Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5]([N:7]=[C:8]([C:10]1[CH:11]=[C:12]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:16][C:15]2=[O:26])[CH3:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[B-]C#N.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO>[CH3:4][C:1]([CH3:2])([S@:5]([NH:7][CH:8]([C:10]1[CH:11]=[C:12]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:16][C:15]2=[O:26])[CH3:9])=[O:6])[CH3:3]
Reactant: CC(=NS(=O)C(C)(C)C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: O=C([O-])[O-]
Agent: [B-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(N[S@](=O)C(C)(C)C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: -15 °C
Reaction time: 5 h
Yield: 5.53 %

Procedure:
The 8-(1-(tert-butylsulfinylimino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was diluted in DCM (35 mL) and MeOH (35 mL), acetic acid (4.6 mL, 80.4 mmol) and sodium cyanotrihydroborate (1.9 g, 30.2 mmol) was added at −15° C. The resulting mixture was stirred at −15° C. for 5 hrs then allowed to warm to 0° C. A sat. sol. of Na2CO3 was added at 0° C. until pH˜8-9 and extracted with DCM (×2). The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (column SiO2, 15-40 μm-150 g Merck) eluting with 5 to 15% EtOH in DCM. The fractions containing impure product were concentrated down and repurified using the same system. The fractions containing pure 8-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide were combined and the solvent was evaporated to dryness to afford 2.48 g, (5.52 mmol, 54.9%) as a white foam. The fractions containing a mixture of diastereoisomers were combined, concentrated and purified by preparative HPLC on a Waters X-Bridge system. The fractions containing the desired compound were evaporated to dryness to afford a further crop of 8-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.25 g, 0.556 mmol, 5.53%) as a white foam. These 2 batches (2.48 g) and (0.25 g) were combined to give 8-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.73 g, 60%, diastereomeric excess >95%). Mass Spectrum: M+H+ 450.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[N:16]=[C:15]2[S:17][CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]2=[C:13]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:12]=1)[C:6](OCC)=[O:7])C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[C:20]1([C:19]2[C:14]3[C:15](=[N:16][C:11]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[CH:12][C:13]=3[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[S:17][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCC(CO)c1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-malonic acid diethyl ester (87 mg, 0.18 mmol) in dry THF (10 ml) was cooled to 0° C. under nitrogen. Diisobutyl Aluminium Hydride (1.46 ml of a 1M solution in hexanes, 1.46 mmol) was added dropwise over 2 min and the mixture stirred at 0° C. for 1 h, then allowed to reach room temperature overnight. The reaction was quenched at 0° C. by adition of 1M Rochelle's salt (10 ml). The mixture was extracted with DCM (3×20 ml), the extracts combined, washed with brine (50 ml), dried over magnesium sulphate and concentrated. The residue was purified on silica, eluting (Ethyl Acetate, 100%) to give 2-{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-propane-1,3-diol as a yellow oil. Yield=22.5 mg, (31.4%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:12][C:11](=[O:13])[C@@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To a solution of 11.19 g (59.1 mmol) of (R)-N-tert-butoxycarbonylalanine in 70 mL of N,N-dimethylformamide was added 6.7 g (48.5 mmol) of K2CO3, and 6.9 mL (58.0 mmol) of benzyl bromide. The reaction was stirred at 80° C. for 40 min, then poured into 350 mL of H2O. The aqueous mixture was extracted with diethyl ether (3×50 mL), then the combined ether layers were back extracted with H2O (2×50 mL), and brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo to furnish the titled compound as a colorless oil. MS (ESI) m/z=280 (M+H)+, 297 (M+NH4)+, 302 (M+Na)+: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25 (d, J=7.5 Hz, 3H) 1.37 (s, 9H) 4.06 (m, 1H) 5.07 (d, J=12.9 Hz, 1H) 5.15 (d, J=12.5 Hz, 1H) 7.34 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:14][C:13]([C:6]1[O:7][C:8]([C:10]2[C:4]([C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:12][CH:11]=2)=[O:9])=[O:15]
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1

