Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:6][N:5]=[C:4]2[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:3]=12.Cl.[NH2:24]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[CH2:21]([N:18]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:24][O:17][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:3]=2[CH:20]=[N:19]1)[CH3:22]
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3cccc(OC)c3)cnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c3noc(-c4cccc(OC)c4)c3cnc21

Procedure:
Five grams of 4-chloro-1-ethyl-5-(3-methoxybenzoyl)-1H-pyrazolo[3,4-b]pyridine was refluxed for 2 hours in 500 ml of acetic acid containing 15 g of hydroxylamine hydrochloride and 1 g of p-toluenesulfonic acid monohydrate. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed well with water, dried, evaporated and chromatographed over 230-400 mesh silica gel. The appropriate fractions were combined and evaporated to give 3.05 g of product, mp 170°-171°. After recrystallization from water it had mp 169°-171° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:21]>CO>[ClH:21].[ClH:21].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCCC1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CN)N1CCCCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A solution of 750 mg (2.6 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-piperidin-1-ylpropanoate in 6 ml of methanol and 6 ml of isopropanolic hydrochloric acid, having a concentration of 5-6N, is stirred at 40° C. for 18 h. After concentration under vacuum, the residue is taken up in ethyl acetate, filtered and dried under vacuum. 670 mg (98%) of methyl(S)-3-amino-2-piperidin-1-ylpropanoate dihydrochloride are obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[C:14]1[C:18]([Cl:19])=[C:17]([C:20]([F:23])([F:22])[F:21])[N:16]([CH3:24])[N:15]=1.[Br:25][C:26]([CH3:31])([CH3:30])[C:27](Br)=[O:28]>O1CCOCC1>[Br:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[C:14]1[C:18]([Cl:19])=[C:17]([C:20]([F:23])([F:22])[F:21])[N:16]([CH3:24])[N:15]=1)=[O:28]
Reactant: Cn1nc(-c2c(F)cc3c(c2N)NC(=O)CO3)c(Cl)c1C(F)(F)F
Reactant: CC(C)(Br)C(=O)Br
Solvent: C1COCCO1
Product: Cn1nc(-c2c(F)cc3c(c2NC(=O)C(C)(C)Br)NC(=O)CO3)c(Cl)c1C(F)(F)F
Yield: 75.4 %

Procedure:
5-Amino-7-fluoro-6-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2H-1,4-benzoxazine-3(4H)-one (1.0 g, 2.64 mmol) was dissolved in anhydrous dioxane (40 ml) and 2-bromoisobutyryl bromide (0.67 g, 2.91 mmol) was added. Solution was refluxed for 2 hr and solvent was then evaporated. The residue was triturated with ether to afford the title compound (1.02 g, 1.99 mmol).
Reaction SMILES: [F:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:8]([CH2:30][CH3:31])[CH2:9][C@@:10]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH:11]=NC2C=C(F)C=C3C=2C=CC(C)=N3)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C([O-])(O)=[O:39].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:32][CH3:33])=[C:4]([C@H:8]([CH2:30][CH3:31])[CH2:9][C@:10]([OH:25])([C:26]([F:27])([F:28])[F:29])[CH:11]=[O:39])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2nc(C)ccc12)C(F)(F)F)c1cccc(F)c1OC
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Temperature: -40 °C

Procedure:
The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are dried over sodium sulphate and the solvent is removed in vacuo to give 205 mg of (2R,4R)-4-(3-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)-hexan-2-ol as a crude product. The crude imine is dissolved in 18 ml of CH2Cl2 and the solution is cooled to −40° C. 3.4 ml (3.4 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the mixture is allowed to warm to 0° C. over 1 hour, and after 30 minutes at 0° C. is poured onto a mixture of saturated NaHCO3 and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (150 ml) with ethyl acetate affords 37 mg of product (analytical HPLC: Rt=9.2 min (Chiralcel OD 5μ, 250×4.6 mm, hexane/ethanol 10%, 1 ml/min flow rate) as the (−)-enantiomer.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:15]([N:17]=[C:18](SC)[S:19][CH3:20])#[N:16]>C(O)C>[C:15]([NH:17][C:18](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1)[S:19][CH3:20])#[N:16]
Reactant: CCOc1cccnc1CSCCN
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CCOc1cccnc1CSCCN=C(NC#N)SC
Reaction time: 8 h
Yield: 95.7 %

