Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:18]([CH2:36][C@@:37]23[CH2:45][CH2:44][CH2:43][N:38]2C(=O)[O:40][CH2:41]3)[C:19]2[C:24]([C:25]=1[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:18]([CH2:36][C@@:37]2([CH2:41][OH:40])[CH2:45][CH2:44][CH2:43][NH:38]2)[C:19]2[C:24]([C:25]=1[CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)=[CH:23][CH:22]=[C:21]([C:32]([O:34][CH3:35])=[O:33])[CH:20]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)n(C[C@@]34CCCN3C(=O)OC4)c2c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)n(C[C@@]3(CO)CCCN3)c2c1

Procedure:
1M aq. KOH (15 eq.) was added to a 0.08M solution of methyl 2-[2-(benzyloxy)phenyl]-3-cyclohexyl-1-{[(7aR)-3-oxodihydro-1H-pyrrolo[1,2-c][1,3]oxazol-7a(5H)-yl]methyl}-1H-indole-6-carboxylate in MeOH, and the mixture was refluxed for 2 days. After quenching with an equivalent amount of aq. HCl and evaporation of volatiles, the residue was taken in toluene:MeOH 4:1 (0.1M) and treated at RT with excess (2.5 eq.) TMS-diazomethane for 1 h; evaporation of solvents gave crude methyl 2-[2-(benzyloxy)phenyl]-3-cyclohexyl-1-{[(2R)-2-(hydroxymethyl)pyrrolidin-2-yl]methyl}-1H-indole-6-carboxylate. To a 0.1M solution of this material in dry DCM were added TEA (3 eq.) and Boc2O (1.5 eq.) and the mixture was stirred at RT overnight, after quenching with sat NaHCO3 the mixture was extracted with EtOAc, washed with brine, dried and concentrated; chromatography (PE/EtOAc 2:1) afforded the title compound (57%).
Reaction SMILES: [CH2:1]([C@@](C(O)=O)(CO)N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(=N)(OCC)C1C=CC=CC=1.Cl.[C:35]([O:39][C:40](=[O:45])[C@H:41]([CH2:43][OH:44])[NH2:42])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:35]([O:39][C:40]([CH:41]1[CH2:43][O:44][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:42]1)=[O:45])([CH3:38])([CH3:37])[CH3:36]
Reactant: N[C@](CO)(Cc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)CO
Agent: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1COC(c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
In order to synthesize α-benzyl-L-serine (Angew. Chem. Int. Ed. 2004, 43, 2382-2385), 1.41 ml of triethylamine was added to a methylene chloride solution in which 939.2 mg of ethyl benzimidate hydrochloride and 1 g of L-serine-tert-butyl ester hydrochloride had been dissolved. The mixture was heated and refluxed for 2.5 hours, and stirred at room temperature for 19 hours. 50 ml of methylene chloride was added to the reaction mixture, which was then washed twice with 20 mL of water, and dried on magnesium sulfate. Magnesium sulfate was removed, and then the solvent was evaporated. A residue was purified by silica gel chromatography (hexane/ethyl acetate, 5/1 to 4/1). After evaporating the solvent, 759 mg of 2-phenyl-2-oxazoline-4-carboxylate tert-butyl ester was yielded. 0.12 ml of benzyl bromide was added to a toluene solution in which 52.4 mg of 2-phenyl-2-oxazoline-4-carboxylate tert-butyl ester, 56.1 mg of potassium hydroxide and 9.55 mg of (S,S)-3,4,5-trifluorophenyl-NAS bromide (Wako Pure Chemical Industries Ltd., code number: 201-16401) had been suspended. The resulting mixture was stirred at 0° C. for 8 hours. 20 ml of ethyl acetate was added to the reaction mixture, which was then washed twice with 5 mL of water, and dried on magnesium sulfate. Magnesium sulfate was removed, and then the solvent was evaporated. A residue was purified by silica gel chromatography (hexane/ethyl acetate, 8/1 to 5/1). After evaporating the solvent, 51 mg of 4-benzyl 2-phenyl-2-oxazoline-4-carboxylate tert-butyl ester was obtained. This was analyzed by HPLC using CHIRALPAK OD-H (4.6×250 mm) (Mobile phase: hexane/isopropyl alcohol=99/1, column temperature: room temperature, flow rate: 1 ml/minute, detection: UV 210 nm), and its optical purity