Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH2:29])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([Si:34]([CH3:40])([CH3:39])[O:35][CH2:36][CH:37]=O)([CH3:33])([CH3:32])[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:37][CH2:36][O:35][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:40])[CH3:39])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Product: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO[Si](C)(C)C(C)(C)C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1

Procedure:
3-Amino-5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-1-carboxylic acid tert-butyl ester (16.1 g, 41.23 mmol), from Synthetic Example 18, was reacted with (tert-butyl-dimethyl-silanyloxy)-acetaldehyde (CAS 102191-92-4, obtained from Aldrich, 10.06 g, 58 mmol), according to the procedure detailed in Synthetic Example 19. The crude 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-indazole-1-carboxylic acid tert-butyl ester thus obtained was used without further purification in the next step.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].Cl[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([CH:26]=[CH2:27])=[CH:21][N:20]=1>COCCOC.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>[Cl:25][C:24]1[C:19]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:20][CH:21]=[C:22]([CH:26]=[CH2:27])[CH:23]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: C=Cc1cnc(Cl)c(Cl)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1cnc(-c2ccc(C=O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
4.1 g of Na2CO3 (39 mmol), 2.0 g of 4-formylphenylboronic acid (13 mmol), and 0.45 g of Pd(PPh3)4 were added to 2.5 g of compound (8) (14.9 mmol) prepared in Example 5 dissolved in 50 mL of 1,2-dimethoxyethane and 50 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: ethyl acetate/hexane=1/4) to obtain 3.0 g 4-(3-chloro-5-vinylpyridin-2-yl)benzaldehyde (yield 82%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:23][CH2:24][C:25](=[O:27])[CH3:26])[C:16](=[O:17])[N:15]([CH3:18])[C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=3[S:12]2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>O1CCCC1>[C:25]([CH2:24][NH:23][C:11]1([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[C:16](=[O:17])[N:15]([CH3:18])[C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[S:12]1)(=[O:27])[CH3:26]
Reactant: CC(=O)CNC1(c2ccc(OC(C)=O)cc2)Sc2ccccc2N(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)CNC1(c2ccc(O)cc2)Sc2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a stirred suspension of 2-(4-acetoxyphenyl)-2-(N-acetylmethylamino)-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine (3.2 g, compound No. 70) in tetrahydrofuran (20 ml), a mixture of 2N sodium hydroxide (20.8 ml) and tetrahydrofuran (20 ml) is added. The mixture is stirred for 20 minutes at room temperature and poured into 2N hydrochloric acid. The separated crystals are collected by filtration to give 2.6 g (91.6%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][CH:8]=[C:9]([C:15]([O:17]CC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[OH-].[Na+]>O>[OH:17][C:15]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:5]2[N:4]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:3]=[C:2]([CH3:1])[C:6]=12
Reactant: CCOC(=O)C(=CNc1cc(C)nn1-c1ccccn1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
A solution of diethyl 2-([[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]methylene)malonate (2.0 g, 5.8 mmol) in polyphosphoric acid (10 g) was heated and stirred at 100° C. for 2 hours. The solution was cooled to room temperature, and iced water was added thereto. The solution was neutralized by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with 10% methanol/chloroform. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (chloroform) gave the title compound (0.98 g, 57% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>C1COCC1>[Si:14]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15]
Reactant: OCc1ccc(Cl)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
A solution of (6-chloropyridin-3-yl)methanol (800 mg, 5.6 mmol) and TBSCl (1000 mg, 6.7 mmol) in THF (15 mL) was added imidazole (455 mg, 6.7 mmol) and the reaction mixture was stirred at rt for 24 h. The mixture was concentrated under vacuum to about ¼ of the original volume and then diluted with EtOAc (30 mL). The resulting mixture was washed with water, aqueous 5% KH2PO4 (30 mL), saturated NaHCO3 (20 mL) and brine (20 mL) sequentially. The organic phase was dried, filtered and concentrated to give the desired product as colorless oil (800 mg, 54%). [LCMS: RtA=1.89 min, m/z 258.2 [M+H]+].
Reaction SMILES: [CH3:1][N:2](C)C=O.Br[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([F:17])=[CH:9][N:8]=1>[C-]#N.[Zn+2].[C-]#N.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.O>[F:17][C:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]([C:1]#[N:2])=[N:8][CH:9]=1
Reactant: Fc1cnc(Br)cc1C(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c(F)cn1
Temperature: 95 °C
Reaction time: 14 h

