Azzindani/Open_Reaction_Data huggingface dataset:
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].[Br:15]Br.C(OCC)C>C(O)(=O)C>[Br:15][CH2:2][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]
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)COc1ccc(C(=O)CBr)cc1
Reaction time: 48 h
Yield: 46 %

Procedure:
2-(4-acetylphenoxy)acetic acid (2.81 g, 14.5 mmol) was dissolved in acetic acid (100 mL) and treated with bromine (740 μL, 14.5 mmol) and stirred 48 hours. Bromine (370 mL, 7.25 mmol) was added and solution was stirred for an additional 16 hours. Volatiles were removed under reduced pressure to provide a brown solid which was titurated with diethyl ether to provide 2-(4-(2-bromoacetyl)phenoxy)acetic acid (1.82 g) as a light brown solid.
Reaction SMILES: [OH:1][CH:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].CCOCC.CO>CC(C)=O>[O:1]=[C:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCCCCCCCCCCCC(O)CC#CCCCC(=O)O
Solvent: CCOCC
Solvent: CO
Solvent: CC(C)=O
Product: CCCCCCCCCCCCC(=O)CC#CCCCC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 4.22 g of 8-hydroxy-5-eicosynoic acid, the product of Example 1d, in 200 ml of acetone with vigorous stirring at 5° was added 5.5 ml of Jone's reagent (2.67M). The reaction mixture was stirred for 30 min and then 700 ml of Et2O and 2 ml of MeOH was added and stirred for additional 3 min. The resulting reaction mixture was washed with H2O, saturated NaCl solution and dried over MgSO4. The crude product after removal of solvent was recrystallized in cyclohexane to yield the title compound, mp 79°-80.5°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:16]1[CH:36]=[CH:35][C:19]([O:20][C@@H:21]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1>C(COC)OC.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>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:16]1[CH:36]=[CH:35][C:19]([O:20][C@@H:21]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccco1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)Oc1ccc(Br)cc1
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: CCOC(=O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 120.6 %

Procedure:
0.024 mmol of tetrakis(triphenylphosphine)palladium, 12.3 mmol of 2-furanboronic acid and 7.5 ml of 2 M sodium carbonate solution are added to a solution of 6.15 mmol of ethyl (2S)-2-(4-bromophenoxy)-4-phenylbutanoate in 25 ml of dimethoxyethane. The mixture is refluxed for 2 hours. After cooling to room temperature, the mixture is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate (Na2SO4) and then evaporated to dryness under vacuum. 2.6 g of a brown oil are obtained. This oil is chromatographed with a 9/1 heptane/ethyl acetate mixture as eluent. 1.5 g of an oil that crystallizes are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH:59][C:8](=[O:10])[CH2:7][CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[S:56][C:46]=2[C:47]([N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[N:48][CH:49]=1
Reactant: O=C(O)CC1CCOCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)CC3CCOCC3)nc12

Procedure:
From tetrahydropyran-4-yl-acetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 393 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.C(O)(=O)C.[O-]S(S([O-])=O)=O.[Na+].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[NH2:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a suspension of 6-chloro-3-nitro-pyridine-2-carbonitrile (5.5 g, 30 mmol) in water (100 ml), was added acetic acid (5.4 ml, 90 mmol). The mixture was stirred at room temperature for 20 minutes. Then, Na2S2O4 (20 g, 86%, 90 mmol) was added slowly. The reaction mixture was stirred at room temperature for another 2 hours. The precipitate was filtered off and washed with cold water (2×10 ml). The precipitate was dried over P2O5 yielding the title compound as a yellowish solid (3.7 g, yield: 80%) which was characterised as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(O)(=O)C>CC(O)C>[C:13]([C@@:10]1([CH2:15][CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:27][CH:28]=3)[N:7]=2)[C:9]1=[O:17])#[N:14]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: CNC(=O)c1ccc(N)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C(=O)NC)cc3)n2)C1=O
Yield: 41.8 %