was 98.4% e.e. 1 ml of ethanol and 0.5 ml of a 6 N sodium hydroxide solution were added to 42 mg of 4-benzyl 2-phenyl-2-oxazoline-4-carboxylic acid tert-butyl ester, which was then heated and refluxed for 1 hour. Then 1 ml of 6 N HCl was added, and the reaction mixture was heated and refluxed for 2 hours. The reaction mixture was neutralized and impurities were removed to obtain a solution containing α-benzyl-L-serine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:22]=[C:21]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:19][N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1.[ClH:32]>O1CCOCC1>[ClH:1].[ClH:32].[NH2:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of tert-butyl [2-(2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-4-yl]carbamate (0.75 g, 1.6 mmol) in 1,4-dioxane (3.0 mL) was added 4 M hydrogen chloride in 1,4-dioxane (7.1 mL). The resultant reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated under vacuum to give the desired product as a light yellow powder (0.67 g, 95%). LCMS for C17H16Cl2N5 (M+H)+: m/z=360.2, 362.0.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].O=[C:14]1[CH2:19][CH2:18][S:17][CH2:16][CH:15]1[C:20](OC)=[O:21].C([O-])(=O)C.[NH4+].O>C(#N)C>[O:21]=[C:20]1[N:3]2[C:2]([NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=32)=[C:10]([C:11]#[N:12])[C:14]2[CH2:19][CH2:18][S:17][CH2:16][C:15]1=2
Reactant: N#CCc1nc2ccccc2[nH]1
Reactant: COC(=O)C1CSCCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: N#Cc1c2c(c(=O)n3c1[nH]c1ccccc13)CSCC2
Temperature: 140 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 1H-benzimidazol-2-ylacetonitrile (13 g), methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (15.3 g), and ammonium acetate (33 g) was heated and stirred at 140° C. for 1 hour. The reaction mixture was cooled to room temperature, water and acetonitrile were added, and the resulting precipitate was collected by filtration and dried under reduced pressure to obtain 12-oxo-3,4,6,12-tetrahydro-1H-thiopyrano[4′,3′:4,5]pyrido[1,2-a]benzimidazole-5-carbonitrile (16 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18](Cl)=[O:19])[CH3:2].[Cl:21][C:22]1[C:23]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[C:37]2[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=2)=[CH:24][C:25]([F:29])=[C:26]([NH2:28])[CH:27]=1>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]1[C:23]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[C:37]2[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=2)=[CH:24][C:25]([F:29])=[C:26]([NH:28][C:18]([C:5]2[C:6](=[O:17])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:19])[CH:27]=1
Reactant: Cn1cc(-c2cnccc2Oc2cc(F)c(N)cc2Cl)cn1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccncc2-c2cnn(C)c2)cc1F
Yield: 37.7 %

Procedure:
To a solution of 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (0.275 g, 0.929 mmol) in CH2Cl2 (2 mL) was added a suspension of 5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (0.148 g, 0.464 mmol) in pyridine (2.00 mL) at 0° C. The resultant mixture was stirred at ambient temp for 30 min. The solvent was completely evaporated and the residue was stirred in water. The precipitate was collected by filtration and was re-crystallized from acetonitrile to provide N-(5-chloro-2-fluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.101 g, 37.6% yield) as an off-white solid. The mesylate salt was prepared by treatment with one equivalent of methanesulfonic acid. 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.20 (s, 1H), 8.62 (d, J=5.5 Hz, 1H), 8.51 (m, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.75 (d, J=11 Hz, 1H), 7.50 (m, 2H), 7.41 (m, 2H), 7.25 (d, J=2.5 Hz, 1H), 6.60 (d, J=5.5 Hz, 1H), 4.30 (q, J=6 Hz, 2H), 3.92 (s, 3H), 2.30 (s, 3H), 1.30 (t, J=6 Hz, 3H); MS (ESI) m/z: 578.2 (M+H+).
