Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccncc1
Reactant: Cc1cc(C(=O)c2sc(N)nc2-c2ccco2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Compound 331 (150 mg, 0.526 mmol) was dissolved in DMF (2.mL), and isonicotinic acid (259 mg, 2.10 mmol), EDC hydrochloride (403 mg, 2.10 mmol) and 1-hydroxybenzotriazole monohydrate (322 mg, 2.10 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 332 (78.0 mg, 38%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9].[CH3:37][O-:38].[Na+].CO>CO>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:11]([O:38][CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9]
Reactant: C[O-]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(Cl)nc2ccccc2c1-c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccccc2c(-c2ccccc2)c1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
To a solution of the compound obtained in Example 269 (100 mg) in methanol (2 ml) was added 28% NaOMe-methanol (2 ml), and the mixture was stirred for 3 hours with heating under reflux. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried and evaporated to yield the title compound as colorless crystals (85 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:8]=[CH:9][CH:10]=1)=[N+]=[N-]>CO.[Pd]>[CH3:16][C:11]1([C:7]2[CH:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[CH:9][CH:8]=2)[O:12][CH2:13][CH2:14][O:15]1
Reactant: CC1(c2cccc(CN=[N+]=[N-])c2)OCCO1
Agent: [Pd]
Solvent: CO
Product: CC1(c2cccc(CN)c2)OCCO1

Procedure:
A mixture of the crude azide (194 mg, 0.88 mmol) in MeOH (5 mL) was hydrogenated in the presence of Pd/C (10%) at rt until completion of the reaction. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a pale yellow solid. LC-MS-conditions 02: tR=0.59 min; [M+H]+=194.64.
Reaction SMILES: CC1(C)O/[C:5](=[CH:7]/[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10])/[CH2:4][O:3]1.[NH:15]([C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16]>C(O)(C)C>[Cl:23][C:22]1[C:17]([N:15]2[C:8]([OH:13])([C:9]([O:11][CH3:12])=[O:10])[CH2:7][C:5]([CH2:4][OH:3])=[N:16]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C(=O)/C=C1\COC(C)(C)O1
Reactant: NNc1ncccc1Cl
Solvent: CC(C)O
Product: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of methyl (3E)-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate (20 g, 0.1 mol) and 2-hydrazino-3-chloropyridine (21.4 g, 0.15 mol) in 150 ml of isopropanol was stirred for 8 hours at RT. The precipitate was filtered off and washed with hexane. This gave 27.6 g (85%) of the product as a pale yellow solid with a m.p. of 113-115° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].Cl>[OH-].[Na+].C1COCC1>[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:15]
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(CC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)N[C@@H](CC(=O)O)C(=O)O
Reaction time: 3 h
Yield: 75 %

Procedure:
10 g of DL-aspartic acid (Aldrich) are dissolved in 105 ml of a 2.5N aqueous sodium hydroxide solution (60 ml)/THF (45 ml) mixture in a 500 ml, three-necked, round-bottomed flask equipped with a phmeter and with two dropping funnels containing, on the one hand, a 2.5N aqueous sodium hydroxide solution and, on the other hand, 2-methoxybenzoyl chloride. The 2-methoxybenzoyl chloride is added dropwise while maintaining the pH above 9 by simultaneous addition of the 2.5N sodium hydroxide solution. The reaction mixture is kept stirring for 3 h after the end of the addition of the acid chloride before being acidified with a concentrated hydrochloric acid solution. The mixture is exhaustively extracted with ethyl acetate. The organic phase is washed, dried and concentrated to dryness to provide crude N-(2-methoxybenzoyl) aspartic acid. The product can be used as is in the second stage (nonoptimized yield 75%) or purified by washing with a suitable organic solvent. 1H NMR 500 MHz (d6 -DMSO, δppm): 2.83 (m, 2H, H9), 3.92 (s, 3H, H12); 4.80 (m, 1H, H8), 7.07 (d.d.d, 1H, H4), 7.18 (d.d, 1H, H2), 7.52 (d.d.d, 1H, H3), 7.91 (d.d, 1H, H5), 8.85 (d, 1H, NH), 12.68 (s, 2H, OH).
Reaction SMILES: CN(C)[C:3](=[CH2:11])[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5].Cl.[NH2:14]O>CO>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]1[O:5][N:14]=[CH:11][CH:3]=1
Reactant: C=C(C(=O)c1cccs1)N(C)C
Reactant: NO
Agent: Cl
Solvent: CO
Product: c1csc(-c2ccno2)c1
Yield: 93.3 %

