Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:20])[F:19])[O:7][C@H:6]1[N:30]1[CH:38]=[N:37][C:36]2[C:35](=[O:39])[NH:34][C:33]([NH:40]C(=O)C(C)C)=[N:32][C:31]1=2)(=O)C.CO>N>[NH2:40][C:33]1[NH:34][C:35](=[O:39])[C:36]2[N:37]=[CH:38][N:30]([C@H:6]3[C@H:5]([OH:4])[C@H:9]([O:10][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C@:8]([CH2:21][O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([CH:18]([F:20])[F:19])[O:7]3)[C:31]=2[N:32]=1
Reactant: CC(=O)O[C@H]1[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Agent: N
Solvent: CO
Product: Nc1nc2c(ncn2[C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1
Yield: 53.6 %

Procedure:
A mixture of compound 21 (0.5 g, crude) in NH3.MeOH (7 N, 40 mL) was stirred at 35° C. for 16 h and then evaporated to dryness. Purification by silica gel chromatography [dichloromethane:methanol (100:1 to 20:1)] to give the product 22 as a white foam (0.22 g, 53%). LC-MS (M+H)+=514
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([C:23]#[N:24])=[CH:18][CH:19]=2)[N:14]=1>>[C:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1)#[N:24]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc2ccc(N)nc2n1
Product: COc1ccc(C(=O)Nc2ccc3ccc(C#N)nc3n2)cc1
Yield: 11.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (8.2 g), N,N'-carbonyldiimidazole (8.7 g) and 2-amino-7-cyano-1,8-naphthyridine (6.9 g), and heating for 4 hours under reflux. The insoluble product is separated by filtration and the filtrate is poured into water (1000 cc). The resulting precipitate is filtered off, washed with water (3×75 cc) and dried in the air. The solid obtained is purified by flash chromatography (under 30 kPa) on a column 40 mm in diameter containing silica (170 g; 0.04-0.06 mm), eluting with pure methylene chloride and collecting 50-cc fractions. After concentration of fractions 5 to 27 to dryness at 40° C. under reduced pressure (4 kPa), the product obtained is purified by recrystallization in dioxane (160 cc). N-(7-Cyano-1,8-naphthyridin-2-yl)-4-methoxybenzamide (1.4 g), m.p. 283° C., is thereby obtained.
Reaction SMILES: C([NH:8][CH:9]([C:16]([O:21][CH3:22])([O:19][CH3:20])[CH2:17][F:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1>CO.[Pd]>[NH2:8][CH:9]([C:16]([O:21][CH3:22])([O:19][CH3:20])[CH2:17][F:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(NCc1ccccc1)C(CF)(OC)OC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(N)C(CF)(OC)OC
Yield: 93.1 %

Procedure:
A solution of ethyl 3-(benzylamino)-5-fluoro-4,4-dimethoxypentanoate (7, R1=ethyl, R2=methyl, R4=benzyl, R5=hydrogen, 32.1 g, 103 mmol) in methanol (321 mL) was treated with 10% palladium catalyst (10% Pd/C) under hydrogen atmosphere (1 atm) for 4 h. The crude mixture was filtered through a pad of Celite® (96 g), washed with methanol (160 mL), and the filtrate was concentrated under reduced pressure to give the title compound (1, R1=ethyl, R2=methyl, 21.4 g, 94%), which was used in the next reaction.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]1[O:20][C:19](=[O:21])[CH2:18][CH2:17]1.C(Br)CC.C(O)(=O)C>C1COCC1>[CH2:2]([CH:18]1[CH2:17][CH:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)[O:20][C:19]1=[O:21])[CH2:1][CH3:3]
Reactant: O=C1CCC(Cc2ccccn2)O1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: CCCBr
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CC(Cc2ccccn2)OC1=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a 2 M lithium diisopropylamine solution in THF of −78° C. is added 5-(pyridin-2-yl-methyl)dihydrofuran-2(3H)-one and the mixture is stirred for 1.5 hours at −78° C. Then 1-propyl bromide is added and the reaction is stirred for another 1.5 hours at −78° C. The reaction mixture is allowed to warm up to 0° C. before ice-cold water with acetic acid is added and subsequently extracted with 3 times dichloromethane. The dichloromethane is concentrated in vacuo and the residue is dissolved in dichloromethane, washed with saturated NaHCO3 and brine. Crude 3-propyl-5-(pyridin-2-ylmethyl)dihydrofuran-2(3H)-one is obtained after removal of the solvents in vacuo. The product is purified by column chromatography.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N:18]([CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:19](=[O:21])[CH3:20])[N:14]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[N:13]=[CH:12]2)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[N:18]([CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)[C:19](=[O:21])[CH3:20])[N:14]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[N:13]=[CH:12]2
Reactant: CC(=O)N(c1cc2c(cnn2C2CCCCO2)cc1OCc1ccccc1)C1CCOCC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)N(c1cc2c(cnn2C2CCCCO2)cc1O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of N-(5-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide (1.7 g, 3.78 mmol) in EtOH (100 mL) and EtOAc (100 mL) is added Pd/C (1 g, 10% wt). After the reaction mixture is stirred at RT under H2 overnight, it is filtered and the filtrate is concentrated. The residue is purified by silica gel column chromatography eluting first with PE:EtOAc (1:1) and then EtOAc to give the product (1.2 g, 88.2% yield). MS (m/z): 360.2 (M+H).
Reaction SMILES: [Na+].[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]([O-:13])=O)[N:10]=1)[C:3]([NH2:5])=[NH:4].Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:16]1>>[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:16]2)=[O:13])[N:10]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1nc(C(=O)[O-])cs1
Reactant: CCOC(=O)CCNC(=O)C1CCCNC1
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)CCNC(=O)C1CCCN(C(=O)c2csc(NC(=N)N)n2)C1