Procedure:
To 12 ml of N,N-dimethylformamide were added 0.8 g of 2-bromo-5-fluoro-4-trifluoromethylpyridine, 1.41 g of zinc cyanide and 0.28 g of tetrakistriphenylphosphinepalladium, and the mixture was stirred at 95° C. for 14 hours. After allowing to cool, the reaction solution was poured into water, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.5 g of 5-fluoro-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20](O)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.NC1C=C(C(C)C)C(OS(=O)(=O)NC(=O)CC2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)=C(C(C)C)C=1.[NH2:59][CH:60]=[C:61]1[CH:66]=[C:65]([CH:67]([CH3:69])[CH3:68])[C:64]([O:70][S:71](=[O:92])(=[O:91])[NH:72][C:73](=[O:90])[CH2:74][C:75]2[C:80]([CH:81]([CH3:83])[CH3:82])=[CH:79][C:78]([CH:84]([CH3:86])[CH3:85])=[CH:77][C:76]=2[CH:87]([CH3:89])[CH3:88])=[C:63]([CH:93]([CH3:95])[CH3:94])[CH2:62]1>N1CCCCC1.CN(C)C=O>[NH2:18][CH2:19][C:20]([NH:59][CH2:60][C:61]1[CH:62]=[C:63]([CH:93]([CH3:95])[CH3:94])[C:64]([O:70][S:71](=[O:91])(=[O:92])[NH:72][C:73](=[O:90])[CH2:74][C:75]2[C:76]([CH:87]([CH3:89])[CH3:88])=[CH:77][C:78]([CH:84]([CH3:85])[CH3:86])=[CH:79][C:80]=2[CH:81]([CH3:82])[CH3:83])=[C:65]([CH:67]([CH3:68])[CH3:69])[CH:66]=1)=[O:21]
Reactant: CC(C)C1=CC(=CN)CC(C(C)C)=C1OS(=O)(=O)NC(=O)Cc1c(C(C)C)cc(C(C)C)cc1C(C)C
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(N)cc2C(C)C)c(C(C)C)c1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(CNC(=O)CN)cc2C(C)C)c(C(C)C)c1

Procedure:
When in the procedure of Example 1, bis-N,N'-(t-butoxycarbonyl)-(S)-lysine is replaced with N-(9-fluorenylmethyoxycarbonyl)-glycine, [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-amino-2,6-diisopropyl-phenyl ester is replaced by [(2,4,6-triisopropyl-phenyl)-acetyl]-sulfamic acid 4-(aminomethylene)-2,6-diisopropyl-phenyl ester, and the crude product is stirred in 20% piperidine/N,N-dimethylformamide for 0.5 hours followed by trituration with hexanes, the title compound is obtained; mp 193-195° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([Si:15]([CH3:42])([CH3:41])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:26]([C:34]3([CH:37]([OH:40])[CH2:38][CH3:39])[CH2:36][CH2:35]3)[O:25][N:24]=2)=[CH:19][CH:18]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([Si:15]([CH3:42])([CH3:41])[O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:26]([C:34]3([C:37](=[O:40])[CH2:38][CH3:39])[CH2:36][CH2:35]3)[O:25][N:24]=2)=[CH:21][CH:22]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CCC(O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 96.2 %

Procedure:
To a stirring solution consisting of oxalyl chloride (5.0 mL) in dichloromethane (115 mL) at −78° C. is added dropwise a solution consisting of dimethyl sulfoxide (8.2 mL) in dichloromethane (25 mL) over ten minutes. The mixture is stirred at −78° C. for 40 minutes and a solution consisting of (±)-1-(1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-propan-1-ol (synthetic intermediate prepared in Example 47, 18.70 g) in dichloromethane (150 mL) is subsequently added dropwise over one hour. The mixture is stirred at −78° C. for an additional 30 minutes and excess triethylamine is subsequently added dropwise. The stirring mixture is allowed to warm gradually to room temperature overnight. The stirring mixture is treated with water. The layers are separated and the aqueous layer is extracted with a fresh portion of dichloromethane. The combined organic extracts are washed with brine solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with hexanes-ethyl acetate (17:3 v/v) afforded the synthetic intermediate 1-(1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-propan-1-one (17.90 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[OH:25][CH:26]([P:28](=[O:33])([O:31][CH3:32])[O:29][CH3:30])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[O:25][CH:26]([P:28](=[O:33])([O:31][CH3:32])[O:29][CH3:30])[CH3:27])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: COP(=O)(OC)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COP(=O)(OC)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (600 mg), dimethyl α-hydroxyethylphosphonate (382 mg), potassium carbonate (343 mg) and 2-butanone (8 ml) is heated under reflux for 24 hours. The reaction mixture is filtered, and the filtrate is concentrated and purified by prep. TLC to give dimethyl α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphonate.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](Br)=[C:11]([C:14]#[N:15])[N:10]([CH3:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.[F-:18].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([F:18])=[C:11]([C:14]#[N:15])[N:10]([CH3:16])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: Cn1c(C#N)c(Br)n(-c2ccc(Cl)cc2)c1=O
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(C#N)c(F)n(-c2ccc(Cl)cc2)c1=O

