Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](N2CCOCC2)[C:9]#N)[CH:5]=[CH:6][CH:7]=1.[O:17]1CCCC1.[OH-].[K+].[C:24](#[N:27])[CH:25]=C>CO.O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([CH2:9][CH2:25][C:24]#[N:27])=[O:17]
Reactant: N#CC(c1cccc(Cl)c1)N1CCOCC1
Reactant: C=CC#N
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: N#CCCC(=O)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 23.6 g. of α-(m-chlorophenyl)-4-morpholineacetonitrile in 100 ml. of tetrahydrofuran is added 120 drops of a 30% solution of KOH in methanol. To the mixture is added 4.1 ml. of acrylonitrile (temperature rose to 45° C.). After stirring 1 hr., the mixture is concentrated to dryness under vacuum. The residue is dissolved in methylene chloride and passed through a short column of hydrous magnesium silicate. The eluent is concentrated under vacuum to give 36.6 g. of a yellow oil. The oil is heated (steam bath) with a mixture of 150 ml. of acetic acid and 10 ml. of water for 1 hr. The solvent is removed under vacuum and the residue treated with water. The mixture is filtered to give 18.8 g. of crystals, m.p. 49°-51° C.
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[C:13]([CH:17]1[CH2:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([SH:28])[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>C(O)(=O)C>[C:13]([CH:17]1[CH2:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([S:28]([OH:3])(=[O:2])=[O:1])[CH2:19][CH2:18]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)C1=C(S)CCC(C(C)(C)C)C1
Reactant: O
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCC(C(C)(C)C)C1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Sodium peroxyborate tetrahydrate (38.2 g) was admixed with acetic acid (270 ml) and heated to 50 to 55° C. and then a solution of ethyl 5-t-butyl-2-mercapto-1-cyclohexene-1-carboxylate (20.1 g) synthesized in Reference Example 15 in acetic acid (31 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 7.5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (445ml) and stirred at room temperature for 3.5 hours and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (110 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (320 ml) and stirred at room temperature for 15 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (250 ml) and the pellet which precipitated was isolated by a filtration and concentrated under reduced pressure to obtain ethyl 5-t-butyl-2-sulfo-1-cyclohexene-1-carboxylate as yellow oil (17.6 g) containing inorganic substances. This (16.4 g) was treated dropwise with thionyl chloride (49.2 ml) at 0° C. over 0.5 hours and then stirred at 80 to 90° C. for 7 hours. The solution was evaporated under reduced pressure to dryness and the residue was partitioned between ethyl acetate (200 ml) and dilute brine (240 ml) and the aqueous layer was extracted with ethyl acetate (100 ml). The combined ethyl acetate layers were washed with saturated brine (120 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/10), and a desired fraction was concentrated under reduced pressure. The residue was crystallized from hexane to yield ethyl 5-t-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate (7.4 g) as a white crystals.
Reaction SMILES: [I:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(O)(=O)C.Cl>C(O)C.[Fe]>[NH2:12][C:3]1[C:2]([I:1])=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1I
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)O)c(N)c1I
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
3-Iodo-4-methyl-2-nitrobenzoic acid (46.00 g, 150 mmol) was suspended in ethanol (500 mL) and acetic acid (86 mL, 1498 mmol). The mixture was heated to 70° C. and iron (33 g, 599 mmol) was added in small portions. Stirring was continued for 3 h, and then the reaction was cooled down to RT and poured on 1.5 kg of crushed ice and 1 L of 5 N aqueous HCl. The mixture was extracted with ethyl acetate and the organic layer was dried with sodium sulfate, concentrated under vacuum and dried to give 2-amino-3-iodo-4-methylbenzoic acid (40 g, 96%) as a tan solid. MS (M+H)+ 278
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:31])[N:25]([CH2:29][OH:30])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[NH:33](C(OC(C)(C)C)=O)[CH2:34][C:35](O)=[O:36].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[ClH:1].[NH2:33][CH2:34][C:35]([O:30][CH2:29][N:25]1[C:24](=[O:31])/[C:23](=[CH:22]/[C:21]2[CH:20]=[N:19][N:12]3[C:13]([NH:15][CH:16]4[CH2:17][CH2:18]4)=[CH:14][C:9]([NH:8][C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[F:32])=[N:10][C:11]=23)/[NH:27][C:26]1=[O:28])=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cl