Procedure:
To a solution of 6-bromo-4-phenylisocoumarin-3-carboxylic acid (10 g) in methanol (200 ml) was added sulfuric acid (20 ml) and the mixture was refluxed for 2 hrs. The reaction mixture was concentrated, and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was crystallized from isopropyl ether to give the title compound (9.76 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:18])=[C:16]([CH3:17])[C:3]=12.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:18])=[C:16]([CH3:17])[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2sc(Br)c(C)c2c(N)c1C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of ethyl 4-amino-2-bromo-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (Description 31) (857 mg, 2.60 mmol) in ethanol (25 mL) was added aqueous NaOH (2M) (2.60 mL, 5.21 mmol) and reaction mixture stirred at 100° C. for 4 h. The mixture was then cooled to RT before the solvent was removed in vacuo. The residue was then taken-up in water (20 mL) before acidifying with aqueous HCl (2M) (2 mL) to form a precipitate. The mixture was then subjected to a centrifuge and the aqueous solution was then decanted off and the solid residue dried under vacuum, to afford the title compound (720 mg). LCMS (A) m/z: 301/303 [M+1]+, Rt 0.67 min (acidic).
Reaction SMILES: C1C2NC3C(=CC=CC=3)SC=2C=CC=1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H]1CCOC1O)=O)CC(C)C)=O)CC(C)C)=O)CC(C)C)=O.[CH:48]1[C:58]2[CH2:57][CH2:56][C:55]3[CH:59]=[CH:60][CH:61]=[CH:62][C:54]=3[NH:53][C:52]=2[CH:51]=[C:50]([C:63]([NH:65][C@H:66]([C:71]([NH:73][C@H:74]([C:79]([NH:81][C@H:82]2[CH2:86][CH2:85][O:84][CH:83]2[O:87]C)=[O:80])[CH2:75][CH:76]([CH3:78])[CH3:77])=[O:72])[CH2:67][CH:68]([CH3:70])[CH3:69])=[O:64])[CH:49]=1>>[CH:48]1[C:58]2[CH2:57][CH2:56][C:55]3[CH:59]=[CH:60][CH:61]=[CH:62][C:54]=3[NH:53][C:52]=2[CH:51]=[C:50]([C:63]([NH:65][C@H:66]([C:71]([NH:73][C@H:74]([C:79]([NH:81][C@H:82]2[CH2:86][CH2:85][O:84][CH:83]2[OH:87])=[O:80])[CH2:75][CH:76]([CH3:78])[CH3:77])=[O:72])[CH2:67][CH:68]([CH3:70])[CH3:69])=[O:64])[CH:49]=1
Reactant: COC1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)c1ccc2c(c1)Nc1ccccc1CC2
Agent: CC(C)C[C@H](NC(=O)c1ccc2c(c1)Nc1ccccc1S2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CCOC1O
Product: CC(C)C[C@H](NC(=O)c1ccc2c(c1)Nc1ccccc1CC2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CCOC1O

