Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O>>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: OB(O)c1cccs1
Reactant: O=Cc1cccc(Br)c1
Product: O=Cc1cccc(-c2cccs2)c1
Yield: 93 %

Procedure:
Ex-42A: 3-(Thiophen-2-yl)-benzaldehyde was prepared from 3-bromobenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. Orange oil, 93% yield. 1H-NMR (CDCl3) δ 10.06 (s, 1H), 8.10 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.55 (dd, J=7.2, 8.4 Hz, 1H), 7.40 (dd, J=1.5, 3.6 Hz, 1H), 7.34 (dd, J=1.5, 5.3 Hz, 1H), 7.11 (dd, J=3.6, 5.3 Hz, 1H). HRMS m/z: calc. 188.0296. found 188.0293.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])C.[CH3:19][NH:20]N>C(O)(=O)C>[CH2:13]([C:11]1[C:10]([O:15][CH3:16])=[N:9][C:8]([CH3:17])=[C:7]([C:6]2[N:20]([CH3:19])[N:2]=[CH:4][N:5]=2)[CH:12]=1)[CH3:14]
Reactant: CCc1cc(C(=O)N=CN(C)C)c(C)nc1OC
Reactant: CNN
Solvent: CC(=O)O
Product: CCc1cc(-c2ncnn2C)c(C)nc1OC
Temperature: 90 °C
Reaction time: 12 h
Yield: 60.7 %

Procedure:
In a round bottom flask under a nitrogen atmosphere N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methyl-nicotinamide (synthesized on 0.567 mmol scale) of Step 2, Example 16 is treated with glacial acetic acid (1 mL) followed by methylhydrazine (50 μL, 0.94 mmol). The resulting mixture is stirred at 90° C. for 12 hr. The reaction mixture is evaporated to dryness and the residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (99:1). Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-pyridine (80 mg, 61% yield) as a light yellow oil. MS: m/e=233 (M+H); 1H NMR (δ, ppm): 7.96 (1H, s), 7.29 (1H, s), 3.99 (3H, s), 3.74 (3H, s), 2.59 (2H, q), 2.30 (3H, s), 1.19 (3H, t).
Reaction SMILES: C(=O)(O)[O-].[Na+].[S:6]=[C:7]1[NH:11][CH2:10][N:9]=[N:8]1.C(O[CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:35])[CH:21]2[NH:25][C:26](=[O:34])[CH2:27][C:28]2[S:29][C:30](=[O:33])[S:31][CH:32]=2)[C:18]=1[C:36]([OH:38])=[O:37])(=O)C>>[C:36]([C:18]1[N:19]2[CH:22]([S:23][CH2:24][C:17]=1[CH2:16][S:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1)[CH:21]([NH:25][C:26](=[O:34])[CH2:27][C:28]1[S:29][C:30](=[O:33])[S:31][CH:32]=1)[C:20]2=[O:35])([OH:38])=[O:37]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)s3)C2SC1
Reactant: S=C1N=NCN1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Cc1csc(=O)s1)NC1C(=O)N2C(C(=O)O)=C(CSc3nc[nH]n3)CSC12
Temperature: 60 °C
Yield: 20.5 %

Procedure:
Sodium bicarbonate (5.55 g.) and 3-thioxo-1,2,4-triazoline (3.63 g.) are added to 3-acetoxymethyl-2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (12.9 g.) in a buffer (250 cc.) of pH 6.4. The mixture is heated to 60° C. for 7 hours. It is allowed to cool, sodium bicarbonate (1 g.) is added and the mixture is washed with ethyl acetate (250 cc.), which is discarded. The aqueous solution is treated with decolourising charcoal and is acidified to pH 2 by adding 4 N hydrochloric acid in the presence of ethyl acetate (200 cc.). The organic phase is separated off and the aqueous phase is then extracted with ethyl acetate (750 cc.). The combined organic extracts are dried over sodium sulphate, treated with decolourising charcoal and concentrated to dryness under reduced pressure (20 mm Hg). A residue (5.5 g.) is obtained, which is triturated with acetonitrile (25 cc.). The solid is filtered off and washed with acetonitrile (25 cc.) and isopropyl ether (20 cc.) to give 2-carboxy-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-3-[(1,2,4-triazol-3-yl)-thiomethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (2.9 g.), m.p. 227° C. (decomposition).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[CH3:21][N:22]([CH3:32])[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[CH3:21][N:22]([CH3:32])[C:23]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:20][CH:19]=2)[CH2:30][CH2:31]1)=[O:24]
Reactant: CN(C)C(=O)NC1CCNCC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)C(=O)NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 61.5 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (200 mg, 0.76 mmol) obtained in Step 6 of Example 1, 1,1-dimethyl-3-(piperidin-4-yl)urea (0.20 ml, 1.14 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg, 1.06 mmol) and N-methylmorpholine (0.18 mL, 1.66 mmol) in a similar manner to Example 5, was crystallized from ethyl acetate to obtain Compound 132 (195 mg, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:16][C:15](=[O:17])[NH:14][S:13]1(=[O:19])=[O:18])[CH:8]=[C:7]([CH2:20][CH2:21][CH:22]([CH3:25])[C:23]#[N:24])[CH:6]=[CH:5]2.CC(C)([O-])C.[K+].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[C:23]([CH:22]([CH3:25])[CH2:21][CH2:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:11]([N:12]1[CH2:16][C:15](=[O:17])[NH:14][S:13]1(=[O:19])=[O:18])=[CH:10]2)#[N:24]
Reactant: CC(C#N)CCc1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C#N)CCc1ccc2cc(OC(=O)c3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2c1
Temperature: 25 °C

