Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](O[CH2:19][C:20]1[CH:21]=[C:22]([C@H:27]2[C@@H:32]([OH:33])[C@@H:31]([OH:34])[C@H:30]([OH:35])[CH:29]([CH2:36][OH:37])[O:28]2)[CH:23]=[CH:24][C:25]=1Cl)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:38][C:39]1[CH:40]=[CH:41][C:42]2[N:43]([C:45](=[O:48])[NH:46][N:47]=2)[CH:44]=1.[C:49](=O)([O-])[O-:50].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.ClCCl.CO>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]2[N:43]([C:45](=[O:48])[N:46]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:50][CH3:49])=[C:22]([C@H:27]4[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@H:30]([OH:35])[C@@H:29]([CH2:36][OH:37])[O:28]4)[CH:21]=3)[N:47]=2)[CH:44]=1
Reactant: O=c1[nH]nc2ccc(Cl)cn12
Reactant: CC(C)(C)[Si](OCc1cc([C@@H]2OC(CO)[C@@H](O)[C@H](O)[C@@H]2O)ccc1Cl)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc3ccc(Cl)cn3c2=O)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 60 °C
Yield: 39.4 %

Procedure:
To a solution of the product (83 mg, 0.15 mmol) from step B and 6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (29.3 mg, 0.17 mmol) in DMF (5.0 mL) was added cesium carbonate (0.11 g, 0.35 mmol) and then heated at 60° C. overnight. The reaction solution was cooled to room temperature, diluted with methanol (10 mL) and added potassium carbonate (43.2 mg, 0.31 mmol) to it. The resultant mixture was stirred at room temperature until complete loss of starting material. The reaction solution was then diluted with 9:1 mixture of dichloromethane/methanol, filtered through a syringe filter and concentrated in vacuo. The residue obtained was purified by preparative thin layer chromatography (dichloromethane/methanol 9:1) to give 6-chloro-2-(4-methoxy-3-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (26.7 mg, 39%): 1H NMR (CD3OD, 500 MHz) δ 7.94 (t, J=1.5 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.30 (dd, J=8.5, 2.0 Hz, 1H), 7.20-7.17 (m, 2H), 6.95 (d, J=8.5 Hz, 1H), 5.09 (s, 2H), 4.68 (d, J=9.5 Hz, 1H), 3.84 (dd, J=12.0, 2.5 Hz, 1H), 3.80 (s, 3H), 3.65 (dd, J=12.0, 7.0 Hz, 1H), 3.53-3.45 (m, 2H), 3.42-3.35 (m, 2H); ESI MS m/z 452 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]1[CH2:10][C@@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[N+:32]([CH3:35])([O-:34])=[O:33]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1([CH2:35][N+:32]([O-:34])=[O:33])[CH2:7][C@@H:8]([CH3:12])[C@H:9]([CH3:11])[CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C=C1C[C@@H](C)[C@H](C)C1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Temperature: 60 °C

Procedure:
To a solution of (2) (2.44 g, 13.4 mmol) in THF (12 mL) was added TBAF (18 mL of a 1 M solution in THF, 18 mmol) followed by nitromethane (2 mL) and the reaction heated at 60° C. for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate (250 mL) and washed with 2N HCl (50 mL) then saturated brine (50 mL). Column chromatography (10:1 heptane/ethyl acetate) gave the product as an oil, 1.351 g, 41%.
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[CH:9][N:8]=1.[Br:17]Br>C(O)(=O)C>[Br:17][C:12]1[C:7]([OH:6])=[N:8][CH:9]=[N:10][C:11]=1[C:13]([F:16])([F:14])[F:15]
Reactant: Oc1cc(C(F)(F)F)ncn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncnc(C(F)(F)F)c1Br
Reaction time: 3 h
Yield: 53.4 %

Procedure:
77.5 g (945.0 mmoles) of anhydrous sodium acetate was added, at room temperature, to a solution of 49.2 g (300.0 mmoles) of 4-hydroxy-6-trifluoromethylpyrimidine dissolved in 600 ml of acetic acid. Thereto was gradually added 50.3 g (315 mmoles) of bromine at 45° C. The resulting mixture was stirred at the same temperature for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 38.9 g (yield: 53.4%) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>CS(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]2[S:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2nc3ccccc3s2)cc1
Temperature: 140 °C