Procedure:
The experimental protocol is the same as that described for the compound of Example 2 using the compound of Example 61 as starting product. A light beige solid is obtained. Melting point: 142-143° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[O:24])=[CH:18][C:14]=1[C:15](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:12][C:13]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[O:24])=[CH:18][C:14]=1[C:15]1[NH:11][C:6]2[C:7]([N:10]=1)=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccco1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(Nc1ccc(Cl)c(-c2nc3ncc([N+](=O)[O-])cc3[nH]2)c1)c1ccco1
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A mixture of 5-nitropyridine-2,3-diamine (1-2) (6 g, 38.93 mmol, 1.00 equiv) and 2-chloro-5-(furan-2-amido)benzoic acid (I-3) (10.4 g, 39.15 mmol, 1.00 equiv) in PPA (100 mL) was stirred overnight at 130° C. The reaction was then poured into water/ice and the pH value of the mixture was adjusted to 9 with sodium carbonate. The solids were collected by filtration and applied onto a silica gel column with ethyl acetate/petroleum ether (31) to give 3.9 g (26%) of N-(4-chloro-3-[6-nitro-1H-imidazo[4,5-b]pyridin-2-yl]phenyl)furan-2-carboxamide (I-3) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C2N=C(C(O)=O)SC=2C2C=C(F)C=C(Cl)C=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:26]1[S:30][C:29]([C:31]([O:33]CC)=[O:32])=[N:28][C:27]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:26]2[S:30][C:29]([C:31]([OH:33])=[O:32])=[N:28][C:27]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Reactant: CCOC(=O)c1nc(-c2cccc(Cl)c2)c(Br)s1
Product: O=C(O)c1nc(-c2cccc(Cl)c2)c(-c2ccc(F)c(Cl)c2)s1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 8A starting with the compound from Example 5A. 59.0 mg (56% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:15][CH:16]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: OB(O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1oc(-c2ccc(Cl)nc2)cc1C=O
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.3 g), 2-chloropyridine-5-boronic acid (1.3 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.1 g, 68%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([C:25]2[N:29](COCC[Si](C)(C)C)[C:28]3[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=3[N:26]=2)([OH:24])[CH3:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.CC1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(O)C)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2>>[CH3:1][C:2]1[C:3]([C:22]([C:25]2[NH:29][C:28]3[CH:38]=[CH:39][C:40]([C:42]#[N:43])=[CH:41][C:27]=3[N:26]=2)([OH:24])[CH3:23])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Product: Cc1cc(C)c2[nH]ccc2c1C(C)(O)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile following similar procedures as described in Example 64-B and 64-C. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (br.s, 1H) 10.80 (s, 1H) 8.18 (m) 7.77-7.82 (m) 7.48-7.54 (m) 7.07 (br. s, 1H) 6.63 (s, 1H) 6.23-6.25 (m) 5.96 (s, 1H) 2.38 (s, 3H) 2.11 (s, 3H) 2.07 (s, 3H). HRMS calcd. for C20H18N4O (M+H)+ 331.1553. found 331.1559.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=O)=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:28][NH2:29]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH:29][CH3:28])=[O:24])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reactant: CN
Solvent: CCO
Product: CNC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 18 h

Procedure:
A suspension of the product of Example 1 (100 mg) in a 33% w/v solution of methylamine in ethanol (3 ml) was stirred for 18 hours. The solid formed, after filtration and washing with a little ethyl acetate, gave the title compound, 65 mg: m.p. 169°-171° C.; NMR (d6 DMSO)δ8.14(2H,d), 8.06(1H,bq), 8.00(2H,d), 7.05(2H,d), 6.80(2H,d), 4.56(2H,s), 3.82(2H,s), 3.30(4H,t), 2.66(3H,d), 2.61(4H,t); m/e 369 (M+H)+ ; calculated for C20H24N4O3 : C, 65.2; H, 6.6; N, 15.2. found: C, 65.0; H, 6.8; N, 15.1%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])=O.[NH3:14].CO>>[NH:14]=[C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])[CH3:1]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: N
Solvent: CO
Product: CC(=N)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 2-hydroxy-5-nitroacetophenone (2.96 g, 16.34 mmol) and ammonia in MeOH (11.67 mL, 82 mmol) was stirred for 1 hr at rt. The reaction mixture was concentrated to afford the crude title product (2.94 g, 16.32 mmol, 100% yield) as a yellow solid. tR: 0.53 min (LC-MS 2); ESI-MS: 181 [M+H]+ (LC-MS 2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:21][CH:20]=2)[N:3]=1.[OH-].[Na+].CCOCC.Cl>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[O:27])=[CH:23][CH:24]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Temperature: 25 °C
Reaction time: 45 h
Yield: 58.7 %

Procedure:
A solution of methyl {4-chloro-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetate (0.085 g, 0.17 mmol) in THF (3 mL) was treated with 1N NaOH (1.5 mL) and the biphasic mixture was stirred at room temperature for 45 hours. Et2O was then added and the organic layer siphoned off. The remaining aqueous layer was cooled to 0° C. and acidified with 6N HCl. The separated solids were collected by suction and rinsed with water. Drying under high vacuum at 45° C. for 5 hours gave {4-chloro-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}acetic acid (0.050 g, 56% yield) as an off-white powder.
Reaction SMILES: BrC1C[C:5](=O)[C:4]([CH2:8]CCCCCC(OCC)=O)=[CH:3]1.[OH:19][CH:20]1[CH2:24][C:23](=[O:25])[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:21]1>C(=O)([O-])[O-].[Ag+2].C(O)(C)(C)C>[C:4]([O:19][CH:20]1[CH2:24][C:23](=[O:25])[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:21]1)([CH3:8])([CH3:5])[CH3:3]
Reactant: CCOC(=O)CCCCCCC1=CC(O)CC1=O
Reactant: CCOC(=O)CCCCCCC1=CC(Br)CC1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Product: CCOC(=O)CCCCCCC1=CC(OC(C)(C)C)CC1=O