Procedure:
A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (51 mg), 4-amino-N-methylbenzamide (32 mg) and acetic acid (12 μL) in 2-propanol (1 mL) was stirred in a microwave reactor at 150° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (31 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[O:5][CH2:6][C:7]#[N:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:2]([NH:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH:3]=1)#[N:8]
Reactant: Cc1ccc(OCC#N)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(OCC#N)cc1NS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
(3-Amino-4-methylphenoxy)-acetonitrile (2.6 g) was dissolved in 10 ml of pyridine, cooled in an ice bath; 2.29 g of methanesulfonyl chloride was added; and the reaction mixture was stirred at 5° C. for 1 hour. The mixture was poured into ethyl acetate, washed with hydrochloric acid, then water, dried, and evaporated giving 3.5 g of N-(5-cyanomethoxy-2-methylphenyl)-methanesulfonamide. ##STR76##
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([C@H:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C@:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]2)=[O:14])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:18]2([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:40])[CH3:41])[NH:16][C@@H:15]([C:13]([NH:12][CH2:11][CH:8]3[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]3)=[O:14])[C@@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])=[C:31]([F:37])[CH:32]=1
Reactant: COC(=O)C1CCC(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCC2CCC(C(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.2 %

Procedure:
To a solution of rac 4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester (54.3 mg, 0.0875 mmol, example XC-1) in THF (5 mL) was added a solution of LiOH (27.8 mg, 0.662 mmol, Aldrich) in water (2.5 mL) and the reaction mixture was stirred at rt for 22 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 6), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid (52.1 mg, 98%). HRMS (ES+) m/z Calcd C31H35Cl2F2N3O3+H [(M+H): 606.2097. Found: 606.2097.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23]OS(C)(=O)=O)[CH2:10][C:11]([N:13]([CH3:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:29]1([C:35]2(O)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:42]([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]([CH3:21])[C:11](=[O:12])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH2:23][N:38]2[CH2:37][CH2:36][CH:35]([CH2:29][C:34]3[CH:42]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:40][CH2:39]2)=[CH:15][CH:16]=1
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)CC(CCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 29.9 %

Procedure:
3,4-Dichloro-beta-(2-methanesulfonyloxyethyl)-N-methyl-N-(4-chlorophenyl)benzene propanamide (1.6 g) in DMF (10 mL) was treated with 4-phenyl-4-hydroxypiperidine (1.14 g) and K2CO3 (0.476 g). The mixture was heated at 60° C. for 18 hours. The cooled reaction mixture was diluted the EtOAc (100 mL) and washed with H2O (2×100 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 95:5 (CH2Cl2 :MeOH) gave the title compound (0.56 g). M.p. 67°-72°, Mass spectrum (CI): 543.
Reaction SMILES: [P:1]([O:32]C1C=CC(C(C)(C)C)=CC=1C(C)(C)C)([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:19]=1[C:28]([CH3:31])([CH3:30])[CH3:29])[O:2]C1C=CC(C(C)(C)C)=CC=1C(C)(C)C.CC(C1C=C(C(C)(C)C)C2[O:55][P:56](OCCN(CCOP3OC4C(C(C)(C)C)=CC(C(C)(C)C)=CC=4C4C=C(C(C)(C)C)C=C(C(C)(C)C)C=4O3)CCOP3O[C:84]4[C:86]([C:94]([CH3:97])([CH3:96])[CH3:95])=[CH:87][C:88]([C:90]([CH3:93])([CH3:92])[CH3:91])=[CH:89][C:83]=4C4C=C(C(C)(C)C)C=C(C(C)(C)C)C=4O3)[O:57]C3C(C(C)(C)C)=CC(C(C)(C)C)=CC=3C=2C=1)(C)C.OP(OP(O)O)O.C(C1C=C(C(C2C=CC=CC=2)(C)C)C=CC=1[C:181](C1C=CC(C(C2C=CC=CC=2)(C)C)=CC=1C(C1C=CC=CC=1)(C)C)([C:183]([CH2:188][OH:189])([CH2:186][OH:187])[CH2:184][OH:185])[OH:182])(C1C=CC=CC=1)(C)C.P(Cl)(Cl)Cl.C1(C2C=CC=CC=2)C=CC=CC=1.CCCCC1(CC)COP(OC2C(C(C)(C)C)=CC(C(C)(C)C)=CC=2C(C)(C)C)OC1.OP(OP(O)O)O.C(C(CCCCCCCCCCCCCCCCCC)(C(CO)(CO)CO)O)CCCCCCCCCCCCCCCCC>>[OH:2][P:1]([O:32][P:56]([OH:57])[OH:55])[OH:17].[C:28]([C:19]1[CH:20]=[C:21]([C:24]([CH3:27])([CH3:25])[CH3:26])[CH:22]=[CH:23][C:18]=1[C:181]([C:84]1[CH:83]=[CH:89][C:88]([C:90]([CH3:93])([CH3:92])[CH3:91])=[CH:87][C:86]=1[C:94]([CH3:96])([CH3:95])[CH3:97])([C:183]([CH2:188][OH:189])([CH2:186][OH:187])[CH2:184][OH:185])[OH:182])([CH3:29])([CH3:31])[CH3:30]
Reactant: CC(C)(c1ccccc1)c1ccc(C(O)(c2ccc(C(C)(C)c3ccccc3)cc2C(C)(C)c2ccccc2)C(CO)(CO)CO)c(C(C)(C)c2ccccc2)c1
Reactant: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2op(OCCN(CCOp3oc4c(C(C)(C)C)cc(C(C)(C)C)cc4c4cc(C(C)(C)C)cc(C(C)(C)C)c4o3)CCOp3oc4c(C(C)(C)C)cc(C(C)(C)C)cc4c4cc(C(C)(C)C)cc(C(C)(C)C)c4o3)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Agent: CCCCC1(CC)COP(Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)OC1
Agent: CCCCCCCCCCCCCCCCCCC(O)(CCCCCCCCCCCCCCCCCC)C(CO)(CO)CO
Agent: OP(O)OP(O)O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: ClP(Cl)Cl
Product: CC(C)(C)c1ccc(C(O)(c2ccc(C(C)(C)C)cc2C(C)(C)C)C(CO)(CO)CO)c(C(C)(C)C)c1