Procedure:
In analogy to Example 4, by coupling 2-guanidino-thiazole-4-carboxylic acid sodium salt with ethyl (RS)-3-[(piperidine-3-carbonyl)-amino]-propionate hydrochloride there is obtained ethyl (RS)-3-[[1-(2-guanidino-thiazole-4-carbonyl)-piperidine-3-carbonyl]-amino]-propionate as a white foam. MS: 397 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([O:15]C)=[CH:14][C:6]=2[C:5]1=[O:17])[CH:2]=[CH2:3].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:6]=2[C:5]1=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCN1CCCc2ccc(OC)cc2C1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN1CCCc2ccc(O)cc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A solution of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (1.10 g, 0.0047 mol) in CH2Cl2 (20 mL) was treated at 0° C. with BBr3 (1M in CH2Cl2, 9.50 mL), and the resulting mixture stirred at 0° C. for 30 minutes. The solution was poured over ice, NaHCO3 was added, and the solution was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to yield ca. 1.0 g (100%) of 2-allyl-8-hydroxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[Cl:12]([O-])(=O)=O.[Na+]>O>[OH:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 50 °C

Procedure:
2-Hydroxy-5-nitro pyridine (1 g, 7.14 mmol) was added portion wise to 4.5 mL of concentrated HCl under constant stirring and then heated to 50° C. To this was added a solution of sodium chlorate (266 mg, 2.5 mmol) in water (4 mL). The reaction was maintained at the same temperature for an additional hour, and then cooled to 0° C. The precipitate obtained was filtered, washed with water and dried to obtain 2-hydroxy-3-chloro-5-nitro pyridine.
Reaction SMILES: [CH2:1]([Zn]CC)C.C(O)(C(F)(F)F)=O.ICI.[CH3:16][C:17]([CH3:25])([CH:23]=[CH2:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CCCCCC.ClCCl>[CH:23]1([C:17]([CH3:25])([CH3:16])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:1][CH2:24]1
Reactant: C=CC(C)(C)CC(=O)OC
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: COC(=O)CC(C)(C)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl zinc (77 mL of a 1.0 M solution in hexane; 77 mmol) in dry dichloromethane (250 mL) at 0° C. under an inert atmosphere was added TFA (5.9 mL, 77 mmol) in dichloromethane (15 mL) dropwise over a period of 1 h. To this suspension was added diiodomethane (6.2 mL, 77 mmol) in dichloromethane (10 mL) dropwise over a period of 15 min. The resulting solution was stirred at 0° C. for 30 min, at which time methyl 3,3-dimethyl-4-pentenoate (5.0 g, 35 mmol) was added. The mixture was stirred at 0° C. for 30 min and then at ambient temperature for 16 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (100 mL). The organic layer was separated and washed with water (100 mL), dried (MgSO4), filtered, and the solvents were removed under reduced pressure. The resulting liquid was distilled under reduced pressure. The fraction boiling at 76-80° C. (18 mm Hg) was collected to give methyl 3-cyclopropyl-3-methylbutanoate as a colorless liquid. 1H NMR 400 MHz, CDCl3, 3.66 ppm (s, 3H), 2.27 ppm (s, 2H), 0.87 ppm (s, 6H), 0.81 ppm (m, 1H), 0.31 ppm (m, 2H), 0.20 ppm (m, 2H)
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23](F)(F)F)=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1.CO.[OH-].[Li+]>O1CCCC1>[C:20]1([C:23]2[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=2)[CH:21]=[CH:22][C:17](/[CH:16]=[N:15]/[O:14][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:41])=[C:5]([NH:27][C:28](=[O:40])[C:29]3[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=3)[CH:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(OCCCO/N=C/c2ccc(-c3ccccc3)cc2)ccc1C(=O)O)c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h
Yield: 192.8 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 28, starting with 2-{[4-(trifluoromethoxy)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid methyl ester (0.31 g, 0.52 mmol), 1:1 methanol:tetrahydrofuran (10 mL) and 4N aqueous lithium hydroxide solution (0.39 mL). The crude material was crystallized from hot chloroform (10 mL) by the addition of room temperature hexanes (100 mL), and allowing the mixture to sit for 2 hours. The product was isolated and then triturated with hexanes to give 4-[3-({[(1E)-1,1′-biphenyl-4-ylmethylidene]amino}oxy)propoxy]-2-{[4-(trifluoromethoxy)benzoyl]amino}benzoic acid (0.29 g, 97%) as a white solid. mp=187.5-188.5° C. 1H NMR (500 MHz, DMSO-d6); δ 13.47 (bs, 1H), 12.45 (s, 1H), 8.38 (s,2H), 8.04 (d, 2H), 7.99 (d, 1H), 7.81-7.72 (AA′BB′, 4H), 7.58 (d, 2H), 6.80 (d, 1H), 4.34 (t, 2H), 4.20 (t, 2H), 2.18 (m, 2H). Mass spec (MW 570.44); (ES−) m/z 569.39. Elemental analysis; Calculated for C26H20F6N2O6: C, 54.74; H, 3.53; N, 4.91. Found: C, 54.05; H, 3.13; N, 4.80.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:14][C:15](=[O:24])[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])(=O)[CH3:2].Cl.[NH2:26][OH:27].C(=O)(O)[O-].[Na+].O>C(O)C>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]([NH:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][C:4]([C:1](=[N:26][OH:27])[CH3:2])=[CH:13]2)=[O:24]
Reactant: NO
Reactant: CC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Yield: 75.3 %