Procedure:
2-(2-Aminoethylthiomethyl)-3-ethoxypyridine (1.0 g) in ethanol (10 cc) was added over 45 minutes to a stirred solution of dimethyl N-cyanodithioimidocarbonate (0.690 g) in ethanol (5 cc) at room temperature. The mixture was allowed to stand overnight at room temperature, nitrogen was bubbled through the solution for one hour, and the mixture was allowed to crystallise to give N-cyano-N'-[2-((3-ethoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (1.4 g) m.p. 98°-99°.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH2:29](Br)[C:30]#[CH:31].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:31][C:30]#[CH:29])[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: C#CCBr
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C#CCn1c(=O)n(C2CCN(C3CCN(C(=O)OC)CC3)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
1-[1-(1-Methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-di-hydro-2H-benzimidazol-2-one (28 mg) as synthesized by the method of Referential Example 1 was dissolved in 5 ml of dimethylformamide, and to which 2.0 mg of sodium hydride was added under cooling with ice, followed by 30 minutes' stirring. Ten(10) mg of propargyl bromide was added to the reaction liquid which was stirred for further 3 hours at room temperature. After adding saturated aqueous sodium bicarbonate solution and concentrating the reaction liquid, the resulting residue was distributed between saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol=20/1). Thus 11.3 mg of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:21]([NH2:24])[C:22]#[CH:23]>O1CCCC1>[CH2:21]([NH:24][S:17]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:19])=[O:18])[C:22]#[CH:23]
Reactant: C#CCN
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: C#CCNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
2,4-Dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) was added to tetrahydrofuran (20 ml) containing propargylamine (0.5 g), and the resultant mixture was allowed to stand overnight at room temperature. Upon completion of the reaction, the mixture was concentrated. A 5% aqueous solution of hydrochloric acid was added to the residue, whereby an oily substance was deposited. The oily substance was extracted with chloroform and washed with a 5% aqueous solution of hydrochloric acid and water in order. The extract was concentrated and recrystallized from toluene to give 1.05 g of N-propargyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 35). M.P., 130.5°-132° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:17])[NH:7][C:6]1=[O:18].C(N(CC)CC)C.Br[C:27]([C:53](=[O:62])[C:54]1[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=1)([Cl:52])[C:28]([N:30]([C:37]([O:39][CH:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)(Cl)Cl>[CH3:61][O:60][C:57]1[CH:56]=[CH:55][C:54]([C:53]([C:27]([N:7]2[C:6](=[O:18])[CH:5]([O:4][CH2:3][CH2:2][NH2:1])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:8]2=[O:17])([Cl:52])[C:28]([N:30]([C:37]([O:39][CH:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])=[O:62])=[CH:59][CH:58]=1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Br)C(=O)c1ccc(OC)cc1)c1ccccc1
Reactant: NCCOC1C(=O)NC(=O)N1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(C(=O)c1ccc(OC)cc1)N1C(=O)C(OCCN)N(Cc2ccccc2)C1=O)c1ccccc1
Yield: 92.4 %