Reaction SMILES: [OH-].[Li+].O1CCCC1.C[O:9][C:10](=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[CH:14][CH:13]=1.Cl>CO>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([OH:28])=[O:9])=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Lithium hydroxide, 2M, (3.0 mL) was added to a 2:1 tetrahydrofuran:methanol (9.0 mL) solution of (4-Naphthalen-2-yl-phenyl)-acetic acid methyl ester (270 mg, 0.977 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was acidified to pH=1 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (233 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 8.01-7.39 (m, 11H), 3.72 (s, 2H)
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][O:21][CH3:22])[C:15]2=[O:23])=[CH:9][N:8]=1)[CH3:3].[Cl:24][C:25]1[S:29][C:28]([O:30][CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:24][C:25]1[S:29][C:28]([O:30][CH2:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:10]3[CH:9]=[N:8][C:7]([NH:6][CH2:5][CH2:4][N:2]([CH3:1])[CH3:3])=[N:12][CH:11]=3)[C:15](=[O:23])[C@@H:16]2[CH2:20][O:21][CH3:22])=[O:33])=[CH:27][CH:26]=1
Reactant: O=C(O)COc1ccc(Cl)s1
Reactant: COC[C@@H]1NCCN(Cc2cnc(NCCN(C)C)nc2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC[C@H]1C(=O)N(Cc2cnc(NCCN(C)C)nc2)CCN1C(=O)COc1ccc(Cl)s1
Reaction time: 12 h

Procedure:
The title compound can be prepared by placing 1-[(2-{[N,N-dimethylaminoethyl]-amino}-pyrimidin-5-yl)-methyl]-3-(S)-methoxymethyl-piperazine-2-one, (5-chloro-thiophen-2-yloxy)-acetic acid, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and triethylamine in DMF and stirring 8-16 h. The mixture is evaporated and is diluted with ethyl acetate. The organic phase is washed with water, 2 N HCl, 1 N NaOH and brine, is dried (MgSO4) and is evaporated. The residue is purified by flash chromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide the title compound.
Reaction SMILES: ClC1C=CC(CCC(C2C=CC(F)=CC=2)=O)=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:22][CH:21]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: O=C(CCc1ccc(Cl)cc1)c1ccc(F)cc1
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)cc1)c1ccc(F)cc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(4-chlorophenyl)-1-(4-fluorophenyl)propan-1-one, (Z)-ethyl 5-(4-chlorophenyl)-3-(4-fluorophenyl)pent-2-enoate and (E)-ethyl 5-(4-chlorophenyl)-3-(4-fluorophenyl)pent-2-enoate were obtained as colourless oils.