Procedure:
44.6 g (0.34 mol) of 4-cyanobenzaldehyde and 54.4 g (0.64 mol) of o-aminobenzenethiol were dissolved in 300 ml of dimethyl sulfoxide, and the temperature of the solution was raised to 140° C. The produced water and the dimethyl sulfoxide were distilled off. After heating for one hr. the residue was cooled, water was added thereto, and the resultant precipitate was collected by filtration and washed with ethanol. The crude crystal thus obtained was recrystallized from ethyl acetate to give 2-(4'-cyanophenyl)benzothiazole. 22.4 g (0.095 mol) of the compound was dissolved in 250 ml of acetic acid, and 18.6 g (0.116 mol) of bromine was dropwise added thereto. As soon as bromine was added, a yellow bromine adduct was produced. Subsequently, 150 ml of water was added, and the mixture was stirred at 80° C. for 2 hr. It was then cooled, and the resultant precipitate was collected by filtration and washed with ethanol. The crude product thus obtained was recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#[N:2].C(N(CC)C(C)C)(C)C.[CH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:21]>CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNC(=O)c2ccc(C=O)cc2)cc1
Yield: 55.5 %

Procedure:
In the same manner as that described in Example 2(1), a reaction was carried out using 4-cyanobenzylamine (329 mg, 2.5 mmol), described in J. Am. Chem. Soc., 81, 4328 (1959), N,N-diisopropylethylamine (0.91 ml, 5.2 mmol), 4-formylbenzoyl chloride (350 mg, 2.1 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 2(1) to afford N-(4-cyanobenzyl)-4-formylbenzamide (308 mg, yield 56) as a white solid which was recrystallized from ethyl acetate to give white fluffy crystals.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.[CH:15]([NH2:17])=[S:16].C(N(CC)CC)C>O1CCOCC1>[S:16]1[CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)[N:17]=[CH:15]1
Reactant: NC=S
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(-c3cscn3)ccc2N1
Temperature: 110 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A suspension of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one (630 mg, 3 mmol), thioformamide (30 mL, 30 mmol; described in: J. Med. Chem. 1995, 858-868) and triethylamine (0.42 mL, 3 mmol) in dioxane was heated at 110° C. for 3 h. Additional thioformamide (10 mL, 10 mmol) was added and the reaction was stirred at 110° C. for 2 h. This batch was combined with an new batch starting from 230 mg of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one and the combined reaction mixtures was concentrated to approximately 10 mL and an aqueous saturated sodium hydrogencarbonate solution (50 mL) was added and the solution was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude product was purified on a silica gel column using heptane/ethyl acetate, (1:2), as the eluent to give 400 mg (35% yield) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 10.47 (s, 1 H), 9.15 (s, 1 H), 7.97 (s, 1 H), 7.83 (br s, 2 H), 6.87 (d, J=8 Hz, 1 H), 3.54 (s, 2 H); MS (ES) m/z 217 (M++1).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:14])=[C:4]([NH2:15])[CH:3]=1.[C:16](=S)=[S:17].[OH-].[K+].[K+].[Br-]>O.C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][C:5]2[N:14]=[C:16]([SH:17])[NH:15][C:4]=2[CH:3]=1
Reactant: S=C=S
Reactant: Nc1cc(F)c(N2CCNCC2)cc1N
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1cc2[nH]c(S)nc2cc1N1CCNCC1
Yield: 81.2 %

Procedure:
6-Fluoro-5-(piperazin-1-yl)-2-mercapto-1H-benzimidazole (4.3 g, 80%) was prepared by an analogous procedure as described in preparation 1 (step 5) using the diamine (4.5 g, 0.021 mol) (obtained in step 2 above), carbon disulfide (1.9 g, 0.025 mol), potassium hydroxide (1.4 g, 0.025 mol), ethanol (25 mL) and water (5 mL). mp 100-10 1 ° C.; IR (KBr) 3133, 1482 cm-1 ; 1H NMR (DMSO-d6) δ 2.25 (s, 1H, SH), 2.90 (m, 4H, N(CH2)2), 4.10 (brs, 1H, NH), 4.48 (m, 4H, N(CH2)2), 6.80 (d, J=8.4 Hz, 1H), 7.00 (d, J=12.3 Hz, 1H), 12.30 (brs, 1H, NH); Mass (m/z) 252 (M+.).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19][CH2:20][CH3:21].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:22][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19]([CH2:20][CH3:21])=[O:31]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SCC)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)CC)c1C

