Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH3:16][S:17][C:18]1[C:26](O)=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[N:21][NH:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:16][S:17][C:18]1[C:26]([O:1][CH:2]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]2)=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[N:21][NH:22]2
Reactant: CSc1c(O)ccc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1c(OC2CCCN(C(=O)OC(C)(C)C)CC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
The tert-butyl 4-hydroxyazepane-1-carboxylate (0.0504 g, 0.23 mmol) obtained in Example 322, (c) and triphenylphosphine (0.0723 g, 0.28 mmol) were added to a solution of the 4-(methylthio)-1H-indazol-5-ol (0.0377 g, 0.21 mmol) obtained in Example 607 in tetrahydrofuran (2 ml), and the resulting mixture was ice-cooled. A solution of diisopropyl azodicarboxylate (0.0557 g, 0.28 mmol) in tetrahydrofuran (1 ml) was added dropwise thereto, and the resulting mixture was slowly heated to room temperature and stirred overnight. The reaction solution was concentrated and then diluted with chloroform, and a 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform (twice). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=3/1˜2/1˜3/2) to obtain tert-butyl 4-{[4-(methylthio)-1H-indazol-5-yl]oxy}azepane-1-carboxylate (0.0318 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Cl)cc1F
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of (4-chloro-2-fluorophenyl)methanol (4.60 g, 28.6 mmol) in THF (100 mL) was added 1H-imidazole (1.95 g, 28.6 mmol) and tert-butylchlorodimethylsilane (4.32 g, 28.6 mmol) at room temperature. The reaction mixture was stirred for 12 h at RT. The white precipitate was filtered and the filtrate was washed with 0.1 N aqueous HCl. The separated aqueous phase was extracted with diethyl ether (2×40 mL). The combined organic phases were washed with saturated aqueous solution of sodium bicarbonate, and brine. The resulting organic solution was dried over magnesium sulfate and concentrated under reduced pressure. Flash chromatography on silica (hexanes) gave (4-chloro-2-fluorobenzyloxy)(tert-butyl)dimethylsilane as colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 7.31 (1H, t, J=8.1 Hz), 7.01 (1H, d, J=8.3 Hz), 6.91 (1 H, dd, J=9.9, 1.8 Hz), 4.64 (2H, s), 0.73-0.86 (9H, m), −0.06 (6H, s)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].I[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH:17]([C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[CH3:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: CC(I)c1ccc([N+](=O)[O-])cc1
Product: CC(c1ccc([N+](=O)[O-])cc1)N(c1ccc(C#N)cc1)c1cncnc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 1-(1-iodoethyl)-4-nitrobenzene
Reaction SMILES: [CH2:1]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[C@H:3]([C:16]([OH:18])=O)[CH2:2]1.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:44]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH2:49])[CH3:45]>C(Cl)Cl.C(N(CC)CC)C>[CH2:44]([O:46][C:47](=[O:54])[C@H:48]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:49][C:16](=[O:18])[C@@H:3]1[CH2:2][CH2:1][CH2:5][N:4]1[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])[CH3:45]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of Z-L-proline (12.7 g, 0.051M) in CH2Cl2 (200 ml) cooled to 0° was added 1-hydroxy benzotriazole (7.0 g) followed by a solution of DCC (10.6 g) in CH2Cl2 (50 ml). After 30 min. at 0° L-leucine ethyl ester (10.0 g, 0.051 molM) was added followed by triethylamine (15 ml) and the reaction mixture was then left to stir and warm up to room temperature overnight. The reaction mixture was then filtered and washed in turn with saturated aq. NaHCO3 (250 ml×3), H2O (250 ml), dilute aq. HCl (1M, 250 ml×3) and water (250 ml×2). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to an oil which subsequently crystallised. Recrystallisation from ethyl acetate/hexane gave N-(benzyloxycarbonyl)-L-prolyl-L-leucine ethyl ester as a white crystalline solid, 15.5 g, (78%); m.p. 67°-68°; (Found: C,64.55; H,7.79; N,7.22. C21H30N2O5 requires C,64.61; H,7.74; N,7.17%); νmax (CHCl3) 1740 and 1680 cm-1 ; δ(CDCl3) 0.7-0.95 (6H,m,CH(CH3)2); 1.18 (3H,m,OCH2CH3); 1.3-1.95 and 2.05-2.25 (7H,m,CH2CH2, CH2CH(CH3)2); 3.4 (2H,m,CH2N); 4.05 (2H,m,OCH2CH3); 4.25 (2H,m,α--CH); 4.98 and 5.05 (together 2H, respectively q,J=7 Hz, and m, CH2C6H5); 7.35 (5H, broad s, C6H5) and 8.26 (1H,m,CONH); m/e 391 (100%, [m+1]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH:16](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH:16]=[N:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in the next step. 1H NMR (CDCl3, 400 MHz) δ 8.09 (s, 1), 7.75 (d, J=1.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m, 2H), 1.27-1.24 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CCCN2
Product: CS(=O)(=O)N1CCCc2cc(Br)ccc21
Yield: 60.2 %