Procedure:
tris (2,4-di-tert-butylphenyl) phosphite (Irgafos 168, Ciba); 2-[[2,4,8,10-tetrakis(1,1-dimethylethyl)dibenzo[d,f][1,3,2]dioxaphosphepin-6-yl]oxy]-N,N-bis[2-[[2,4,8,10-tetrakis(1,1-dimethylethyl)dibenzo[d,f][1,3,2]dioxaphosphepin-6-yl]oxy]-ethyl]ethanamine (Irgafos 12, Ciba), 2,4,6 tri-t-butylphenyl 2 butyl 2 ethyl 1,3 propane diphosphite (Ultranox 641, GE Specialty Chemicals); bis(2,4-dicumylphenyl) pentaerythritol diphosphite (Doverphos S-9228, Dover Chemical Corporation); bis(2,6-di-t-butyl-4-methylphenyl)pentaerythritol-di-phosphite (PEP-36, Amfine Chemical); reaction product of phosphorous trichloride with 1,1'-biphenyl and 2,4 bis (1,1'-dimethyl) phenol (Sandostab P-EPQ, Clariant), 2,4,6 tri-t-butylphenyl 2 butyl 2 ethyl 1,3 propane diphosphite (Ultranox 641, GE Specialty Chemicals); distearyl pentaerythritol diphosphite (Weston 619, GE Specialty Chemicals).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]([C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)=[O:57])[CH3:54])=[O:51])[N:5]=1.C1(C)C=CC=CC=1.C(O)=O>CO>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1

Procedure:
Typically, the deprotection step comprises heating to reflux trityl candesartan cilexetil in methanol. Optionally, the deprotection solvent mixture further comprises an organic solvent, such as toluene, and/or an acid, such as formic acid. The cilexetil trityl candesartan is heated to reflux until a clear solution is obtained. Typically, the reaction temperature is from about 30° C. to about 90° C., preferably from about 50° C. to about 90° C., and the heating takes place for about 5 to about 19 hours, preferably for about 8 to about 12 hours. Thereafter, the solvents are removed by evaporation to obtain crude deprotected candesartan cilexetil. The solvents may be removed at a temperature of about 30° C. to about 70° C., preferably at a temperature of about 50° C., and at a reduce pressure of about 30 mbar.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][CH:11]([O:15][CH3:16])[C:12]([CH3:14])=[O:13]>CC(O)CC>[CH3:3][N:4]([CH3:6])/[CH:5]=[CH:14]/[C:12](=[O:13])[CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: COC(OC)N(C)C
Reactant: COC(OC)C(C)=O
Solvent: CCC(C)O
Product: COC(OC)C(=O)/C=C/N(C)C

