Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[C:15]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][CH:36]4[CH2:39][N:38]([CH2:40][CH2:41][F:42])[CH2:37]4)=[CH:31][C:30]=3[O:43][CH3:44])[N:16]=[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.NN.O>[Pd].CO>[NH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:17]1[C:12]2[CH:11]=[CH:10][NH:9][C:13]=2[N:14]=[C:15]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][CH:36]3[CH2:39][N:38]([CH2:40][CH2:41][F:42])[CH2:37]3)=[CH:31][C:30]=2[O:43][CH3:44])[N:16]=1
Reactant: COc1cc(NC2CN(CCF)C2)ccc1Nc1nc(Oc2cccc([N+](=O)[O-])c2)c2ccn(COC(=O)C(C)(C)C)c2n1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(NC2CN(CCF)C2)ccc1Nc1nc(Oc2cccc(N)c2)c2cc[nH]c2n1
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture of (2-(4-(1-(2-fluoroethyl)azetidin-3-ylamino)-2-methoxyphenylamino)-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (530 mg, 0.87 mmol), NH2NH2.H2O (98%, 2.5 mL), Pd/C (110 mg), a magnetite, and MeOH (10 mL) was stirred at reflux temperature overnight. The mixture was cooled to room temperature, and was filtered through diatomaceous earth, washing with MeOH (20 mL). The filtrate was concentrated under reduced pressure. NaHCO3(aq) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were concentrated under reduced pressure. The crude material was purified by column chromatography (DCM/MeOH=40/1 as elution) to give the title compound (125 mg, yield 31%, M+H+=464.2) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:30])[CH2:14][C:15]2[C:16](O)=[C:17]3[C:22](=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:21]2[CH2:27][CH2:28][CH:18]3[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:30][C:16]3[C:17]4[CH:18]5[CH2:19][CH2:20][CH:21]([C:22]=4[C:23]([O:25][CH3:26])=[CH:24][C:15]=3[CH2:14]2)[CH2:27][CH2:28]5)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c(O)c2c1C1CCC2CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(c3c1C1CCC3CC1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 75.1 %

Procedure:
Treatment of (±)-2-hydroxy-3-(5-hydroxy-8-methoxy-1,2,3,4-tetrahydro-1,4-ethanonaphthalen-6-yl)propyl 4-methylbenzenesulfonate (15.14 g, 35.0 mmol) with triphenylphosphine (10.10 g, 38.5 mmol) followed by diethylazodicarboxylate (6.71 g, 38.5 mmol) generally according to the procedure described for Intermediate 5 afforded 10.9 g (75%) of (±)-(5-methoxy-2,3,6,7,8,9-hexahydro-6,9-ethanonaphtho[1,2-b]furan-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 136-141° C.; Anal. calcd. for C23H26O5S: C, 66.64; H, 6.32. Found: C, 66.53; H, 6.51.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[F:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[O:25][CH2:26][CH2:27]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:27][CH2:26][O:25][C:24]2[CH:29]=[CH:30][CH:31]=[C:22]([F:21])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1cccc(F)c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2cccc(F)c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylforrnamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(3-fluorophenoxy)ethanol (1.17 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The dichloromethane extract was evaporated and the residue was purified by HPLC (dichloromethane-hexane; 4: 1) and the resulting solids were crystallized from diethyl etherhexane to give 0.84 g of 4-[[2-(3-fluorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 68°-69° C.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.[CH:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([CH:32]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole, prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.2 mL, 0.315 mmol) dropwise. The resulting mixture was stirred at −78° C. for 30 min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF (0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction was quenched with saturated NH4Cl (aq) and diluted with EtOAc (10 mL) and H2O (3 mL). The phases were separated and the aqueous was extracted 2×10 mL EtOAc. The pooled EtOAc was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 4:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanol (68 mg, 50% yield). Rf sm=0.72; Rf p=0.39 (7:3 hexane:EtOAc); FTIR (thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835 cm−1. MS (ESI) [M+H]/z Calc'd 457. found 457.