Procedure:
This compound was prepared according to the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 6-bromo-1,2,3,4-tetrahydroquinoline (0.40 g, 1.89 mmol) and methanesulfonyl chloride (0.22 mL, 2.8 mmol) to provide 6-bromo-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline (0.33 g). MS (ES) m/z 289.7; HPLC purity 97.2% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:27])[CH:25]=2)[CH:20]=[C:19]([C:28]#[N:29])[N:18]=1>C1COCC1>[Cl:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[C:19]([C:28]#[N:29])[N:18]=[C:17]2[O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[CH:22][CH:23]=1
Reactant: N#Cc1cc2ccc(Cl)cc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (201 mg, 1.076 mmol) in THF (5 mL) at 0° C. was added NaH (81 mg, 1.35 mmol). The reaction mixture was stirred at RT for 30 minutes. Next, 1,7-dichloroisoquinoline-3-carbonitrile (200 mg, 0.897 mmol) was added and the reaction mixture was warmed to RT over a 1 hour period. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and the resulting mixture was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative TLC eluting with petroleum ether and ethyl acetate (PE/EtOAc=3:1) to give the title compound (200 mg, 59%). 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1H), 7.65-7.71 (m, 3H), 5.74 (br, 1H), 3.46-3.69 (m, 4H), 2.23 (s, 1H), 1.49 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18]C)=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:3]=1.Cl>[OH-].[Na+].C1COCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[N:3]=1
Reactant: COC(=O)C1CCCC(c2cc(-c3ccccc3O)nc(N)c2C#N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(C2CCCC(C(=O)O)C2)cc(-c2ccccc2O)nc1N
Temperature: 60 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A suspension of methyl 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]cyclohexanecarboxylate (151 mg, 0.43 mmol) in 2N NaOH (1 mL) and THF (2 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was neutralized with 1N HCl (2 mL), and then diluted with water. The resulting precipitates were collected by filtration, washed with EtOH, and dried (60° C., 2 hrs, under reduced pressure) to give 3-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]cyclohexanecarboxylic acid as a yellow solid (105 mg, yield; 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]([CH3:21])[N:13]=1.C[Li].[CH3:26]COCC.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([C:18](=[O:20])[CH3:26])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: CCN(c1nc(C)cc(C(=O)O)n1)c1ccc(C(C)C)cc1Br
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(c1nc(C)cc(C(C)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 78 °C
Reaction time: 5 h
Yield: 67.8 %

Procedure:
A solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-carboxy-6-methylpyrimidinamine (3.7 g, 9.8 mmol) in anhydrous THF (25 mL) was cooled with stirring to 31 78° C. under a nitrogen atmosphere. A solution of methyl lithium in ether (1.4M, 7 mL, 9.8 mmol) was added dropwise and the reaction mixture was stirred at -78° C. for 1 h. The CeCl3 suspension was transferred via cannula into the reaction mixture and stirring at -78° C. was continued for 5 h. A solution of methyl lithium in ether (1.4M, 7 mL, 9.8 mmol) was added dropwise and the reaction mixture was then warmed gradually to room temperature over 16 h. After cooling the reaction mixture to -78° C., the reaction was quenched with a 1N HCl solution and warmed to room temperature. The resulting mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an orange yellow oil. Column chromatography (ethyl acetate:hexanes::1:4) afforded the title product as an oil (2.5 g, 68% yield, Rf 0.5): NMR (CDCl3, 300 MHz): 7.55 (d, 1H, J=1), 7.25-7.15 (m, 2H), 6.95 (s, 1H), 4.30-4.10 (m, 1H), 3.90-3.70 (m, 1H), 3.00-2.85 (m, 1H), 2.80-2.05 (m, 6H), 1.35-1.20 (m, 9H); CI-HRMS: Calcd (C18H22BrN3O): 376.1024 (M+H), Found: 376.1042.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1)[NH2:5].[NH:14]1[CH2:21][CH2:20]C[C@H:15]1[C:16](O)=[O:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O1CCOCC1.[Cu]I>[O:17]1[CH2:16][CH2:15][N:14]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([N:9]3[CH:13]=[CH:12][CH:11]=[N:10]3)[CH:8]=2)[NH2:5])[CH2:21][CH2:20]1
Reactant: Nc1cc(Br)cc(-n2cccn2)c1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Nc1cc(N2CCOCC2)cc(-n2cccn2)c1
Temperature: 120 °C
Reaction time: 96 h
Yield: 149.3 %