Procedure:
A solution of the product of Example 66, 1-(4-chlorophenyl)-5-bromo-4-cyano-3-methyl-1,3-dihydro-2H-imidazol-2-one (0.4 g, 1.3 mmol) and potassium fluoride (0.14 g, 2.66 mmol) in 100 mL of dry dimethyl sulfoxide was heated to 130° C. for two hours, then cooled and poured into 100 mL of water. The product was extracted into ethyl acetate, washed with saturated brine solution, dried, and concentrated to an oil. The oil was chromatographed through silica gel (25:75 ethyl acetate:petroleum ether). Collection of the appropriate fractions furnished 0.14 g of 1-(4-chlorophenyl)-4-cyano-5-fluoro-3-methyl-1,3-dihydro-2H-imidazol-2-one (m.p. 105° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:27][CH:28]=1
Reactant: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)nc1
Temperature: 70 °C
Yield: 78.7 %

Procedure:
To a solution of ethyl (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (2.16 g) in MeOH (30 mL) and dioxane (30 mL) was added 1N NaOH aq solution (27.1 mL). The mixture was heated at 70° C. for 1.5 hour and diluted with water (120 mL) and washed with ether. The pH value of aqueous phase was adjusted to 5.5, and the precipitate was collected by filtration and dried in vacuo to give (2E)-3-(6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylic acid (1.58 g) as pale yellow powder.
Reaction SMILES: N1CCC(CCCC(N(CC)CC(N[C@H](C([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=O)CC(=O)O)=O)=O)CC1.[CH:38]1(C[C@@H](C(O)=O)N)CCCCC1>CO.Cl>[CH3:38][O:35][C:33](=[O:34])[C@H:25]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[NH2:24]
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CCN(CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1CCCCC1)C(=O)O)C(=O)CCCC1CCNCC1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CC1CCCCC1