Reaction SMILES: C([Si](C)(C)[C:6]1[N:10]([CH3:11])[C:9]([C:12]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)([OH:40])[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH:17]=[C:16]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[C:35][Si](C)(C)C)[CH:29]=2)=[CH:8][N:7]=1)(C)(C)C.O>C1COCC1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:12]([OH:40])([C:9]2[N:10]([CH3:11])[CH:6]=[N:7][CH:8]=2)[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:18](=[O:27])[CH:17]=[C:16]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=2)=[CH:42][CH:43]=1
Reactant: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(C#C[Si](C)(C)C)c2)cc(=O)n3CC2CC2)cnc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccc(-c2cc(=O)n(CC3CC3)c3ccc(C(O)(c4ccc(Cl)cc4)c4cncn4C)cc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
A solution of 6-[[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (4.50 g crude) in THF (100 mL) was treated with tetrabutylammonium chloride (1 M in THF, 10.0 mmol). The reaction mixture was stirred at room temperature for 12 hours, poured into H2O (200 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 1N HCl (100 mL), aqueous NaHCO3 (100 mL), and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a light green foam. Purification by flash column chromatography (silica, EtOAc:pet. ether:NH4OH 1:1:0.01) gave 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one (1.82 g, 51%) as a yellow powder.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[S:16][C:15]3[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10][C:9]=3[C:8]=2[CH:22]=1>CCO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[S:16][C:15]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[C:8]=2[CH:22]=1
Reactant: CCOC(=O)N1CCc2sc3ccc(Br)cc3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccc2sc3c(c2c1)CCNCC3

Procedure:
30.0 g (53.5 mmol) KOH in 700 mL EtOH are added to a solution of 19.0 g (53.5 mmol) ethyl 3-bromo-5,6,8,9-tetrahydro-10-thia-7-aza-benzo[a]azulen-7-carboxylate. EtOH is distilled off at normal pressure and the residue is taken up in water. The solution is acidified with HCl. Then it is made basic with NaOH and the aqueous phase is extracted four times with chloroform. The organic phase is dried over Na2SO4 and K2CO3 and the solvent is eliminated i.vac. The purification is carried out by repeated column chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:30])#[N:25]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccc(C#N)c4)nc3cc21

Procedure:
3-Cyano-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3-cyano-benzoyl chloride (146 mg, 0.89 mmol). The title compound was obtained as light brown powder (90 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:22][CH3:23])[C:9]3[C:14]([Br:15])=[CH:13][N:12]=[C:11]([CH2:16][O:17]C(=O)C)[C:10]=3[N:21]=2)=[N:4][O:5][N:6]=1.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:22][CH3:23])[C:9]3[C:14]([Br:15])=[CH:13][N:12]=[C:11]([CH2:16][OH:17])[C:10]=3[N:21]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2c(COC(C)=O)ncc(Br)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(-c2nonc2N)nc2c(CO)ncc(Br)c21
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a suspension of the product of step 2 (312 mg, 0.74 mmol) in methanol (10 ml) was added a 2M aqueous solution of sodium hydroxide (1.1 ml, 2.21 mmol) and the reaction heated at reflux for 1 hour. The reaction was then diluted with water (20 ml) and aged at room temperature for 2 hours. The resulting precipitate was collected, washed with water and dried in vacuo at 45° C. for 16 hours to afford the title compound (220 mg, 88%); MS (ES+), m/e 339/341 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2=[C:7]([CH:21]=1)[O:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1/[C:12]/2=[C:13](\[CH3:16])/[C:14]#[N:15].[CH3:22][C:23]1[NH:33][C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1.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>C1COCC1>[CH3:22][C:23]1[N:33]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]3=[C:7]([CH:21]=2)[O:8][CH2:9][C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2/[C:12]/3=[C:13](\[CH3:16])/[C:14]#[N:15])[C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1
Reactant: Cc1cc(C)c2nc(C)[nH]c2n1
Reactant: C/C(C#N)=C1\c2ccccc2COc2cc(CO)ccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C/C(C#N)=C1\c2ccccc2COc2cc(Cn3c(C)nc4c(C)cc(C)nc43)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
[step 1] (Z)-2-(3-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (400 mg, 1.44 mmol) obtained in Reference Example B6 and 2,5,7-trimethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 349 mg, 2.16 mmol) were dissolved in THF (14 mL), polymer-supported triphenylphosphine (962 mg, 2.88 mmol) and di-tert-butyl azodicarboxylate (664 mg, 2.88 mmol) were added at 0° C., and the mixture was stirred at room temperature for 2 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/6) to give (Z)-2-[3-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (310 mg, 51%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: CSc1ccccc1B(O)O