Procedure:
The mixture of 3-bromo-5-(1H-pyrazol-1-yl)aniline (200 mg, 0.84 mmol), morphoine (0.22 mL, 2.52 mmol), proline (39 mg, 0.34 mmol), CuI (33 mg, 0.17 mmol) and K3PO4 (540 mg, 2.52 mmol) in 10 mL DMSO was stirred at 120° C. in a sealed tube for 4 days. It was diluted with dioxane, filtered through celite, concentrated in vacuo and subjected to reverse phase preparative HPLC to isolate 3-morpholino-5-(1H-pyrazol-1-yl)aniline (124 mg).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@:15]1([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22](=[O:23])[N:21]2[C@@H:17]([S:18][CH2:19][C@H:20]2[C:24]([OH:26])=[O:25])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC.CO>[CH2:8]([C@:15]1([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22](=[O:23])[N:21]2[C@@H:17]([S:18][CH2:19][C@H:20]2[C:24]([O:26][CH3:1])=[O:25])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C(=O)O)N2C1=O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)[C@@H]1CS[C@H]2C[C@@](Cc3ccccc3)(NC(=O)OC(C)(C)C)C(=O)N21
Temperature: 25 °C

Procedure:
A total of 1.5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 250 mg of (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid in 8 ml of methanol while stirring at room temperature. After the reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40° C. The residue is purified on a column (silica gel, mobile phase:ethyl acetate:n-heptane=1:1.5).
Reaction SMILES: [C:1]1([C:7](=[O:19])[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][CH:8]([C:7](=[O:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(=O)CC(=O)c2ccccc2)cc1
Product: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccc(OC)cc1

Procedure:
By a method analogous to that described in Example 28, 1-phenyl-3-(p-methoxyphenyl)-1,3-propanedione was reacted with bromoacetic acid-ethyl ester to form 3-benzoyl-3-p-anisoyl-propionic acid-ethyl ester, which was further reacted with phenylhydrazine to form 1,3-diphenyl-5-(p-methoxyphenyl)-pyrazol-4-acetic acid-ethyl ester, from which was obtained by saponification 1,3-diphenyl-5-(p-methoxyphenyl)-pyrazol-4-acetic acid having a melting point of 160°-163° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([CH:24]=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1.[Br:31]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:31][C:24]1[C:25]2[C:30]([C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)=[CH:12][CH:13]=3)=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: c1ccc2cc(-c3ccc(-c4c5ccccc5cc5ccccc45)cc3)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2ccccc2c(-c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
9-(4-Naphthalene-2-yl-phenyl)anthracene 13.25 g was dispersed in DMF (dimethylformamide) 100 ml, and a DMF solution (100 ml) of NBS (N-bromosuccinimide) 7.44 g was dropwise added thereto at room temperature. The solution was stirred at room temperature for 7 hours and then left standing for a nigh. Water 200 ml was added thereto, and the deposited crystal was filtered, sufficiently washed with ethanol and dried, whereby targeted (9-bromo-10-(4-naphthalene-2-yl-phenyl)anthracene 15.84 g was obtained (yield: 99%).
Reaction SMILES: N1C=CC=CC=1.[O:7]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13]2)[CH2:9][CH2:8]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][N:34]1[C:39](=[O:40])[CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:36]=[C:35]1[CH2:47][C:48]([O-])=[O:49].[Na+]>CN(C)C=O>[CH3:33][N:34]1[C:39](=[O:40])[CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[N:36]=[C:35]1[CH2:47][C:48](=[O:49])[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2([CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[CH2:13]1
Reactant: c1ccc2c(c1)NCC21CCOCC1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CC3(CCOCC3)c3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
3.8 ml of pyridine, 378 mg of 1,2,2′,3′,5′,6′-hexahydrospiro[3H-indole-3,4′-[4H]pyran] and 575 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 770 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 4d, step 2d) in 11.3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. The residue is taken up in 15 ml of water and 20 ml of ethyl acetate, and then left to stir at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and diethyl ether. 45 mg of 3-methyl-6-(morpholin-4-yl)-2-[2-oxo-2-(2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)ethyl]pyrimidin-4(3H)-one are thus obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[NH:19]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:20]([NH2:22])=[NH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:21]=[C:20]([NH:19][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:22]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)NCCCC(=O)O
Product: O=C(O)CCCNc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 4-guanidino butyric acid were converted to I-19 (6%): HRMS Calcd. for C16H15ClN4O3: 347.091, Found 347.092.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH2:31][CH2:32][C:33]1[O:34][CH:35]=[CH:36][CH:37]=1.CC(O)C>O>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[CH2:32][NH:31][C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[C:6]=2[N:7]=1
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1cc(NCc2ccco2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Yield: 29.6 %