Procedure:
A mixture of Compound 3 (18.1g, 100 mmol) and hydroxylamine hydrochloride (7.0 g, 101 mmol) in 100 mL of anhydrous methanol was refluxed under nitrogen for 2 hours. The reaction mixture was cooled, concentrated and partitioned between water and dichloromethane. The dichloromethane layer was dried with anhydrous sodium sulfate, filtered and concentrated to yield compound 4 as a dark yellow-orange oil (14.1 g, 93.3 mmol, 93%). GC/MS, m/z=151 at tR=8.30 min (100%). LC/MS, [M+H]=152.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1>[Ni].[Fe]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([NH2:12])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])c(NCCO)n1
Agent: [Fe]
Agent: [Ni]
Product: Nc1ncc(N)c(NCCO)n1

Procedure:
As shown in reaction scheme (7) below, 2-amino-4-(2-hydroxyethylamino)-5-nitropyrimidine is reacted with a reducing agent, such as Raney-nickel or iron powder, in a polar organic solvent at a temperature of about 0-100° C., and preferably about 30-50° C., for about 1-10 hours, and preferably about 2-5 hours, to give 2,5-diamino-4-(2-hydroxyethylamino)pyrimidine of formula (XXV). Then, the compound of formula (XXV) is allowed to react immediately without separation, in triethylorthoformate of formula (XVIII) at a temperature of about 50-150° C., and preferably about 70-90° C., for about 5-15 hours, and preferably about 8-10 hours, to give 2-amino-9-(2-hydroxyethyl)purine.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[CH3:30][NH:31][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[CH3:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(C)ccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3cc(C)ccc3C)c2O1

Procedure:
The title compound was prepared (0.091 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.091 g, 0.22 mmol) and methylamine (0.069 g, 2.22 mmol). mp 186-189° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[NH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([NH:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CC(C)(CN)CO
Product: Cn1ncc2c(NCC(C)(C)CO)cc(-c3cccc4[nH]ncc34)nc21

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (70 mg) and 3-amino-2,2-dimethyl-1-propanol (3 equiv.) were heated in microwave at 170° C. for two hours. Volatiles were removed in vacuo; the residue was purified by prep HPLC to give 114 as a white solid (55 mg). NMR (CDCl3): 1.11 (6H, s), 1.72 (1H, br, OH), 3.42 (2H, d), 3.64 (2H, d), 4.19 (3H, s), 5.70 (1H, br, NH), 6.78 (1H, s), 7.49-7.58 (2H, m), 7.71 (1H, d), 7.94 (1H, s), 8.82 (1H, s), 10.10 (1H, br, NH). MS: MH+ 351
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]3[CH2:20][CH2:19]3)[N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([NH:10][C:11]2[N:16]=[C:15]([N:2]([CH3:3])[CH3:1])[CH:14]=[C:13]([CH:18]3[CH2:20][CH2:19]3)[N:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC
Reactant: Clc1cc(C2CC2)nc(Nc2ccccc2)n1
Solvent: CCO
Product: CN(C)c1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 50 °C

Procedure:
17.9 ml of 33% (100 mmol) absolute ethanolic dimethylamine solution are added dropwise to 9.8 g (40 mmol) of 2-phenylamino-4-chloro-6-cyclopropyl-pyrimidine in 20 ml of absolute ethanol at room temperature in the course of 10 minutes, while stirring, and the yellow suspension formed is heated at 50° C. for one hour and then refluxed for a further hour. After evaporation of the solvent, the residue is taken up in 200 ml of methylene chloride and the mixture is washed twice with 100 ml of water each time, dried over sodium sulfate, filtered and freed from the methylene chloride by evaporation. The 10.2 g of a yellow oil which remain are purified by column chromatography over silica gel using methylene chloride as the mobile phase. After evaporation of the methylene chloride, a pale yellow oil remains, which crystallizes after some hours. The pale yellow crystals melt at 90°-91° C. Yield: 8.9 g (35 mmol; 87.5% of theory).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3Cl)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[N-:20]=[N+:21]=[N-:22].[Li+]>CN(C=O)C>[C@@H:1]1([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[N:20]=[N+:21]=[N-:22])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: [N-]=[N+]=[N-]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H](O)[C@@H]1O
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.3 %