Product: CSc1ccccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 272 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2-(methylthio)phenylboronic acid. colorless crystals (yield 39%). MS (APCI−): 377 (M−H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[S:17][C:16]([CH:18]=[CH:19][CH2:20][OH:21])=[CH:15][CH:14]=1>ClCCl>[O:9]1[CH:18]([C:16]2[S:17][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:19]1[CH2:20][OH:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCC=Cc1ccc(Cl)s1
Solvent: ClCCl
Product: OCC1OC1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.75 g of m-chloroperbenzoic acid is added to a stirred solution of 0.6 g of 3-(5-chlorothiophen-2-yl)-prop-2-enol according to c) in 50 ml of dichloromethane. The solution is stirred at room temperature for 5 hours, washed with 10% sodium carbonate solution, dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ether and the title compound is obtained in the form of a light-yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]N.C(Cl)(Cl)Cl.CO>CO>[C:11]1([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:6]2[C:5](=[O:19])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)CCn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Reaction time: 14 h

Procedure:
To a suspension of 1.542 g of 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-4-pyridone in 10 ml of methanol is added 4.408 g of N,N-dimethylethylenediamine, and the mixture is stirred for 14 hours. The reaction mixture is condensed under reduced pressure, and subjected to flash column chromatography on 50 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (10:1) to perform separation and purification. The title compound is obtained as colorless crystal in a yield of 1.174 g.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[CH3:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][CH:16]([C:21]([CH3:23])=O)[C:17](OC)=[O:18])=[CH:13][CH:12]=1.O>CO>[CH3:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][C:16]2[C:17](=[O:18])[NH:4][C:2]([CH3:3])=[N:5][C:21]=2[CH3:23])=[CH:13][CH:12]=1
Reactant: CC(=N)N
Reactant: COC(=O)C(Cc1ccc(OC)cc1)C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Cc2c(C)nc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of methyl acetoacetate (3.2 mL) 4-methoxy-benzyl chloride (4.1 mL), lithium bromide (2.6 g) and diisopropylethylamine (5.2 mL) in tetrahydrofuran (60 mL) was heated under reflux for 15 hours. After the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give methyl 2-(4-methoxybenzyl)acetoacetate. To a suspension of acetoamidine hydrochloride (2.0 g) in methanol (60 mL) was added sodium methoxide (28% solution in methanol, 2.6 mL), and the mixture was stirred for 5 minutes at room temperature. To the reaction mixture was added a solution of methyl 2-(4-methoxy-benzyl)acetoacetate in methanol (6 mL), and the mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue was added ethyl acetate, and the resulting precipitated crystals were collected by filtration and dried to give 5-(4-methoxybenzyl)-2,6-dimethyl-3H-pyrimidin-4-one (0.54 g).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22](O)=[O:23])=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1.Cl.[F:28][CH:29]1[CH2:32][NH:31][CH2:30]1>>[F:1][CH2:2][CH2:3][N:4]([CH3:26])[C:5]1[N:25]=[C:8]2[CH:9]=[C:10]([NH:13][C:14]([C:16]3[N:20]([CH3:21])[N:19]=[CH:18][C:17]=3[C:22]([N:31]3[CH2:32][CH:29]([F:28])[CH2:30]3)=[O:23])=[O:15])[CH:11]=[CH:12][N:7]2[N:6]=1
Reactant: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: FC1CNC1
Agent: Cl
Product: CN(CCF)c1nc2cc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)ccn2n1
Yield: 84.7 %

Procedure:
The product was prepared in the same manner as described in example 70f using 5-(2-((2-fluoroethyl)(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (100 mg, 277 μmol) and 3-fluoroazetidine hydrochloride (92.6 mg, 830 μmol) as starting materials. The reaction affords 4-(3-fluoro-azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid {2-[(2-fluoro-ethyl)-methyl-amino]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide (98.2 mg, 84.8%) as white solid. mp: 233-236° C., MS: m/z=419.0 (M+H+).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:29])[CH:19]=[CH:20]2)[C@@H:15]([CH3:30])[CH2:14]3)[CH2:11][CH2:10]1)[C:6](=[O:9])[CH2:7][O:8][C:31](=[O:33])[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A solution of 1.0 g of 17-acetoxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione in 10 ml of pyridine is stirred with 5 ml of acetic anhydride for one hour at 0° C. Then the mixture is poured on an ice water-sodium chloride solution; the precipitate is filtered off and purified by crystallization from acetone/hexane, thus isolating 810 mg of 17,21-diacetoxy-11β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 216° C.