Procedure:
N-[N-[N-(4-(piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-β-cyclohexylalanine ##STR6##A. β-cyclohexylalanine (1.12 g) is dissolved in of methanol (50 ml) and hydrogen chloride gas is bubbled through the solution for about 15 minutes. The solution is evaporated in vacuo and toluene azeotroped from the residue to give β-cyclohexyl-L-alanine methyl ester as the hydrochloride salt.
Reaction SMILES: CO.[Li+].[BH4-].[CH3:5][O:6][C:7]1[CH:43]=[CH:42][C:10]([CH2:11][O:12][CH2:13][C@H:14]([CH3:41])[C@H:15]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C@@H:16]([CH3:32])[C:17](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:18])=[CH:9][CH:8]=1.[OH-].[Na+]>C1COCC1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][O:12][CH2:13][C@H:14]([CH3:41])[C@H:15]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[C@@H:16]([CH3:32])[CH2:17][OH:18])=[CH:42][CH:43]=1
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Dry MeOH (1.05 mL, 26.0 mmol) then LiBH4 (13 mL, 2.0 M solution in THF, 26 mmol) were added to a stirred solution of 20 (4.79 g, 8.62 mmol) in THF (75 mL) at 0° C. The resulting mixture was stirred at 0° C. for 45 min and at room temperature for 1 h. The solution was cooled to 0° C. and treated carefully with a 1.0 M aqueous NaOH (50 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc 7:3) to give the alcohol 21 (2.98 g, 90%) as a colorless oil: IR (film) 3425, 1613, 1513, 1463, 1249, 1091, 1037 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 4.47 (d, J=11.7 Hz, 1H), 4.40 (d, J=11.7 Hz, 1H), 3.84 (s, 3H), 3.75 (dd, J=5.7, 2.9 Hz, 1H), 3.52 (m, 3H), 3.28 (dd, J=9.1, 7.1 Hz, 1H), 2.10 (br, 1H), 2.05 (m, 1H), 1.93-1.81 (m, 1H), 0.97 (d, J=7.0 Hz, 3H), 0.90 (s, 9H), 0.87 (d, J=7.1 Hz, 3H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 130.7, 129.3, 113.8, 74.8, 72.8, 72.7, 66.3, 55.4, 39.0, 37.7, 26.2, 18.4, 15.2, 12.0, −4.1; HRMS (ESI) calcd for C18H31O3SiNa 323.2042 [M+Na]+, found 323.2035; [α]20D−0.76 (c 2.9, CHCl3).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:10](Cl)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[C:13]1([S:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH:5]1([C:10]([C:16]2[CH:17]=[CH:18][C:13]([S:19][CH3:20])=[CH:14][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a suspension of anhydrous aluminum chloride (9.3 g, 69.6 mmol) in 58 mL CHCl3 at 0° C. was added dropwise cyclopentanecarbonyl chloride (10.0 g, 75.4 mmol), followed by thioanisole (7.21 g, 58.0 mmol). The ice bath was removed and the mixture was stirred at room temperature for 2 h. Water (200 ml) was added with cooling, the layers were separated and the aqueous layer was extracted with CHCl3 (3×50 mL). The combined aqueous layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (4% EtOAc/hexane) to give 11.9 g of the title ketone (93%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12](=[O:18])[C:13]([C:15](O)=[O:16])=[CH:14][N:8]3[N:7]([CH3:19])[CH2:6][CH2:5]2)[CH:11]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>O1CCCC1.CCOCC>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:15]([C:13]2[C:12](=[O:18])[C:10]3[CH:11]=[C:2]([I:1])[CH:3]=[C:4]4[C:9]=3[N:8]([CH:14]=2)[N:7]([CH3:19])[CH2:6][CH2:5]4)=[O:16])=[CH:35][CH:34]=1
Reactant: CN1CCc2cc(I)cc3c(=O)c(C(=O)O)cn1c23
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCc2cc(I)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C

Procedure:
A solution of 5-Iodo-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxylic acid (Preparation 39, 0.900 g) in tetrahydrofuran (25 mL) is refluxed with 1,1′-carbonyldiimidazole (0.631 g) for 5 h. The reaction mixture is cooled to room temperature and treated with 4-chlorobenzylamine (0.828 g). The reaction mixture is diluted with ether (75 mL), filtered, and the filtrate is concentrated at reduced pressure. The crude product is purified by chromatography, using 75 g of silica gel packed and eluted with EtOAc-CH2Cl2-heptane (1:4:5), to afford the title compound. Physical characteristics: 1H NMR (CDCl3) δ8.91, 8.70, 7.87, 7.32, 4.65, 3.51, 3.13, 2.90; MS (ESI+) m/z 494.0; HRMS (FAB) m/z 494.0142 (C20H17ClIN3O2+H); TLC (silica gel GF): Rf=0.27 EtOAc/CH2Cl2 (1/6).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21](SC)[N:20]=[C:19]2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=1)(=[O:4])=[O:3]>C(O)C.[Ni]>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]=[C:19]2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=1)(=[O:3])=[O:4]
Reactant: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: [Ni]
Solvent: CCO
Product: CCCCc1ncc(C(=O)OCC)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Yield: 90.5 %

Procedure:
244 mg of ethyl 1-[[2′-(aminosulfonyl)(1,1′-biphenyl)-4-yl]methyl]-2-butyl-4-(methylthio)-1-H-imidazole-5-carboxylate (J. Med. Chem. 1995, 38, 2357) are dissolved in 10 ml of ethanol and 200 mg of Raney nickel are added. The mixture is then refluxed for 6 h, a further 200 mg of Raney nickel are added and it is again refluxed for 3 h. The residue is filtered off and the solvent is removed in vacuo. 200 mg of a colorless oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnn2-c2ccc(Cl)nn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(-n2ncc3c2CCNC3)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 1-(6-chloropyridazin-3-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.14 g, 6.4 mmol) in dioxane (20 ml) is added 4N HCl in dioxane (20 mL, 80 mmol), and the mixture is stirred at rt overnight. The solvent is removed and the residue is washed with ether to give the title compound as a white solid. MS (M+1): 236.1.