Product: NCC(=O)OCN1C(=O)N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione (100 mg, 0.218 mmol) in DMF (3 mL) was added Boc-Gly-OH (153 mg, 0.873 mmol), dicyclohexylcarbodiimide (180 mg, 0.873 mmol), and DMAP (13 mg, 0.109 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate and washed 1× with 1M HCl followed by 3× brine. The organic layer was dried with MgSO4, filtered and adsorbed onto silica gel. The crude material was purified by column chromatography eluting with 5-15% EtOAc/CH2Cl2 gradient. Pure fractions were combined and the solvent was removed. To the residue was added 4M HCl/dioxane (4 mL) and stirred at room temperature for 2 h. Removed excess HCl/dioxane. To the residue was added diethyl ether and the suspension was sonicated. The resulting solid was filtered off and washed with diethyl ether. Dried under vacuum to provide 23 mg (21%) of (Z)-(4-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl 2-aminoacetate hydrogen chloride as a yellow solid. (LCMS (ES): >95% pure, m/z 515 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7](=[O:15])[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:3])[NH2:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([Cl:27])=[O:26].Cl.Cl.C(O)C>C(Cl)Cl.C(N(CC)CC)C>[OH2:3].[ClH:27].[C:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7](=[O:15])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:22]([O:21][CH3:20])[CH:23]=2)[CH2:11][CH2:10]1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NC(=O)c1ccccc1NC(=O)CN1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(CC(=O)Nc3ccccc3C(N)=O)CC2)cc1OC
Product: O
Reaction time: 1 h

Procedure:
6.15 Grams of o-carbamoyl-α-(1-piperazinyl)acetanilide and 2.4 g of triethylamine were dissolved in 50 ml of methylene chloride, then to this solution was added dropwise a methylene chloride solution of 5.4 g of 3,4-dimethoxybenzoyl chloride under ice-cooled condition with stirring. The reaction was carried out at the same temperature for 1 hour, then the reaction mixture was washed with water, 5%-sodium bicarbonate aqueous solution, and an aqueous solution of potassium carbonate, then dried. Methylene chloride was removed by distillation, the residue was purified by a silica gel column chromatography, the product obtained was converted into a hydrochloride by adding hydrochloric acid-ethanol, then recrystallized from water-acetone to obtain 5.1 g of o-carbamoyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride monohydrate in the form of colorless needle-like crystals. Melting point: 122.0°-125.0° C. (decomposed).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.CC(=O)OCC.O.[CH3:20][N:21](C)C=O>[C-]#N.[C-]#N.[Zn+2].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>[C:20]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:21]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(O)c(I)c1
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: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 4-hydroxy-3-iodobenzoate (2.78 g) and Zn(CN)2 (1.409 g) in N,N-dimethylformamide (DMF) (30 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (1.155 g). The reaction mixture was stirred at 140° C. for 12 h. After cooling the reaction, EA (100 mL) and water (40 mL) were added to the solution. After filtration, the filtrate was washed with water and brine, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to afford methyl 3-cyano-4-hydroxybenzoate (D21) (1.3 g) as a white solid. MS (ES): C9H7NO3 requires 177. found 178.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([Cl:19])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (664 mg) in DCM (10 mL) at 0° C. was added oxalyl chloride (4.7 mmol), followed by one drop of DMF. After stirring at rt for 2 hours, the solvent was concentrated to give S)-2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (350 mg, 2.6 mmol) was added TEA (362μL) and (S)-2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (dissolved in 10 mL of DCM). After stirring at rt for overnight, the reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 410 mg of (S)-2-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown liquid.
