Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]2=[O:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH:39][CH2:40][CH2:41][CH3:42])=[N-]>CO.C(OCC)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:36][CH2:39][CH2:40][CH2:41][CH3:42])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Reactant: CCCC=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: CCCCOC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution, cooled to 0° C., of 2.0 g of 7β-phenylacetylamino-cepham-3-one-4ξ-carboxylic acid diphenylmethyl ester in 75 ml of methanol is treated with excess diazo-n-butane in diethyl ether. The mixture is stirred for 15 minutes at 0° C. and is then evaporated under reduced pressure. The oily residue is purified by means of preparative thin layer chromatography (silica gel plates, 6×100 cm; system: toluene/ethyl acetate, 3:1). The layer which is visible under ultraviolet light (λ=254 mμ) is removed and in each case eluted with acetone. This zone (Rf~0.33) yields 3-n-butoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester which after crystallisation from a mixture of methylene chloride and diethyl ether is in the form of colourless flakes which melt at 168°-170° C., [α]D20 =+55°±1° (c=0.38 in chloroform); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): λmax =264 mμ (ε=7,300); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98μ, 5.62μ, 5.81μ, 5.92μ, 6.25μ and 6.62μ.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[N:6]1([C:15]2[O:16][C:17]([CH2:27][CH2:28][C:29](O)=[O:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:19]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[N:6]1([C:15]2[O:16][C:17]([CH2:27][CH2:28][C:29]([N:3]3[CH2:4][CH2:5][S:1][CH2:2]3)=[O:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:19]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: O=C(O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Reactant: C1CSCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: O=C(CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1)N1CCSC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
A mixture of thiazolidine (145 mg), 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl}-5-oxazolyl]propionic acid (300 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (222 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (253 mg) and N,N-dimethylformamide (1 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (16 ml) and the reaction mixture was extracted with ethyl acetate (5 ml). The organic layer was concentrated, introduced into preparative HPLC and purified to give 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propanoyl}thiazolidine (165 mg, 46%). Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 125–126° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:45]([NH:52][CH2:53][CH:54]([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:45]([N:52]([CH2:53][CH:54]([O:55][CH2:56][CH3:57])[O:58][CH2:59][CH3:60])[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:23])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(CNCc1ccccc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](C)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid 1.98 g (6.0 mmol), a solution of 1-hydroxybenzotriazol 1.01 g (7.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 1.44 g (7.5 mmol) in dichloromethane 20 ml, and a solution of N-benzyl-2,2-diethoxyethanamine (Compound IV-1) 1.12 g (5.0 mmol) and 4-dimethylaminopyridine 61 mg (0.5 mmol) in dichloromethane 5 ml were added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 20 ml and washed with saturated aqueous sodium bicarbonate 20 ml, water 20 ml and brine 20 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 70:30) to obtain the title compound 1.1 g (yield 42%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.C1CCCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[N:7][N:8]2[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[CH:4][CH:3]=1
Reactant: O=Cc1n[nH]c2cc(Br)ccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: O=Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 6-bromo-1H-indazole-3-carbaldehyde (13.97 g, 61.9 mmol) in DCM (150 mL) was added p-TsOH (2.36 g, 12.4 mmol) and the mixture was cooled to 0° C. 3,4-Dihydro-2H-pyran (8.47 mL, 92.8 mmol) was added dropwise to the solution and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM (200 mL) and washed with a solution of saturated aqueous sodium hydrogen carbonate (500 mL). The aqueous layer was re-extracted with DCM (500 mL) and the combined organic layers were washed with brine (2×1 L), dried over MgSO4 and concentrated in vacuo to yield a black oil. The crude material was refluxed in cyclohexane (20 mL) and filtered while hot. The filtrate was concentrated in vacuo and the residue was stirred in heptane for 48 hours. The resulting solid was collected by filtration to give the title compound (13.87 g) in a 73% yield.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C=C(C2NC3=NC=CC=C3C=2)C2C=CC(S(C)=[O:40])=CC=2)CCCC1.[Mn]([O-])(=O)(=O)=O.[K+]>CO.O>[CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:16])(=[O:40])=[O:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reactant: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Reaction time: 1.5 h
Yield: 23 %