Procedure:
A solution of 4 (170 mg, 0.63 mmol) in DMF (5 ml) was treated with lithium azide (270 mg, 5.52 mmol) and stirred for two days at room temperature. The solvent was evaporated under reduced pressure at 40° C. and the crude oil was recrystallized from MeOH to obtain pure 5 (67 mg, 38.4%): mp 185-190° C. (dec.); UVλmax (water) pH 2: 205.0 (15,506), 287.0 (6,496); pH 7: 208.5 nm (12,943), 287.5 nm (6033); pH 11: 222.5 nm (6,730); 1H NMR (DMSO-d6) δ 3.66-3.90 (m, 3H, H-5′, H-4′), 4.16-4.33 (m, 2H, H-2′, H-3′), 5.14 (t, 1H, 5′-OH, exchangeable with D2O), 6.50 (d, 1H, H-1′), 8.75 (s, 1H, H-8), 10.12 (s, 1H, H-2); IR (KBr) 2037, 1649; Anal. (C10H11N7O4&Circlesolid;0.65 CH3OH): C, H, N.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][C:23](O)=[O:24].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:23](=[O:24])[CH2:22][O:21][C:12]3[CH:13]=[CH:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)COc1ccc2ccccc2c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(COc1ccc2ccccc2c1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.24 g (1.2 mmol) of 2-naphthoxyacetic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1). The resulting product was washed with diethyl ether to yield the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[C:19]([Cl:20])=[C:18]([S:21]([CH3:24])(=[O:23])=[O:22])[N:17]([CH3:25])[N:16]=2)[C:7]=1[CH:8](OCC)[O:9]CC)#[N:2].S(=O)(=O)(O)O>O1CCOCC1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[C:19]([Cl:20])=[C:18]([S:21]([CH3:24])(=[O:22])=[O:23])[N:17]([CH3:25])[N:16]=2)[C:7]=1[CH:8]=[O:9])#[N:2]
Reactant: CCOC(OCC)c1c(C#N)cnn1-c1nn(C)c(S(C)(=O)=O)c1Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cn1nc(-n2ncc(C#N)c2C=O)c(Cl)c1S(C)(=O)=O
Yield: 86.5 %

Procedure:
1.10 g (3.5 mmol) of 4-cyano-5-diethoxymethyl-1-(4-chloro-1-methyl-5-methylsulfonyl-3-pyrazolyl)pyrazole are dissolved in 20 ml of 1,4-dioxane and, after addition of 2 ml of 50% strength sulfuric acid, heated under reflux for 2 hours. The solution is cooled and the volatile components are then distilled off, and the residue taken up in dichloromethane and extracted with water and sodium bicarbonate solution. Drying with sodium sulfate and concentration using a rotary evaporator gives 0.95 g (86%) of the desired aldehyde which can be reacted without any further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22])=[CH:29][CH:30]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccccc4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (91 mg) and commercially available 4-hydroxybenzophenone (243 mg) were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was purified in the same manner as described in Example 31 to obtain 38 mg of the title compound (yield: 24%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15](=O)[CH3:16].C[O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([CH:28]=O)[CH:22]=1.[OH-].[K+].C(O)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:28][C:23]2[C:24](=[CH:25][CH:26]=[C:21]([C:20]([OH:30])=[O:19])[CH:22]=2)[N:27]=1
Reactant: CC(=O)c1cc(C(=O)N2CCCC2)ccc1O
Reactant: COC(=O)c1ccc(N)c(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3O)ccc2c1

Procedure:
Compound 18 (410 mg, 1.75 mmol) and Compound 7 (315 mg, 1.75 mmol) were dissolved in 30 mL of ethanol, 2.45 mL of a 10% KOH/ethanol solution was added and the mixture was refluxed overnight under argon. The ethanol was evaporated, the residue dissolved in water, and acidified with 3 mL of 1M HCl. The formed gel was solidified by addition of 30 mL of ethyl acetate and 30 mL of a saturated NaCl solution. The solid was filtered, awashed with water, and dried. Yield 302 mg (48%) Compound 19.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)n(-c2cc(C#N)ccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)n(-c2cc(C#N)ccn2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 4.6 %