Reaction SMILES: [CH3:1][C:2]([C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][N:19]=[CH:20][C:13]=23)[S:10][CH:11]=1)([CH2:5]C)[C:3]#[N:4].[OH-].[Na+].[Cl:23][O-].[Na+]>O.C([O-])([O-])=O.[Na+].[Na+]>[Cl:23][C:20]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[C:9]2[S:10][CH:11]=[C:7]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])[N:8]=2)[NH:18][N:19]=1
Reactant: [O-]Cl
Reactant: CCC(C)(C#N)c1csc(-c2ccnc3[nH]ncc23)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C#N)c1csc(-c2ccnc3[nH]nc(Cl)c23)n1
Yield: 4.4 %

Procedure:
2-methyl-2-[2-(1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]butanenitrile (82 mg, 0.2894 mmol) was suspended in a solution of NaOH (46.32 mg, 1.158 mmol) in Water (5.000 mL). The mixture was sonicated to give smaller particle size and cooled in an ice-bath. Sodium hypochlorite (282.8 μL of 8% w/v, 0.3039 mmol) was added slowly dropwise over 2 minutes and the resultant mixture was stirred at ambient temperature for 3 hours. The reaction was diluted with saturated aqueous Na2CO3 and then extracted twice with EtOAc. The combined organics were dried (MgSO4), filtered, concentrated and purified by column chromatography (1:1, Petroleum ether/EtOAc) to give the pure compound as a white solid (3.9 mg, 4% Yield). 1H NMR (DMSO, 400 MHz) δ 0.93 (3H, t), 1.76 (3H, s), 1.99-2.21 (2H, m), 7.54 (1H, s), 8.00 (1H, s), 8.71 (1H, s), 14.29 (1H, br s); MS (ES+) 318.08
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][CH:31]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:30][CH3:31])[CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2noc(-c3cc4cnccc4o3)n2)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(Cc1noc(-c2cc3cnccc3o2)n1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 4-[(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)amino]-piperidine-1-carboxylic acid tert-butyl ester (Example 30, 50 mg, 120 μmol), MeCHO (6 μL, 120 μmol), and NaBH(OAc)3 (36 mg, 168 μmol) in CH2Cl2 (5 mL) was stirred for 3 d at ambient temperature. The reaction mixture was washed with water, before being dried (MgSO4) and purified by column chromatography to furnish the title compound: RT=2.40 min; m/z (ES+)=428.2 [M+H]+.
Reaction SMILES: CC([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C:7]1[C:15]2[N:14]=[C:13]([CH3:16])[N:12]([CH2:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:10]=[C:9]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:16][C:13]1[N:12]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:10]=[C:9]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:8]=[C:7]([OH:6])[C:15]=2[N:14]=1
Reactant: Cc1nc2c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2c(O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 4-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole in THF (50 mL) was added TBAF (0.64 mL, 1 mol/L) at room temperature and the mixture was stirred for 1 h. TLC showed consumption of starting material. The solvent was removed in-vacuo and the residue was purified by silica gel chromatography eluted with MeOH:DCM=1:60 to afford the desired product as a white solid (150 mg, 94%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 2.94 (t, 4H, J=4.8 Hz), 3.65 (t, 4H, J=4.8 Hz), 5.87 (s, 2H), 6.30 (d, 1H, J=1.8 Hz), 6.35 (d, 1H, J=1.8 Hz), 6.39 (d, 1H, J=7.5 Hz), 7.35 (t, 1H, J=7.5 Hz), 7.60-7.71 (m, 2H), 7.86 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=7.5 Hz), 8.23 (d, 1H, J=8.4 Hz); LC-MS: m/e=374[M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30]CS(C)(=O)=O)[CH2:25][CH2:24]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.N1(CC[NH:65][S:66]([CH3:69])(=[O:68])=[O:67])CCNCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][NH:65][S:66]([CH3:69])(=[O:68])=[O:67])[CH2:27][CH2:28]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:47])([CH3:48])[CH3:49])(=[O:43])=[O:44])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C37H48N6O6S2Cl3 [(M+H)+] 841.2137, observed 841.2129.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:8][C:7]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:6][C:5]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=O)[CH3:2].C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:11]([O:10][C:9]1[C:4]([CH2:1][CH3:2])=[C:5]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:6]=[C:7]([O:14][CH2:15][CH:16]=[CH2:17])[CH:8]=1)[CH:12]=[CH2:13]