Reaction SMILES: [Cl:1][C:2]1[S:21][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[C:4]=2[CH:3]=1.[C:22]([NH:25][NH2:26])(=O)[CH3:23]>C(O)CCC>[Cl:1][C:2]1[S:21][C:5]2[N:6]3[C:22]([CH3:23])=[N:25][N:26]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1C1=NCC(=S)Nc2sc(Cl)cc21
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1[N+](=O)[O-])=NC2

Procedure:
0.2 g of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione are heated to reflux for 5 hours under a nitrogen atmosphere with 0.2 g of acetic acid hydrazide in 30 ml of n-butanol. After evaporation of the solvent, the product is taken up in methylene chloride and extracted several times with 1-N hydrochloric acid, the organic phase being treated portionwise with ether such that it comes to the surface in the separating funnel. After neutralization of the aqueous phase with sodium bicarbonate, the mixture is extracted with methylene chloride, the solvent evaporated after drying over sodium sulphate and the residue made into a paste with ethyl acetate. The resulting crystals are recrystallized from ethyl acetate containing active carbon to give colorless crystals of 2-chloro-9-methyl-4-(o-nitrophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine, melting point 210°-212° C.
Reaction SMILES: C(OC([N:11]([CH2:19][CH2:20][CH2:21][N:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([CH3:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][C:26]=2[O:25][CH2:24][C:23]1=[O:46])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-])=O)C1C=CC=CC=1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][CH2:19][CH2:20][CH2:21][N:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([CH3:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][C:26]=2[O:25][CH2:24][C:23]1=[O:46]
Reactant: CCOC(=O)CC(C)(c1ccccc1)c1ccc2c(c1)OCC(=O)N2CCCN(C(=O)OCc1ccccc1)c1cccc[n+]1[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(c1ccccc1)c1ccc2c(c1)OCC(=O)N2CCCNc1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of titanium (IV) chloride in tetrahydrofuran under nitrogen atmosphere, is added an equimolar amount of stannous chloride dihydrate, and the mixture is stirred 1 hour at room temperature. Then, a solution of ethyl 3-[(4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)]-3-phenylbutanoate is added and the mixture heated 3 hours at 40° C. After evaporation of the solvent, ice and aqueous sodium bicarbonate are added, the mixture extracted with ethyl acetate, and the organic layers are combined and dried over sodium sulfate. The solvent is evaporated, the residue is dissolved in ethanol, 10% Pd/C is added and the compound hydrogenated in a Parr apparatus. The solvent is then evaporated and the product is isolated by column chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[CH3:47][S:48]([C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)(=[O:50])=[O:49]>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:38]=[C:2]([C:54]3[CH:55]=[CH:56][C:51]([S:48]([CH3:47])(=[O:50])=[O:49])=[CH:52][CH:53]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Product: CS(=O)(=O)c1ccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 88.8 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-methanesulfonyl-phenyl boronic acid (0.141 mg, 0.69 mmol) by following general procedure D yielding the title compound (102 mg, 87%) as a light yellow solid.