Reaction SMILES: [OH:1][C@@H:2]1[C:7]2=[C:8]3[C:17](=[C:18]([O:20][CH3:21])[CH:19]=[C:6]2[O:5][C:4]([CH3:29])([CH3:28])[C@@H:3]1[OH:30])[C:16](=[O:22])[C:15]1[C:10](=[CH:11][CH:12]=[C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]2=1)[N:9]3[CH3:27].[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH2:33][CH2:32]1.CN(C1C=CC=CN=1)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>N1C=CC=CC=1>[C:47]([O:1][C@@H:2]1[C:7]2=[C:8]3[C:17](=[C:18]([O:20][CH3:21])[CH:19]=[C:6]2[O:5][C:4]([CH3:28])([CH3:29])[C@@H:3]1[O:30][CH:33]([CH2:32][CH:31]=[O:37])[C:34]([OH:36])=[O:35])[C:16](=[O:22])[C:15]1[C:10](=[CH:11][CH:12]=[C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]2=1)[N:9]3[CH3:27])(=[O:49])[CH3:48]
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)[C@@H](OC(C)=O)[C@@H](OC(CC=O)C(=O)O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 0.5 mmol of the compound of Example 4 in 3 ml of anhydrous pyridine there are added 1.1 equivalents of succinic anhydride and 1 mg of dimethylaminopyridine. Stir for 2 days in the dark and at ambient temperature, then add 25 ml of acetic anhydride at −15° C. and stir for 1.5 hours before concentrating under reduced pressure. Chromatography over silica gel (dichloromethane/acetic acid: 99/1) allows the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.Cl.[C:17]([O:21][C:22](=[O:27])[C:23]([NH2:26])([CH3:25])[CH3:24])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[C:17]([O:21][C:22](=[O:27])[C:23]([NH:26][C:13]([C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12])=[O:15])([CH3:25])[CH3:24])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)c1cc(Cl)c2ccccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1cc(Cl)c2ccccc2c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
2.25 g of 4-chloro-1-hydroxy-naphthalene-2-carboxylic acid, 3.57 2-amino-2-methyl-propionic acid tert-butyl ester hydrochloride, 6.93 g HATU and 5.29 mL of N,N′diisopropylethylamine were dissolved in 100 mL of dimethylformamide. The reaction was heated at 60° C. for 1.5 hour followed by room temperature overnight. Water was added and the mixture was extracted with diethyl ether twice. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica with heptanes/ethyl acetate afforded 1.016 g (28%) of 2-[(4-chloro-1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid tert-butyl ester as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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:8][C:5]1[CH:4]=[CH:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][N:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1ccc(Br)cn1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (2.33 g, 13.2 mmol) in toluene (100 mL) and ethanol (25 mL) were added Pd(PPh3)4 (764 mg, 0.66 mmol), phenylboronic acid (2.42 g, 19.8 mmol, 1.5 eq) and a solution of sodium carbonate (9.6 g, 90.7 mmol, 6.85 eq) in water (50 mL). The reaction mixture was heated to 90 C for 2 hours, allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was dried and evaporated and the residue purified by column chromatography (petrol/ethyl acetate gradient) to afford the title compound as a colorless oil (2.14 g, 93%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:23][O:24][CH2:26][CH2:27][OH:28])[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@@](CO)(c2ccc(Cl)c(Cl)c2)CC1
Product: Cl
Product: OCCOC[C@]1(c2ccc(Cl)c(Cl)c2)CCNCCO1

Procedure:
Using tert-butyl (7R)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate and (2-bromoethoxy)(tert-butyl)dimethylsilane, and by a method similar to that of Example 363, step B and Example 39, step B, the title compound was obtained.