Procedure:
A mixture of 3-acetyl-8-(2,6-dichlorobenzoylamino)quinoline (399 mg), hydroxylamine hydrochloride (232 mg) and sodium bicarbonate (467 mg) in ethanol was refluxed for 5 hours. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-3-(1-hydroxyiminoethyl)quinoline (313 mg).
Reaction SMILES: N[C:2]1[CH:7]=[C:6](OC)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2.Cl.[N:25]([O-:27])=[O:26].[Na+].O>C(O)(=O)C>[N+:25]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2)([O-:27])=[O:26]
Reactant: COc1ccc(-c2ccc3cc(OC)c(OC)cc3c2)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ccc(-c3ccccc3[N+](=O)[O-])cc2cc1OC
Reaction time: 8 h
Yield: 41.4 %

Procedure:
6-(2-Amino-4-methoxyphenyl)-2,3-dimethoxynaphthalene (32) (12 mg, 0.039 mmol) was dissolved in acetic acid (0.6 mL) and concentrated hydrochloric acid (0.06 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.026 g in 0.5 mL water). The resulting diazonium solution was allowed to rise to room temperature slowly and left overnight. To the resulting red solution which contained some precipitate was added 30 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The ethyl acetate extracts were dried with anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 40:60 hexanes:ethyl acetate to give the pure 4 (5 mg) in 40% yield; mp 244-246° C.; IR (KBr) 2919, 1619, 1507, 1388, 1292, 1277, 1204 cm−1; UV (MeOH) 292, 266, 216 nm; 1H NMR (CDCl3) δ4.10 (6H, s), 4.22 (3H, s), 7.32 (1H, s), 7.54 (1H, dd, J1=9.1, J2=2.6), 8.04-8.08 (2H, m), 8.28 (1H, d, J=8.9), 8.49 (1H, d, J=9.1), 9.16 (1H, s); 13C NMR δ56.33, 56.52, 56.92, 104.36, 107.93, 108.92, 116.88, 117.08, 119.48, 123.51, 124.54, 127.14, 128.42, 132.46, 141.77, 148.52, 151.12, 151.40, 160.45; HRMS (EI) calcd for C19H16N2O3 m/z: 320.1161; found: 320.0384.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(#N)C>[CH3:1][N:2]([CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:25][C@H:23]([OH:24])[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=1
Reactant: CNCc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(OC[C@@H]2CO2)cc1
Solvent: CC#N
Product: CN(Cc1ccc2ccccc2n1)C[C@H](O)COc1ccc([N+](=O)[O-])cc1
Yield: 62.9 %