Procedure:
A solution of the mixture of 2-[2-cyclopentyl-1-(4-methanesulfinyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine and 2-[2-cyclopentyl-1-(4-methanesulfinyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (1.7 g) in methanol (50 mL) at 0° C. was treated dropwise with a solution of potassium permanganate (800 mg, 5.09 mmol) in water (15 mL). The resulting mixture was stirred to 1.5 h. The mixture was then partitioned between water (100 mL) and chloroform (100 mL). The aqueous layer was then extracted with ethyl acetate (2×100 mL). The combined organic layers were then dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. Purification using a Biotage flash chromatography system (40 M column, 50% ethyl acetate/hexanes) afforded 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (420 mg, 23%) as a yellow foam which still contained some impurities. After standing overnight, a white solid had formed and this was then collected by filtration and the solids lightly washed with 10% ethyl acetate/hexanes to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (300 mg) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 9.81 (br s, 1H), 8.18 (dd, J=4.8, 1.5 Hz, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.81-7.90 (m, 1H), 7.48 (d, J=8.2 Hz, 2H), 7.05 (dd, J=7.7, 4.8 Hz, 1H), 6.37 (d, J=1.5 Hz, 1H), 4.25 (t, J=7.9 Hz, 1H), 3.02 (s, 3H), 2.19-2.31 (m, 1H), 2.05-2.17 (m, 1H), 1.61-1.88 (m, 5H), 1.41-1.54 (m, 2H), 1.08-1.24 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH:12](B(OCCCC)OCCCC)=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:3]1[C:2]([CH:12]=[CH2:13])=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: C=CB(OCCCC)OCCCC
Reactant: O=C(O)c1ccnc(Cl)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=Cc1nccc(C(=O)O)c1F
Temperature: 135 °C

Procedure:
A solution of 2-chloro-3-fluoroisonicotinic acid (1.50 g, 8.55 mmol, Matrix), dibutyl vinylboronate (2.82 mL, 12.8 mmol, Aldrich), and potassium carbonate (1.42 g, 10.25 mmol) in N,N-dimethylacetamide (9 mL) and water (3 mL) was degassed by bubbling a stream of nitrogen through the solution for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.59 g, 0.51 mmol) was added and the mixture was similarly degassed for a further 10 minutes. The reaction vessel was sealed and heated in the microwave for 25 minutes at 135° C. The reaction mixture was filtered and purified using preparative HPLC (UV-detection) eluting with a gradient of H2O/MeCN containing 0.1% TFA. This reaction was run again on the same scale and the product of both runs were pooled. Solvent was removed from the eluent containing desired product in vacuo (1.3 g, 46%). 1H NMR (300 MHz, CD3OD): δ 8.45 (d, 1H), 7.69 (dd, 1H), 7.07 (ddd, 1H), 6.44 (dd, 1H), 5.65 (dd, 1H); 19F NMR (282 MHz, CD3OD): δ−129.64 (d, 1F); LCMS (M+H)+: 167.9.
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]=1B(O)O.[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)=[O:17].CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][N:21]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:22]=1)=[O:17]
Reactant: COC(=O)c1c[nH]cn1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cn(-c2ccc3ccccc3c2)cn1
Temperature: 20 °C
Reaction time: 24 h
Yield: 24.3 %

Procedure:
A suspension of 2-naphtylboronic acid (1.4 g, 8 mmol), 1H-imidazole-4-carboxylic acid methyl ester (1.0 g, 8 mmol) and cupric acetate (1.4 g, 8 mmol) in CH2Cl2 (20 ml) was stirred at 20° C. for 24 h. AcOEt (100 ml) and saturated aqueous Seignette salt solution (50 ml) was added and the resulting mixture was stirred for another 2 h. After separation the organic phase was dried (Na2SO4), concentrated and chromatographed (silica, elution with CH2Cl2/MeOH 99:1) to yield the title compound (0.49 g, 24%) of the title compound as a white crystalline material. Mp. 143-144° C. (AcOEt), MS: m/e=252 (M+).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[N+:18]([C:21]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])=[CH:29][C:22]=1[O:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])([O-:20])=[O:19]>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)[C:25](=[O:26])[CH:24]([O:23][C:22]1[CH:29]=[C:30]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[Cl:44])[CH:31]=[CH:32][C:21]=1[N+:18]([O-:20])=[O:19])[CH3:28])[CH:2]=[CH2:3]
Reactant: C=CCNCC1OCCO1
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCN(CC1OCCO1)C(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
N-Allyl-N-(1,3-dioxolan-2-ylmethyl)amine (1.32 grams; 0.0092 mole), dry toluene (70 ml) and triethylamine (3.0 ml) were charged into a glass reaction vessel equipped with a magnetic stirrer, thermometer, gas inlet tube and addition funnel. The mixture was blanketed with nitrogen gas, cooled to 10° C. and a solution of 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride (3.8 grams; 0.0092 mole) in toluene (40 ml) was added dropwise with stirring. After the addition was completed the mixture was allowed to warm to room temperature and stirring was continued for a period of about 1.5 hours. After this time the reaction mixture was transferred to a separatory funnel and was washed with water and with aqueous sodium bicarbonate. The washed solution was dried by passing it through phase separation paper. The dried solution was then chromatographed through a clay column using mixtures of ethyl acetate and hexane as the eluant. Nine fractions were collected. Fraction five was stripped of solvents and thereafter further dried by letting the residue stand under vacuum at 110° C. for a period of four hours to yield the desired product N-allyl-N-(1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionamide as an amber gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCC1CCCCO1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: C1CCOC1
Product: COc1cn(C(CC2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
4.20 g (11.2 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 4.17 g (16.8 mmol) of tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate (racemate) and 11.8 ml (11.8 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 125 ml of THF were reacted according to General Method 7B. Purification by column chromatography (100 g silica cartridge, flow rate: 50 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 2.6 g (49% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:29][C:30]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[S:29][C:30]=3[CH3:31])=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (1.20 g), 4-chloromethyl-5-methyl-2-phenylthiazole (0.95 g), potassium carbonate (1.06 g), and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml), and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (10 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (1.46 g, yield: 81%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 73–74%.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[C:36]([CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[NH:34][CH:33]=[CH:32]2.[Cl-].[NH4+]>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:32]2[C:31]3[C:35](=[C:36]([CH2:38][S:39]([CH3:42])(=[O:40])=[O:41])[CH:37]=[C:29]([F:28])[CH:30]=3)[NH:34][CH:33]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: COc1cc(Cl)ccc1C(O)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)ccc1C(c1c[nH]c2c(CS(C)(=O)=O)cc(F)cc12)C1CC1C#N