Procedure:
A stirred mixture of 6.35 g. (20 mmoles) of 4-bromo-2-(carbethoxyhexyl)cyclopent-2-en-1-one (Example 94), 3.01 g. (11 moles) of silver carbonate, and 40 ml. of t-butanol is heated at 70° C. for 17 hours. The mixture is cooled and filtered. After evaporation of t-butanol the residue is treated with aq. sodium chloride and extracted with 3:1 ether-hexane. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on silica gel to give, in order of elution: the subject compound as an oil; λ maxMeOH. = 219 mμ (8860); ν max. = 1735 (ester carbonyl group), 1725 ketone carbonyl group), and 1365 cm-1 (tert.-butyl group); and 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one also as an oil.
Reaction SMILES: [Na].C([CH:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6])#N.Br>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:4][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[O:6])=[CH:14][CH:15]=1
Reactant: N#CC(C(=O)c1ccncc1)c1ccc(F)cc1
Agent: Br
Agent: [Na]
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)c1ccncc1

Procedure:
The starting materials are converted in a condensation reaction with the aid of metallic sodium in an alcohol, for example ethanol, into 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (compound 1). The cyano group is then removed by hydrolysis, for example with hydrobromic acid, and decarboxylation, giving 2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (compound 2). In the next step, compound 2 is nitrosated in the 2-position using, for example, nitrites, such as sodium nitrite or isoamyl nitrite.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3]1.[H-].[Na+].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]OC1C=C(S([O-])(=O)=O)C=CC=1C>CN(C)C=O>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:6]1[C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[NH:3][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)NC(=O)C(C)(C)N1
Reactant: COCCOCCOCCOc1cc(S(=O)(=O)[O-])ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCN1C(=O)C(C)(C)NC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
2,2,5,5-Tetramethylimidazolidin-4-one (20.00 g, 140.6 mmol), prepared as described in U.S. Pat. No. 5,126,057 (Worely et al., Jun. 30, 1992), was dissolved in N,N-dimethylformamide (300 ml). To the stirring room temperature solution was added sodium hydride (60%, 5.06 g, 126.5 mmol), in 8 portions over 30 minutes. After an additional one hour of stirring at room temperature, [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]p-toluenesulfonate (40.15 g, 126.1 mmol) was slowly added to the basic solution over a 20 minute period. The reaction mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was concentrated under high vacuum. The solid material was dissolved in dichloromethane and the solution was filtered to remove any solid material. The organic layer was concentrated in vacuo, and crude material was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give 15.51 g (38%) of the title compound. 1H NMR (D2O, 400 MHz) δ 3.70-3.46 (m, 12H), 3.64-3.59 (m, 2H), 3.46 (t, J=6.2 Hz, 2H), 3.26 (s, 3H), 1.31 (s, 6H), 13C NMR (D2O, 100 MHz) δ 179.48, 76.22, 70.99, 69.59, 69.56, 69.39, 67.71, 58.90, 58.00, 39.70, 27.28, 25.67; LRMS (ESI/APCI) m/z 289 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH2:5].Br[CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH:5][CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: BrCC1OCCO1
Reactant: CCOC(CN)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CNCC1OCCO1)OC
Temperature: 25 °C

Procedure:
2-Methoxy-2-ethoxyethylamine (0.11 mole), 2-bromomethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](#[N:20])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[NH2:15][C:13]1[N:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:17])[N:10]=[C:11]([C:18]#[N:20])[N:12]=1
Reactant: CN(Cc1ccccc1)c1nc(N)nc(Cl)n1
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)c1nc(N)nc(C#N)n1
Reaction time: 1 h

Procedure:
To N-Benzyl-6-chloro-N-methyl-[1,3,5]triazine-2,4-diamine (Intermediate 34, 350 mg, 1.40 mmol) was added tetra n-butylammonium cyanide (1.15 g, 4.28 mmol) and anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 50 C for 1 h, diluted with EtOAc (20 mL), extracted with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to furnish the desired product, which was used directly without further purification (327 mg, 97%). Method C HPLC-MS: MH+ requires m/z=241. Found: m/z=241, Rt=1.29 min (86%).