Procedure:
Prepared from product of Example 4 (7.0 g, 20.4 mmol) and MCPBA (4.15 g of an 85% mixture with MCBA, 20.4 mmol) as described above. Recrystallization (ether) afforded the product as a white solid (6.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[N:8]=1.[N:30]1[CH:31]=[CH:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][C:34]=12.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:36]2[CH2:37][CH2:38][N:33]3[CH:32]=[CH:31][N:30]=[C:34]3[CH2:35]2)[N:10]=[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[N:8]=1
Reactant: c1cn2c(n1)CNCC2
Reactant: COC(=O)c1c(Cl)nc(N2CCC(O)CC2)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCC(O)CC2)nc1N1CCn2ccnc2C1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-(4-hydroxypiperidin-1-yl)pyrimidine (prepared in the above (3)) 56 mg in N,N-dimethylacetamide 0.5 ml are added a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 31 mg in N,N-dimethylacetamide 0.5 ml and triethylamine 27 μl at room temperature, and the mixture is stirred at 80-90° C. for 5 hours. The reaction mixture is diluted with an aqueous citric acid solution, made basic with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-(4-hydroxypiperidin-1-yl)pyrimidine as a pale yellow powder, 66 mg.
Reaction SMILES: C(OC1C=CC(C=O)=CC=1)(C)C.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1>>[N:22]1[CH:21]=[C:20]([O:19][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:25]=[N:24][CH:23]=1
Reactant: BrC1=NOCC1
Reactant: Oc1cncnc1
Agent: CC(C)Oc1ccc(C=O)cc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-141a and I-141b were prepared in 3 steps from 4-iso-propoxybenzaldehyde using Method 8 followed by cycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=299.3 m/z. Activity: A
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][CH:42]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:43]1[CH:48]=[CH:47][C:46]([P:49](=[O:56])([O:53][CH2:54][CH3:55])[O:50][CH2:51][CH3:52])=[CH:45][CH:44]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:41][CH:42]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:43]2[CH:48]=[CH:47][C:46]([P:49](=[O:56])([O:50][CH2:51][CH3:52])[O:53][CH2:54][CH3:55])=[CH:45][CH:44]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-c3cccnn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (137 mg, 0.63 mmol) in MeCN (10 mL) was added HATU (357 mg, 0.94 mmol), TEA (190 mg, 1.88 mmol) and diethyl 4-(amino(phenyl)methyl)phenylphosphonate, 2-c, (200 mg, 0.63 mmol). The solution was stirred at room temperature for 1 h. The product was precipitated from ice water (50 mL, crush ice). The product was collected by vacuum filtration and dried in a vacuum to afford a syrup, which was purified by pre-HPLC to yield title crude, 8-5, product as pale yellow (100 mg, 31%) 1H NMR (300 MHz, DMSO-d6) δ1.19-1.24 (t, J=7.5 Hz, 6H), 3.96-4.01 (q, J=7.5 Hz, 4H), 6.34-6.36 (d, J=6.0 Hz, 1H), 7.37-7.70 (m, 11H), 7.70 (m, 1H), 8.50 (m, 2H), 9.494 (d, J=3.0 Hz, 1H), 10.52 (s, 1H); LC-MS: (M+H)+ 520.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]Cl)([O-:3])=[O:2].[OH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][N:15]([CH2:16][CH2:17][OH:18])[CH2:14][CH2:13][OH:12])([O-:3])=[O:2]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccccc1SCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1SN(CCO)CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 379 g (2 mol) of 2-nitrophenylsulphenyl chloride in 2 l of methylene chloride is added to a solution of 210 g (2 mol) of bis(2-hydroxyethyl)amine and 202 g (2 mol) of triethylamine in 3 l of methylene chloride in the course of 90 minutes, the temperature rising from 21° to 34°. The mixture is subsequently stirred at room temperature for 2 hours and is left to stand overnight and the solution is washed six times with 1 l of water each time, dried with sodium sulphate and concentrated in vacuo. The residue is an orange-yellow solid product of melting point 82°-86°, which is sufficiently pure for further reaction. Yield: 499 g.
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:8][C:7]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[C:2]([C:4]1[O:8][C:7]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)#[N:1]