Procedure:
104 mg (0.47 mmol) of indium(III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid were added to 93.0 mg (0.39 mmol) of the compound from Example 163A and 121 mg (0.47 mmol) of the compound from Example 87A with a purity of 88% under argon in 5 ml of 1,2-dichloroethane, and the mixture was heated under reflux for 2 h. Addition of the reaction mixture to saturated aqueous ammonium chloride solution was followed by extraction with dichloromethane, drying over magnesium sulfate, filtration and concentration. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 35.0 mg (20% of theory) of diastereomer 1 and 31.3 mg (18% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30](F)[CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:34]5[CH:35]=[C:28]([Br:27])[CH:29]=[CH:30][C:31]=5[C:32]#[N:33])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cc(Br)ccc5C#N)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-bromo-2-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 12.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:26])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:34][C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=[C:37]([CH3:45])[CH:36]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:26])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:34][C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=[C:37]([CH3:45])[CH:36]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: CC(C)(C)ONC(=O)[C@@]1(C)COCC[C@H]1NS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCOC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
The crude (3R,4R)-N-tert-butoxy-4-(4-hydroxyphenylsulfonamido)-3-methyl-tetrahydro-2H-pyran-3-carboxamide (1.76 mmol) from Step 9 was dissolved in DMF (20 mL) and cesium carbonate (2.9 g, 8.80 mmol, 5.0 eq) and 4-chloromethyl-2-methylquinoline (602 mg, 2.64 mmol, 1.5 eq) were added. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate (200 mL) and washed with water (100 mL×3). The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica eluting with 75% ethyl acetate/hexane to yield 0.53 g (56% for three steps) of (3R,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)-tetrahydro-2H-pyran-3-carboxamide as white solid. MS: (M+H)+=542.0
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([NH2:18])=O)=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1.S(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]#[N:18])=[N:15][N:6]3[C:5](=[O:19])[C:4]=2[CH:3]=1
Reactant: Cn1c2ccc(F)cc2c(=O)n2nc(C(N)=O)cc12
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1c2ccc(F)cc2c(=O)n2nc(C#N)cc12
Temperature: 65 °C

Procedure:
A mixture of 9.2 g of 7-fluoro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide, 25 ml of thionyl chloride and 175 ml of dimethylformamide is stirred and heated at 65° C. for 20 hours, then evaporated at reduced pressure. The residue is stirred with 1 liter of ice water and the resulting solid 7-fluoro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]-quinazoline-2-carbonitrile is collected by filtration, washed with water and dried; mp 331°-340° C., after crystallization from dimethylformamide/ethanol.
Reaction SMILES: C(OC(Cl)=O)(C)C.[Cl:8][C:9]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C:13]([OH:15])=O.CN1CCOCC1.[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:35]=[CH:34][C:33]=1[NH2:46]>C1COCC1>[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:35]=[CH:34][C:33]=1[NH:46][C:13](=[O:15])[CH2:12][O:11][C:10]1[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:9]=1[Cl:8]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)c(Cl)c1
Agent: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.141 mL (1.080 mmol) chloroformic acid-isopropylester was added dropwise at −10° C. to a solution of 0.254 g (0.982 mmol) (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 0.119 mL (1.080 mmol) N-methylmorpholine in 20 mL abs. THF and the mixture was stirred for a further 10 min. 0.250 g (1.031 mmol) 2-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z27b) was added, the mixture was stirred for 1 h at RT and then evaporated down i. vac. Water was added and the aqueous phase was exhaustively extracted with dichloromethane. The combined org. phases were dried over sodium sulphate, evaporated down i. vac. and the residue stirred with ether. The precipitate was filtered off, washed with ether and dried in a HV.