Procedure:
To a solution of 4-[6-hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-2-methylbutyronitrile (Example 9-3, 29 mg, 0.08 mmol) in DMF (0.6 mL) is added potassium t-butoxide (0.097 mL, 0.097 mmol) followed by benzoyl chloride. The reaction is stirred at RT until the reaction is completed. The reaction mixture is then purified by HPLC to give the title compound: Retention time 1.23 min (Method A); (M+H)+=462.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]#[N:12])=[CH:4][N:3]=1.[S:13]([F:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14]>CC(O)CC>[C:11]([C:5]1[C:6]([NH:8][CH2:9][CH3:10])=[N:7][C:2]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([S:13]([F:23])(=[O:22])=[O:14])=[CH:16][CH:17]=2)=[N:3][CH:4]=1)#[N:12]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CCNc1nc(Cl)ncc1C#N
Solvent: CCC(C)O
Product: CCNc1nc(Nc2ccc(S(=O)(=O)F)cc2)ncc1C#N
Reaction time: 48 h
Yield: 93.3 %

Procedure:
2-Chloro-5-cyano-4-ethylaminopyrimidine (Method 56; 6.35 g, 34.88 mmol) and sulphanilyl fluoride (6.11 g, 34.88 mmol) in 2-butanol (120 ml) were heated at 95° C. for 4 hours and then stirred at ambient temperatures for 48 hours. The volatiles were evaporated and the residue triturated with ether to give the title compound (10.46 g, 93%). NMR: 1.20 (t, 3H), 3.45 (m, 2H), 8.00 (d, 2H), 8.13 (d, 2H), 8.41 (s, 1H), 10.52 (s, 1H); m/z: 321.
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[N:7]([CH3:15])[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([OH:14])[C:13]=3[C@:5]2([CH3:16])[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1.[CH3:28][CH:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH3:28][C@@H:29]([NH:36][C:37](=[O:38])[O:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C@@:5]1([CH3:16])[CH2:4][CH2:3][N:2]([CH3:1])[C@H:6]1[N:7]2[CH3:15])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(N=C=O)c1ccccc1
Reactant: CN1CC[C@@]2(C)c3c(O)cccc3N(C)[C@@H]12
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)Oc1cccc2c1[C@@]1(C)CCN(C)[C@H]1N2C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
cis-(±)-1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo [2,3-b]indol-4-ol (2g) was dissolved in degassed THF (200 ml). DBU (0.8 ml) was added to the mixture followed by R-(+)-α-methylbenzyl isocyanate (2 g). The reaction was stirred at room temperature overnight under nitrogen. The solvent was evaporated under reduced pressure and the residue was purified using Prep 500 chromatography (4% MeOH/DCM) to yield 1.2 g of a solid. This material was combined with 600 mg of identically prepared material, which was found to be pure by thin layer analysis. The combined product was triturated with isopropyl ether and filtered to yield 1.8 g of (±)-(3aR*, 8aS*)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo [2,3-b]indol-4-yl (R)-(α-methylbenzyl)carbamate, m.p. 151°-155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][N:16]([CH:25]([CH3:27])[CH3:26])[C:15]=3[N:14]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Cl:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33].C(OC(C)C)(C)C>O1CCOCC1>[Cl:28][CH2:29][CH2:30][NH:31][C:32]([NH:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[C:4]([NH:12][C:13]2[N:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][N:16]([CH:25]([CH3:27])[CH3:26])[C:15]=3[N:14]=2)[CH:3]=1)=[O:33]
Reactant: O=C=NCCCl
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)NCCCl)cc(S(C)(=O)=O)c3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (300 mg; 0.768 mmol) was diluted under nitrogen atmosphere in 3 ml of dry 1,4-dioxane, then a solution of 2-chloroethyl-isocyanate (0.09 ml; 0.999 mmol) in 2 ml of dry 1,4-dioxane was added drop-wise. The reaction mixture was stirred at room temperature for 3 h, then warmed to 60° C. and maintained at that temperature for 3 h. The reaction mixture was then concentrated in vacuo. The crude obtained was treated with isopropyl ether. The solid obtained was filtered. 261 mg (0.001 mol; 68.5 yield) of the desired compound were obtained.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[NH:20][NH2:21].C(Cl)Cl.Cl>CCO>[NH2:10][C:9]1[N:20]([C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[F:11])[N:21]=[C:4]([CH3:5])[C:6]=1[C:7]#[N:8]
Reactant: COc1ccc(NN)c(F)c1
Reactant: CCOC(C)=C(C#N)C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-n2nc(C)c(C#N)c2N)c(F)c1
Temperature: 105 °C
Yield: 84.5 %