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(C(N)=O)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(C#N)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of tert-butyl {[1-{[5-(aminocarbonyl)-2-furyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (285 mg) in tetrahydrofuran (2.5 mL) were added pyridine (181 mg) and trifluoroacetic anhydride (211 mg) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica-gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 258 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.O>C(COC)OC>[C:19]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reactant: O=C1CCCC(=O)O1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)CCCC(=O)O)cc2)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a hot (70° C.) solution of 10.0 g (0.0336 mole) of the known compound 4'-amino-3,5-di-tertiary-butyl-4-hydroxybiphenyl in 100 ml of glyme was added 5.0 g (0.044 mole) of glutaric anhydride. After stirring for one hour, the mixture was cooled and poured into water. The precipitate was separated by filtration and recrystallized from a chloroform-hexane mixture to provide tan needles of N-(3',5'-di-tertiary-butyl-4'-hydroxy-4-biphenylyl)-glutaramic acid, m.p. 217.5°-219° C. Analysis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 72.6; % H, 8.1; % N, 3.1.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:11])[CH:8]([CH3:10])[CH3:9].[BH4-].[Na+]>C(O)C>[CH:1]1([NH:11][CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: CC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CNC1CCCC1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of cyclopentanone (10 g, 0.12 mol) and isobutyl amine (29.5 ml, 0.297 mol) was heated at 70° C. for 3 h under nitrogen. After cooling to 0° C., absolute ethanol (50 ml) was added to the reaction mixture, followed by sodium borohydride (6.59 g, 0.178 mol) in portions. The reaction mixture stirred at RT for 12 h, the solvent was removed under vacuum. The residue was taken up in MTBE and washed with water and brine. The organic layer was dried over Na2SO4, evaporated to dryness and the crude was purified by chromatography using silica gel (60-120 mesh), dichloromethane\methanol as eluent to afford of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:34]([CH2:35]OS(C)(=O)=O)=[C:33]([CH3:41])[O:32][N:31]=1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:34]2[C:30]([CH3:29])=[N:31][O:32][C:33]=2[CH3:41])=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1COS(C)(=O)=O
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with methanesulfonic acid 3,5-dimethyl-isoxazol-4-ylmethyl ester (prepared by mesylation of the commercially available 1,5-dimethyl-1H-pyrazol-3-yl)-methanol) gave the title compound. ES-MS m/e (%): 508.2(M+H+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]#[N:13])=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Mg]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)CC.[BH4-].[Na+]>O1CCCC1.CO>[C:15]1([CH2:14][CH:12]([C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][CH:10]=2)[NH2:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1cnnn1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCC(C)O
Solvent: CO
Product: NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 9C (280 mg, 1.63 mmol) in tetrahydrofuran (5 mL), benzylmagnesium chloride (2M in THF) (1.23 mL, 2.46 mmol) was added dropwise. After 3 hours, 3 mL of 2-butanol was added to the reaction and sodium borohydride (0.5 g) was added to the mixture by portion. The reaction was monitored by LC/Mass until it was done. Methanol (5 mL) was added to the mixture. The organic layer was washed with brine and extracted with ethyl acetate (50 mL twice). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash column (Rf: 0.3, 3% MeOH/DCM) to provide the desired product. MS (m/z) 265 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:5][O:4][C:2]([NH:6][C@H:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Reaction time: 5.5 h
Yield: 71.6 %

Procedure:
ClCO2Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water) THF (410 mL) semi-solution of (R)-tert-butyl 2-amino-2-phenylacetate/HCl (9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol) over 6 min, and stirred at similar temperature for 5.5 hours. The volatile component was removed in vacuo, and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with 1N HCl (25 mL) and saturated NaHCO3 solution (30 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resultant colorless oil was triturated from hexanes, filtered and washed with hexanes (100 mL) to provide (R)-tert-butyl 2-(methoxycarbonylamino)-2-phenylacetate as a white solid (7.7 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.98 (d, J=8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, J=8, 1H), 3.56 (s, 3H), 1.33 (s, 9H). LC (Cond. I): RT=1.53 min; ˜90% homogeneity index; LC/MS: Anal. Calcd. for [M+Na]+ C14H19NNaO4: 288.12; found 288.15.