Procedure:
2-(Methylaminomethyl)quinoline (4.47 g, 25.96 mmol) in acetonitrile (30 mL) was added to a stirring solution of (S)-(+)-2-[(4-nitrophenoxy)methyl]oxirane (4.23 g, 21.67 mmol) in acetonitrile (10 mL). The reaction was lightly refluxed under N2 for 24 hours, cooled and concentrated in vacuo. The residue was purified by HPLC dried and heated under vacuum to afford 5.01 g (63%) of product which was used directly in the next step.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[NH2:11][CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14].[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:28])[CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O>>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:11][CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[O:24])=[C:21]([F:28])[CH:20]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: COC(=O)C(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)NC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
N,N-Diisopropylethylamine (2.0 mL, 0.011 mol) was added to a mixture of methyl 2-aminopropanoate hydrochloride (0.64 g, 0.0046 mol), 4-bromo-2-fluorobenzoic acid (1.0 g, 0.0046 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.12 g, 0.00479 mol) in N,N-dimethylformamide (10.0 mL, 0.129 mol). The reaction mixture was stirred overnight at RT, quenched with saturated sodium bicarbonate (25 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with 60% EtOAc in hexanes to afford the desired product (1.33 g, 96%). LCMS: (M+H)=303.9/305.9.
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:28]=2[N:29]=[CH:30][N:31]=1)[C@@H:15]1[O:27][C@H:24]([CH2:25][OH:26])[C@@H:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:16]1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:55]=[CH:54][C:37]([C:38](Cl)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:28]=2[N:29]=[CH:30][N:31]=1)[C@@H:15]1[O:27][C@H:24]([CH2:25][O:26][C:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:37]2[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:55][CH:54]=2)[C@@H:18]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:16]1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
A solution of N6-Benzoyl-3′-O-(2-methoxyethyl) adenosine (11.0 g, 0.285 mol) in pyridine (100 mL) was evaporated under reduced pressure to an oil. The residue was redissolved in dry pyridine (300 mL) and 4,4′-dimethoxytrityl chloride (DMT-Cl, 10.9 g, 95%, 0.31 mol) was added. The mixture was stirred at 25° C. for 16 h and then poured onto a solution of sodium bicarbonate (20 g) in ice water (500 mL). The product was extracted with ethyl acetate (2×150 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate (powdered) and evaporated under reduced pressure (below 40° C.). The residue was chromatographed on silica gel (400 g, ethyl acetate-acetonitrile-triethylamine 99:1:1→95:5:1). Selected fractions were combined, concentrated under reduced pressure and dried at 25° C./0.2 mmHg to give 16.8 g (73%) of foam; TLC homogenous.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[Cl:29])[CH3:37])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CC(O)c1ccccc1Cl
Product: CC(Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccccc1Cl

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 1-(2-chloro-phenyl)-ethanol. MS (ESI) m/z 519.
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21](=[O:34])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](O)=[O:14])=[CH:5]1.C1C[N:38]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[O:1]=[C:2]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21](=[O:34])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:32])([F:31])[F:33])[CH:24]=1)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH2:38])=[O:14])=[CH:5]1
Reactant: O=C(O)c1cn(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc12
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cn(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-{2-oxo-2-[(S)-2-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidin-1-yl]-ethyl}-1H-indole-3-carboxylic acid (11 mg, 0.023 mmol), was treated with PyBOP (12 mg, 0.023 mmol), HOBt (3.54 mg, 0.023 mmol), DIPEA (16 μL, 0.092 mmol), and NH4Cl (1 mg, 0.069 mmol) in DMF (1 mL) and the reaction mixture was stirred at RT under nitrogen for 3 h, then poured into an aqueous saturated solution of NaHCO3, EtOAc (20 mL) was added and the layers were separated. The aqueous layer was back-extracted twice with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 20% CH3CN/H2O 2.5 min, 20-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the desired compound. TLC, Rf (CH2Cl2/MeOH 95:5)=0.17; MS (LC/MS): 473.2 [M−H]−; tR (HPLC conditions a): 3.24 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=1)[C:7]2=[O:55])([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH2:15][CH2:16][CH3:17])[N:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=1)[C:7]2=[O:55]
Reactant: CCCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 98.3 %

Procedure:
A solution of 3.2 g (4.4 mmol) of the 6-nitroquinazolinone from Example 29 in 100 mL of EtOAc was hydrogenated over night under atmospheric pressure in the presence of 0.5 g of 10% Pd/C. The solution was filtered through celite and the celite was washed with CH2Cl2 to remove any of the yellow coloured product. The filtrate was concentrated in vacuo to give 3.0 g of a pale yellow solid. The material was not purified further, 98% yield. 1H-NMR (CDCl3 300 MHz): 0.89 (t, 3H, J=7.3 Hz), 1.32 (m, 2H), 1.69 (m, 2H), 2.62 (3 line m, 2H, J=7.9 Hz), 4.00 (bs, 2H), 5.29 (bs, 2H), 6.88-7.02 (m, 6H), 7.08-7.15 (m, 4H), 7.22-7.38 (m, 11H), 7.45-7.55 (m, 4H), 7.93 (dd, 1H, J=2.5, 7.0 Hz).