Procedure:
A solution of N,N-dimethylformamide dimethyl acetal (147 g, 1.23 mol) and 1,1-dimethoxyacetone (146 g, 1.24 mol) in 2-butanol (1 L) was heated at reflux for 20 hours. After removal of solvent in vacuo, the residue was distilled under vacuum to provide the product as an oil. Yield: 145 g, 0.837 mol, 68%. Boiling point: 132-140° C./0.15 torr. NMR and MS data were obtained using the product of a reaction run under similar conditions. LCMS m/z 174.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.77 (br s, 3H), 3.02 (br s, 3H), 3.30 (s, 6H), 4.47 (s, 1H), 5.23 (br d, J=12.6 Hz, 1H), 7.63 (d, J=12.6 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23]C3CCCCO3)=[CH:19][CH:18]=2)[C@H:10]([NH:31][C:32](=[O:46])[C:33]2[CH:38]=[CH:37][C:36]([O:39]C3CCCCO3)=[CH:35][CH:34]=2)[CH2:9]1)=O)(C)(C)C.[ClH:47]>C(COC)OC.C(O)(C)C>[ClH:47].[OH:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([NH:31][C@H:10]2[C@H:11]([O:15][C:16](=[O:30])[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9]2)=[O:46])=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(OC3CCCCO3)cc2)[C@H](NC(=O)c2ccc(OC3CCCCO3)cc2)C1
Agent: Cl
Solvent: COCCOC
Solvent: CC(C)O
Product: O=C(N[C@@H]1CNCCC[C@H]1OC(=O)c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
108.9 g (3R,4R)-3-[4-(Tetrahydro-pyran-2-yloxy)-benzoylamino]-4-[4-(tetrahydro-pyran-2-yloxy)-benzoyloxy]-azepane-1-carboxylic acid tert-butyl ester (mixture of 4 diast.) was dissolved in 200 ml of a 2N dimethoxyethane and i-Pr-OH (1:1) HCl solution at 0° C. The solution was kept at room temperature for 24 h. The deprotected azepine crystallized, and the reaction mixture was cooled to 0° C. before filtration. The white crystals were washed with dry ether then dissolved in pure water. The water solution was extracted twice with ether before being yand lyophilised. 66.4 g (95% yield) 4-Hydroxy-benzoic acid (3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1) was obtained as a white powder
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[F:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH:44]=[CH:45][C:46]=1[F:47]>CC(O)=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:38][NH:54][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][C:46]([F:47])=[C:41]([F:40])[CH:42]=3)=[CH:53][CH:52]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: Nc1ccc(-c2ccc(F)c(F)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(F)c3)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (116 mg, 0.55 mmol) was added to a DCM solution (1 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (95 mg, 0.27 mmol), 3′,4′-difluoro-[1,1′-biphenyl]-4-amine (73 mg, 0.36 mmol), and 1 drop of AcOH and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture diluted with DCM and saturated aqueous NaHCO3 and the layers were separated. The organic phase was washed with brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:52][C@H:50]([C:47]1[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=1)[CH3:51])=[O:41]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (9 mg, yield 21%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20])(=[O:13])=[O:12])([O-:4])=[O:3].[N:21]1([CH2:30][C:31](O)=[O:32])[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]1=[O:23].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(O)C>[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:31](=[O:32])[CH2:30][N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:16][C:15]1=[O:20])(=[O:12])=[O:13])([O-:4])=[O:3]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a mixture of 1-(2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.13 g, 3.5 mmol), (thymin-1-yl)-acetic acid (0.64 g, 3.5 mmol), and PyBOP (2.00 g, 3.85 mmol) in DMF (11 mL) was addeed N,N-diisopropylethylamine (0.91 mL) at room temperature. After stirring for additional 2 h, the reaction mixture was slowly added to a solution of aqueous ethyl alcohol to precipitate solid. The solid was filtered off, washed with ethanol and ethyl ether, and dried in vacuo to give the titled compound (1.50 g, 95%).
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:14][CH2:15][CH3:16])[NH:10][C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31](=[O:36])[C:32]([O:34]C)=[O:33])=[CH:21][CH:20]=1.C(=O)([O-])[O-:38].[K+].[K+]>>[OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:14][CH2:15][CH3:16])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:32]([OH:34])=[O:33])=[O:36])=[CH:21][CH:20]=2)[C:11]=1[C:12]([NH2:13])=[O:38])[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)C(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C#N)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Yield: 70.2 %

Procedure:
Following a procedure similar to that described in Example 10(a), but using 170 mg of 4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazole-5-carbonitrile, 307 mg of methyl (4'-bromomethylbiphenyl-2-yl)glyoxylate (prepared as described in Preparation 8) and 106 mg of potassium carbonate, 257 mg of the title compound were obtained as crystals, melting at 128°-130° C.