Procedure:
To a stirred solution of 2-(1-ethoxyethylidene)malononitrile (167 mg, 1.23 mmol) was added (2-fluoro-4-methoxyphenyl)hydrazine (220 mg, 1.41 mmol) in EtOH (3 mL). The solution was heated to 105° C. in the microwave for 30 min. CH2Cl2 and 1 M HCl was added and separated, the organic extract was washed with aqueous NaHCO3. The solution was dried using a phase separator and concentrated under reduced pressure to give 5-amino-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (256 mg, 85%), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1)=O.Cl.[NH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][C:13](=[N:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1
Reactant: NN1CCCC1=O
Reactant: Cc1cccc(C(=O)Cc2ccnc3ccc(Br)cc23)n1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc(C(Cc2ccnc3ccc(Br)cc23)=NN2CCCC2=O)n1
Yield: 69.6 %

Procedure:
Stir a mixture of 2-(6-bromo-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone (38.5 g, 113 mmol) and 1-aminopyrrolidinone hydrochloride (20 g, 147 mmol) in 115 mL pyridine at ambient temperature for 10 hours. Add about 50 g of 4 Å unactivated sieves. Continue stirring an additional 13 h and add 10-15 g silica and filter the mixture through a 50 g silica plug. Elute the silica plug with 3 L ethyl acetate. Combine the filtrates and concentrate in vacuo. Collect the hydrazone precipitate by filtration and suction dry to yield 33.3 g (69.7%) of the desired subtitled intermediate as an off-white solid. MS ES+=423 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([Br:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[C:5]([Cl:20])=[CH:4][C:3]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]([Cl:33])=[CH:30][CH2:31]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([Br:15])=[CH:13][C:12]([C:16]([F:17])([F:19])[F:18])=[CH:11][N:10]=2)[C:5]([Cl:20])=[CH:4][C:3]=1[O:21][CH2:31][CH:30]=[C:29]([Cl:33])[Cl:28]
Reactant: ClCC=C(Cl)Cl
Reactant: Oc1cc(Cl)c(Oc2ncc(C(F)(F)F)cc2Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cnc(Oc2cc(Cl)c(OCC=C(Cl)Cl)cc2Cl)c(Br)c1
Temperature: 0 °C
Yield: 82.8 %