Procedure:
To a solution of 2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (300 mg, 1.5 mmol) and K2CO3 (518 mg, 3.75 mmol) in DMF was added benzyl bromide (308 mg, 1.8 mmol) dropwise at −20° C., then the mixture was warmed to 0° C. and stirred for 3 h. Water was added, and the reaction mixture was extracted with EtOAc, then washed with water and brine. The organic phase was dried, concentrated, and purified by prep-HPLC to afford the title compound (20 mg). [M+H] calc'd for C17H14N4O 291; Found, 291.
Reaction SMILES: C([O:3][C:4](=[O:32])[C@H:5]([CH3:31])[CH2:6][C@H:7]([NH:22][C:23]([C:25]1[O:29][N:28]=[C:27]([OH:30])[CH:26]=1)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>C(O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:22][C:23]([C:25]3[O:29][N:28]=[C:27]([OH:30])[CH:26]=3)=[O:24])[CH2:6][C@@H:5]([CH3:31])[C:4]([OH:32])=[O:3])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of (2R,4S)-5-(3′-chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (73 mg, 0.16 mmol) in ethanol (4 mL) is added 1N NaOH (2 mL) and the resulting mixture is stirred at room temperature for 2 hours. The mixture is acidified with 1N HCl and the solvent is removed under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to give (2R,4S)-5-(3′-chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid; HPLC Retention time 1.05 minutes (condition A): MS 429.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, 3 H) 1.58 (ddd, J=13.89, 9.98, 4.42 Hz, 1 H) 1.87 (ddd, J=13.71, 9.66, 3.92 Hz, 1 H) 2.41 (ddd, J=9.54, 7.14, 4.55 Hz, 1 H) 2.82 (dd, J=6.69, 3.41 Hz, 2 H) 4.10-4.24 (m, 1 H) 6.50 (s, 1 H) 7.28 (d, J=8.34 Hz, 2 H) 7.36-7.42 (m, 1 H) 7.47 (t, J=7.83 Hz, 1 H) 7.58-7.65 (m, 3 H) 7.70 (t, J=1.89 Hz, 1 H) 8.66 (d, J=8.59 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: O=C(O)c1oc(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c1OCc1ccccc1
Product: Cn1c(CNS(=O)(=O)c2ccccc2Cl)cc(=O)c(OCc2ccccc2)c1C(=O)O
Yield: 77.6 %

Procedure:
3-Benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-03) (1.7 g, 77.6%) was synthesized as a white solid from 3-benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-03) (2.0 g, 4.45 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([NH:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1)(=[O:18])[CH3:17].C(NNC1C=CC(NC(N(CC2C=CC=CC=2)CC2C=CC=CC=2)=S)=CC=1)=O>>[C:16]([NH:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:29])=[CH:23][CH:22]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)NNc1ccc(N=C=S)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Product: CC(=O)NNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
Dibenzylamine (0.20 g, 0.001 mole) and 4-(2-acetylhydrazino)phenyl isothiocyanate (0.21 g, 0.001 mole) were reacted according to the procedure described for NA-11 in Example 3. Yield 0.35 g (88 percent), m.p. 207°-209° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14](=[O:21])[CH2:15][NH:16][CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:6][C:5]=1[Cl:22].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:7]([CH:14]([OH:21])[CH2:15][NH:16][CH:17]2[CH2:18][CH2:19][CH2:20]2)=[CH:6][C:5]=1[Cl:22]
Reactant: Nc1c(Cl)cc(C(=O)CNC2CCC2)cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(Cl)cc(C(O)CNC2CCC2)cc1C(F)(F)F

Procedure:
m.p. of the hydrochloride: 177°-178° C., was prepared from 4'-amino-3'-chloro-2-cyclobutylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:7]([CH3:10])=[N:8][CH:9]=1)(O)=O.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[O:11][C:6]1[C:7]([CH3:10])=[N:8][CH:9]=[C:4]([CH2:1][NH:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[C:5]=1[CH3:20])#[N:16]
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ncc(C(=O)O)c(C)c1Oc1cccc(C#N)c1
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(C)c1Oc1cccc(C#N)c1
Yield: 76.3 %

Procedure:
The reductive amination of 3-(5-carboxy-2,4-dimethyl-pyridin-3-yloxy)-benzonitrile (188 mg, 0.74 mmol) and 4-aminobenzonitrile (500 mg, 4.2 mmol), as described in Example 21, gave 4-{[3-(3-cyano-phenoxy)-2,4-dimethyl-pyridin-5-ylmethyl]-amino}-benzonitrile (95) (200 mg, 77% yield) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH:16]=1.O>CS(C)=O>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:17]1[CH:16]=[C:15]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: Oc1ccccc1-c1cc(Cl)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2cc(-c3ccccc3O)nc3ccccc23)C1
Yield: 42.3 %

Procedure:
A solution of (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (0.218 g, 1.173 mmol) and 2-(4-chloroquinolin-2-yl)phenol (0.100 g, 0.391 mmol) in DMSO (2 mL) was heated under microwave conditions at 155° C. for 1.5 hours. The mixture was added to water (50 mL) and extracted with diethyl ether (2×20 mL). The organic layers were combined, dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (30-40% ethyl acetate/hexane) to give the title compound (0.067 g, 42%).