Reactant: C=CCOc1cc(CC(=O)OC)c(C(C)=O)c(OCC=C)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1cc(CC(=O)OC)c(CC)c(OCC=C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
Methyl 2-acetyl-3,5-diallyloxyphenylacetate (1.1 g, 3.7 mmol) obtained in Example 5, Step 2 was dissolved in trifluoroacetic acid (5.0 mL), and triethylsilane (1.2 mL, 7.5 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was gradually added to a saturated aqueous solution of sodium hydrogencarbonate for neutralization, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate/hexane=1/4) to obtain methyl 3,5-diallyloxy-2-ethylphenylacetate (0.66 g, 62%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[NH2:15].CC(O)=O>O1CCOCC1.C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: FC(F)c1ccnc(Cl)n1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2nccc(C(F)F)n2)c1
Reaction time: 30 h
Yield: 72.2 %

Procedure:
The product of Step 1 (4.75 g, 23 mmol) and 3-bromo-5-methylaniline (5.59 g, 30 mmol) were diluted with dioxane (33 mL) to which AcOH (1.32 mL, 23 mmol) was added. The resulting mixture was heated to reflux and kept stirring for 30 h after which it was recooled to room temperature, diluted with CH2Cl2 and absorbed on silica prior to purification by flash chromatography to afford N-(3-bromo-5-methylphenyl)-4-(difluoromethyl)pyrimidin-2-amine (5.2 g, 16.6 mmol). 1H NMR (600 MHz, CDCl3) δ 8.58 (d, J=4.9, 1H), 7.75 (s, 1H), 7.32 (s, 1H), 7.21 (s, 1H), 7.06-6.92 (m, 2H), 6.50-6.27 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:12]([NH:15][S:16](Cl)(=[O:18])=[O:17])([CH3:14])[CH3:13]>C1C=CC=CC=1>[CH3:13][CH:12]([NH:15][S:16]([NH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:18])=[O:17])[CH3:14]
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: COC(=O)c1cccnc1N
Solvent: c1ccccc1
Product: COC(=O)c1cccnc1NS(=O)(=O)NC(C)C

Procedure:
Methyl 2-amino-3-pyridine carboxylate (10.0 grams; 0.066 mole) and isopropyl sulfamoyl chloride (11.4 grams; 0.066 mole) were mixed with 300 ml of benzene and the resulting reaction mixture heated at reflux temperatures for a period of 48 hours. Following the reaction period, the reaction mixture was cooled and the solvent removed in vacuo. The oily residue thus obtained was extracted with 200 ml of cyclohexane and the extracts combined and cooled. The resulting precipitate was recovered by filtration and recrystallized from carbon tetrachloride. As a result of these operations, the desired title compound having a melting point of 121° C.-123° C. was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][C@H:37]([CH3:40])[CH2:38][OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-1-propanol using methods similar to Example 563 to provide a tan solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.74 Hz, 3 H), 1.65-1.81 (m, 6 H), 2.19 (t, J=5.79 Hz, 2 H), 3.21 (t, J=5.90 Hz, 2 H), 3.37 (t, J=6.95 Hz, 2 H), 3.48 (t, J=5.05 Hz, 2 H), 4.05 (t, J=6.00 Hz, 1 H), 4.14-4.23 (m, 4 H), 5.00 (t, J=5.16 Hz, 1 H), 7.10-7.18 (m, 2 H), 7.37-7.44 (m, 2 H), 7.98 (s, 1 H), 8.56 (d, J=1.26 Hz, 1 H), 10.31-10.39 (m, 1 H), 17.24 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(Cl)Cl.S(=O)(=O)(O)O>[CH2:19]([O:18][C:16]([C:9]1[C:10]2[C:15](=[CH:14][C:13]([Br:21])=[CH:12][CH:11]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(=O)OCC)c2cc(Br)ccc12
Reaction time: 8 h

Procedure:
Naphthalene-1,4-dicarboxylic-acid diethyl ester 35.0 g was dissolved in a mixed solvents 280 ml of methylene chloride and concentrated sulfuric acid (weight ratio 3:7), and N-bromo succinimide 22.9 g was added here at a room temperature. After stirring overnight, the reaction mixture was poured into ice, and extracted with ethyl acetate. The extracted solution was washed with diluted alkaline water, subsequently with water, and then dried by magnesium sulfate. The solution was concentrated, and treaded with column processing (silica gel/chloroform), and 28.0 g of a crude product of 6-bromonaphthalene-1,4-dicarboxylic-acid diethyl ester was obtained.