90% potassium hydroxide, 100 ml. of water and 60 grams of N-methylpiperazine. The solution was cooled to 20° C with an ice bath and thereafter 38 grams of carbon disulfide was added drop-wise. When the addition of carbon disulfide had been completed, 100 ml. toluene was added and a Dean-Stark trap placed on the flask. The water was azeotroped off, followed by distillation of toluene. The solid salt was then dissolved in an equal amount of diethylene glycol to give a 50% solution of potassium N-methylpiperazine dithiocarbamate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH3:15]I>C(O)C>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH3:15])[NH:9][C:5]=2[CH:4]=1
Reactant: CI
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Solvent: CCO
Product: CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Yield: 81.9 %

Procedure:
A suspension of 20.0 g (0.092 mole) of 5-trifluoromethyl-2-mercaptobenzimidazole and 13.1 g (0.092 mole) of methyl iodide in 200 ml of ethanol is heated to the boil for three hours. The solvent is stripped off in vacuo and the residue is recrystallized from acetonitrile. 17.5 g (82%) of 5-trifluoromethyl-2-methylthio-benzimidazole of m.p. 145°-146° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=O)[S:10][C:3]=12.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH2:11][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:10][C:3]=12
Reactant: O=Cc1cc2nccc(Cl)c2s1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccnc2cc(CN3CCOCC3)sc12
Reaction time: 18 h
Yield: 29.4 %

Procedure:
To a solution of aldehyde 14 (scheme 3) (316 mg, 1.6 mmol) and morpholine (0.15 ml, 1.52 mmol) in MeOH (20 mL) was added acetic acid (0.88 ml, 15 mmol), followed by sodium cyanoborohydride (105 mg, 1.67 mmol). The resultant mixture was allowed to stir for 18 h, quenched with saturated aqueous potassium carbonate solution (5 mL), evaporated under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and the remained solid was purified by column chromatography, eluents EtOAc/hexane (30:70), then MeOH/EtOAc (1:99), to afford the title compound 131 (120 mg, 29% yield). MS (m/z) 269.0/271.0 (M+H).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[C:5]21[CH2:18][CH2:17][CH2:16][CH2:15]2.O.[NH2:20][CH2:21][C@H:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]3[CH:3]=[CH:2][N:20]([CH2:21][C@H:22]([OH:24])[CH3:23])[C:12]=32)=[CH:7][CH:8]=1
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCC1
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
A solution of 2.42 g of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 3:2). 2.06 g (73%) of (R)-1-[7'-methyl-1',4'-dihydro-spiro[cyclopentane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a red oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:32][CH2:31][C:21]3[N:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:24][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1sc(-c2ccccc2)nc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield {6-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-indol-1-yl}-acetic acid tert-butyl ester as yellow oil.