Procedure:
To a mixture of 0.77 g of 2,5-dichloro-4-(3-bromo-5-trifluoromethyl-2-pyridyloxy)phenol, 0.29 g of potassium carbonate and 20 ml of N,N-dimethylformamide, a solution prepared by dissolving 0.31 g of 1,1,3-trichloropropene in 5 ml of N,N-dimethylformamide was added dropwise at room temperature with stirring. After stirring at room temperature for 10 hours, the reaction solution was poured into ice-water, and extracted twice with 50 ml of ethyl acetate. Then, the ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 0.81 g of 2,5-dichloro-4-(3-bromo-5-trifluoromethyl-2-pyridyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, yield 83%; m.p., 95.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[C:11]([O:15][C:16]([NH:18][C@@:19]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]2[C@H:20]1[C@H:21]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:17])([CH3:14])([CH3:13])[CH3:12]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(OCC)C.[Ag]=O>[C:11]([O:15][C:16]([NH:18][C@@:19]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:24]([O:25][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C@H:23]([OH:26])[C@@H:22]2[C@H:20]1[C@H:21]2[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=[Ag]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
Add 3,4-dichlorobenzyl bromide (1.02 mL, 1.02 g, 4.26 mmol) to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3,4-dihydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (1.22 g, 2.84 mmol), tetra-n-butylammonium iodide (1.07 g, 2.84 mmol) and silver oxide (987.35 mg, 4.26 mmol) in dimethylformamide (17 mL) at room temperature. Stir overnight. Dilute with diethyl ether and hexanes (1:1), filter through celite, and then wash with ether and hexanes (1:1). The filtrate is washed with water, brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography, eluting with 0-30% ethyl acetate:hexanes to give the title compound (1.7 g, 2.84 mmol, 78%): MS (m/z): 610/612 (M+Na).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([NH2:22])=[O:21])[N:17]=[CH:16]1)[CH2:12][CH2:13][OH:14])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C@H:9]([C@H:11]([N:15]1[CH:19]=[C:18]([C:20]([NH2:22])=[O:21])[N:17]=[CH:16]1)[CH2:12][CH2:13][O:14][S:24]([CH3:23])(=[O:26])=[O:25])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCO)n1cnc(C(N)=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](OCc1ccccc1)[C@@H](CCOS(C)(=O)=O)n1cnc(C(N)=O)c1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a stirred mixture of 1-[(2S,3R)-2-benzyloxy-5-hydroxy-3-pentyl]imidazole-4-carboxamide (330 mg, 1.09 mmol) and methanesulfonyl chloride (249 mg, 2.18 mmol) in dichloromethane (10 ml) was added dropwise triethylamine (220 mg, 2.18 mmol) at ice-bath temperature. After 1 hour, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo to give 1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamide (430 mg, 103%) as an oil. This material was used for the next reaction without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1>O1CCCC1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[N:22][CH:23]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)cn1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 7 ml of water and 1.5 ml of tetrahydrofuran in place of the methanol, and 134 mg of 2-amino-5-fluoropyridine in place of the 3-(tert-butyl)aniline. After stirring for 1 h 30 at ambient temperature, a precipitate forms. The reaction mixture is filtered through sintered glass. The solid obtained is washed with water, ethyl acetate and ethyl ether. 130 mg of N-(5-fluoropyridin-2-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[N:8]([CH:21]1[CH2:24][CH2:23][CH2:22]1)[C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:21]1([N:8]([C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:3]2[NH:2][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[C:9](=[O:20])[C:10]2[C:11]([O:18][CH3:19])=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:24][CH2:23][CH2:22]1
Reactant: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1

Procedure:
To a solution of N-[(1S,2S)-2-aminocyclopentyl]-N-cyclobutyl-2,6-dimethoxybenzamide hydrochloride (Intermediate 18; 200 mg, 0.56 mmol) in dry DMSO (1.9 ml) was added 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 153 mg, 0.85 mmol) and DIPEA (295 μl, 1.69 mmol). The reaction subjected to microwave irradiation at 150° C. for 2 hours and then was partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified using column chromatography (silica, 0-100% ethyl acetate/petrol) and then further purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:20][C:19]([CH3:31])=[N:18][C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.Cl.[OH-].[Na+]>O1CCOCC1>[CH3:31][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH2:23][CH2:24][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=3)[CH2:16][C:17]=2[N:18]=1
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(nc(C)nc3-c3ccccc3)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c(c(-c3ccccc3)n1)CCN(c1ccnc([C@@H](C)O)n1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (R)-1-[4-(2-methyl-4-phenyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 86, Step E, 11.0 g, 26.4 mmol) in dioxane (13 mL) was added concentrated hydrochloric acid (22 mL, 264 mmol). This mixture was stirred at room temperature overnight, cooled to 0° C., neutralized via slow addition of 6 N aqueous sodium hydroxide, and extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2→5% methanol/ethyl acetate) to give an oil which after tritration with hexanes provided 8.0 g (88%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH2:20][CH3:21])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>CN(C=O)C>[F:79][C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([F:80])[CH:76]=1)[CH2:72][C@H:58]([NH:57][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[C:5]([C:3]([N:2]([CH3:1])[CH2:19][CH2:20][CH3:21])=[O:4])[CH:6]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-{[Methyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (350 mg, 1.2 mmol) in DMF (5 mL) is added diisopropylethylamine (835 μL, 4.8 mmol), HATU (554 mg, 1.5 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of Example SP-272 (488 mg, 1.2 mmol). The reaction is stirred for 16 h at room temperature. The reaction is partitioned between chloroform and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/chloroform) gives the title compound. ESI MS m/z 605.3 [M+H]+.