Reaction SMILES: N[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.C([N:11](CC)CC)C.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:11][C:4]1[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:22]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CBr
Reactant: NCc1cccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1C
Temperature: 25 °C
Yield: 38.7 %

Procedure:
3-Aminomethylpyridine (21.6g, 0.2 mol) and equal molar triethylamine (20.2 g) were dissolved in tetrahydrofuran and cooled by means of an ice water bath to 0°-5° C. Ethyl bromoacetate (33.4 g, 0.2 mol) was added dropwise to the solution where by a suspension formed. The mixture was allowed to stir at room temperature over the weekend. The solvent was concentrated under vacuum. The residue was treated with water and extracted into ethyl acetate. The organic extract was washed repeatedly with water and dried over magnesium sulfate. After filtering from the drying agent the solvent was concentrated and the residue was treated with anhydrous ether. The cloudy solution was filtered through a pad of Celite and afterwards cooled to 0° C. with an ice bath. Slow addition of ether which had previously been saturated with anhydrous hydrogen chloride resulted in the product to precipitate as the HCl-salt. The solid product was filtered and washed with ether to give 15.0 g of a hygroscopic material with a melting point of 125°-127° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[N:16]=[CH:17][CH:18]=1)[CH3:2].[CH2:27](OC(OCC)OCC)C.[N-:37]=[N+:38]=[N-:39].[Na+].O>C(O)(=O)C>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH:27]=[N:39][N:38]=[N:37]3)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[N:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1c(Cc2ccnn2-c2cc(F)ccc2F)nc2cc(N)ccc21
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(Cc2ccnn2-c2cc(F)ccc2F)nc2cc(-n3cnnn3)ccc21
Temperature: 70 °C

Procedure:
1-Ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-amino-1H-benzimidazole (104 mg) is treated with triethylorthoformate (4 eq) in acetic acid (10 mL) at reflux for 4 h. After concentrating the solution, acetic acid is re-added, sodium azide (4 eq) added, and the mixture heated at 70° C. for 3 h. After cooling, water (15 mL) is added and the mixture concentrated. The residue is taken up in ethyl acetate, washed with aqueous sodium bicarbonate (2×) then saturated aqueous sodium chloride, dried (MgSO4), concentrated, and purified by preparative silica gel chromatography to give 1-ethyl-2-{[2-(2,5-difluorophenyl)-pyrazol-3-yl]methyl}-5-(1,2,3,4-tetrazol-1-yl)-1H-benzimidazole, which is converted to the hydrochloride salt in ethyl acetate. LCMS MH+ 395.018
Reaction SMILES: [OH:1][CH:2]([CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:19]=[C:18]([O:33][C@@H:34]([CH3:38])[CH2:35][O:36][CH3:37])[CH:17]=2)=[CH:14][CH:15]=1)=O)[C:3]([O:5][CH3:6])=[O:4].CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:37][O:36][CH2:35][C@H:34]([CH3:38])[O:33][C:18]1[CH:17]=[C:16]([C:13]2[NH:12][C:11]([C:9]3[O:1][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:7][N:8]=3)=[CH:15][CH:14]=2)[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(O)C(=O)OC)[nH]2)c1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)OC)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
Methyl 2-hydroxy-3-{[(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)carbonyl]amino}propanoate (686 mg, 1.26 mmol) synthesized in Example (27a) was dissolved in tetrahydrofuran (15 mL), and methanesulfonic anhydride (330 mg, 1.89 mmol) and triethylamine (0.53 mL, 3.80 mmol) were added, followed by stirring at room temperature for 19 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-70%) to afford the desired product (586 mg, yield 88%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3].[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[OH-].[Na+].O1CCCC1>O>[CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)c1ccc(S(=O)(=O)NCCCCC(=O)O)cc1
Reaction time: 2 h
Yield: 71.4 %

Procedure:
6.5 g of 4-dipropylaminobenzenesulphonyl chloride, in solution, are added to a solution comprising 2.76 g of 5-aminovaleric acid and 2.82 g of sodium hydroxide dissolved in 28 cm3 of water, followed by the addition of 28 cm3 of tetrahydrofuran. The mixture is kept stirring for 2 hours, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and the solid formed is filtered off, washed with water and dried. 6 g of expected product are obtained. M.p. 95°-98° C. After crystallization in an isopropanol/water mixture (1:1), 5 g of product, melting point 98°-99° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=[O:12].C([N-]C(C)C)(C)C.[Li+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[CH2:1]([C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=[O:12])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: BrCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: O=C(O)c1oc2ccccc2c1CCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
3-Methyl-benzofuran-2-carboxylic acid (9.99 g, 56.7 mmol) in 150 mL of anhydrous THF was added under nitrogen dropwise to a solution of lithium diisopropylamide (60 mL of a 2.0 M solution in heptane/THF/ethylbenzene; 120 mmol) in 350 mL of anhydrous THF at −10° C. After the addition was complete the reaction was stirred at −10° C. for approximately 10 minutes. Benzyl bromide (13.5 mL, 113 mmol) was then added dropwise to the reaction. After the addition the reaction was allowed to warm to room temperature and then stirred at room temperature for 2 h. The reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure to remove the THF. The residue was partitioned between 1 N HCl and methylene chloride. The aqueous layer was separated and extracted two times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure. The residue was recrystallized from ethyl acetate to give 3-phenethyl-benzofuran-2-carboxylic acid (1.62 g, 11%) as a white solid, mp 169-172° C.