Procedure:
(see, e.g., WO2013039988A1). A pressure vessel was charged with 50 (119 mg, 0.28 mmol), 2-aminomethylfuran (0.12 mL, 1.36 mmol) and iPrOH (4 mL). The vessel was sealed and the reaction mixture was heated at 100° C. overnight. An additional 1 mL (11.3 mmol) of amine was added and the mixture was heated at 150° C. overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL×2). Combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Crude was subjected to flash column chromatography on silica gel to provide the title compound (40 mg, 30%) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 5H), 7.07 (t, J=7.3 Hz, 1H), 6.97 (d, J=8.2 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 6.80 (s, 1H), 6.30 (s, 1H), 6.22 (s, 1H), 5.47 (s, 2H), 5.14 (t, J=5.4 Hz, 1H), 4.68 (d, J=5.5 Hz, 2H), 4.43 (q, J=7.1 Hz, 2H), 2.58 (s, 3H), 1.42 (t, J=7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.83, 157.16, 156.86, 156.51, 152.16, 152.06, 141.97, 141.27, 134.71, 132.57, 129.67, 129.44, 123.17, 118.82, 110.40, 107.27, 106.91, 104.45, 61.66, 49.53, 38.75, 16.15, 14.23. ESI MS: m/z 483.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Reactant: CCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCOC(=O)COc1ccc(C(C)=O)cc1

Procedure:
A mixture of 4-acetylphenoxyacetic acid (20.0g.), n-hexanol (10.5g.) and concentrated sulphuric acid (2ml.) in benzene (100ml.) was heated under reflux for 6 hours using a water separator.cThe mixture was then evaporated and the residue dissolved in n-pentane (50ml.). The solution was washed with water (3 × 30ml.) sodium bicarbonate solution (1 × 50ml.) and water again (1 × 50ml.). The solution was evaporated and the residue chromatographed on alumina to give n-hexyl 4-acetylphenoxyacetate, I.R. peaks at 1760 and 1680 cm-1.
Reaction SMILES: ClC(Cl)C.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17][CH2:18][CH2:19][CH2:20][OH:21].[O-:22]O.C1(C(C)C)C=CC=CC=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S@:17]([CH2:18][CH2:19][CH2:20][OH:21])=[O:22]
Reactant: Cc1ccccc1-n1ccnc1SCCCO
Reactant: [O-]O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)c1ccccc1
Solvent: CC(Cl)Cl
Product: Cc1ccccc1-n1ccnc1[S@@](=O)CCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.2 %

Procedure:
To 3 l of dichloroethane were added 123 g of 3-[1-(2-methylphenyl)-2-imidazolylthio]propanol, 414 g of L-(+)-diethyl tartarate and 120 g of a powder of Molecular Sieve 4A. The mixture was stirred at room temperature for 2 days. Thereto was added 142 g of titanium tetraisopropoxide. The mixture was stirred at room temperature for 30 minutes. Thereto was added 91 g of cumene hydroperoxide. The mixture was stirred at 5° C. for 24 hours. The reaction mixture per se was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=50/1). Recrystallization from methyl ethyl ketone was repeated to obtain 50 g of (S)-(+)-3-[1-(2-methylphenyl)2-imidazolylsulfinyl]propanol.