Procedure:
Into 100 ml of chloroform were dissolved 10 g of 5-(2-aminoethyloxy)-1-benzylhydantoin and 4 g of triethylamine. While stirring, a solution of 11.9 g of α-bromo-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide in 50 ml of chloroform was added dropwise over a period of about 1 hour at room temperature. After being stirred for an additional 2 hours, the reaction mixture was condensed under reduced pressure, and the residue was purified by the use of a chromatographic column to give 14.1 g of α-(4-methoxybenzoyl)-α-[5-(2-aminoethyloxy)-1-benzyl-3-hydantoinyl]-2-chloro-5-dodecyloxycarbonylacetanilide. Yield. 92%. Oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C(=O)C2C=CC=CC=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:20]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@:21]21[O:24][CH2:23][CH2:22]2.CO.C[O-].[Na+].[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[C@@H:20]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@:21]32[O:24][CH2:23][CH2:22]3)=[C:2]([NH:39][CH:36]2[CH2:38][CH2:37]2)[N:10]=1
Reactant: NC1CC1
Reactant: O=C(Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@]34CCO4)c2n1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(NC2CC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@]34CCO4)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
110 (800 mg, 1.85 mmol) in cyclopropylamine (10 mL) was stirred at room temperature for 24 h. To the solution were added MeOH (10 mL) and 5.4 M NaOMe (1.71 mL, 9.26 mmol) and the resulting mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0 to 20% MeOH in CH2Cl2) to give 6-cyclopropylamino-nucleoside 111 (500 mg, 76%) as a white solid. 1H NMR (400 MHz, CD3OD) δ: 8.02 (s, 1H), 6.21 (s, 1H), 4.53 (m, 2H), 4.43 (d, 1H, J=8.8 Hz), 3.96 (m, 1H), 3.82-3.77 (m, 2H), 2.91 (m, 1H), 2.56 (m, 1H), 2.27 (m, 1H), 0.83 (m, 2H), 0.60 (m, 2H). LCMS (ESI): 349 (M+H)+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-])[CH:3]=1.[C-]#N.[Na+].[CH2:14]([N:16](CC)CC)C.C[Si](Cl)(C)C>CN(C=O)C>[C:14]([C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:10])=[O:9])=[CH:3][N:4]=1)#[N:16]
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)O)cn1
Temperature: 110 °C
Reaction time: 10 h
Yield: 21.9 %

Procedure:
To a solution of the nicotinic acid N-oxide (51 g, 0.37 mol) in 1.2 L of DMF, NaCN (54 g, 1.1 mol) was added, followed by triethylamine (255 mL, 1.83 mol) and TMSCl (185 mL). The reaction mixture was stirred at 110° C. for 10 h, filtered. and the filtrate was concentrated. The residue was dissolved in 100 mL of 2N HCl and extracted with methylene chloride. The organic layers were combined, concentrated and recrystallised from water to yield 12 g (22%) of the product.
Reaction SMILES: C(O)(=O)C(O)=O.C([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22]([C:24]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]3[CH2:33][CH2:34][CH2:35][O:36][C:25]=23)=[O:23])[CH2:16][CH2:15]1)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C:22]([C:24]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]3[CH2:33][CH2:34][CH2:35][O:36][C:25]=23)=[O:23])[CH2:16][CH2:15]1
Reactant: O=C(NCC1CCN(Cc2ccccc2)CC1)c1c2n(c3ccccc13)CCCO2
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Yield: 105.4 %

Procedure:
A stirred suspension of N-[(1-benzyl-4-piperidyl)methyl] 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide oxalate salt (E20, 2.25 g, 0.0046 mole) in ethanol (100 ml) and glacial acetic acid (4 ml) was hydrogenated over 10% Pd-C (0.8 g) at atmospheric pressure and 45° C. for 18 h. The mixture was filtered and the filtrate concentrated in vacuo. The majority of the product was in the solid which had been filtered off. This material was shaken with concentrated potassium carbonate solution (50 ml) and chloroform (50 ml) together with the residue from the filtrate. The mixture was filtered, the chloroform layer separated and dried (Na2SO4), then concentrated in vacuo to afford the title compound as a white solid (1.52 g, 100%). This was recrystallised from chlorofornm/60-80 petrol mp 139-141° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:29]=[O:30])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:20]([CH3:28])=[N:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=3)[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:28])=[N:21][C:22]([N:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=4)[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:29]([OH:30])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: Cc1nc(N(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.24 mL, 0.72 mmol) was added to a stirred solution of 9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (240 mg, 0.649 mmol) in tetrahydrofuran (3.5 mL) at 0° C., and the mixture was stirred at 0° C. for 40 min. The reaction wars quenched by aqueous saturated ammonium chloride, and the mixture was extracted with tetrahydrofuran/ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (207 mg, 0.518 mmol, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)[N:3]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[N:5]=[C:4]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[N:3]=1
Reactant: Nc1nc(NCc2ccc(OCc3ccccc3)cc2)nc2nc(-c3ccco3)nn12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nc(NCc2ccc(O)cc2)nc2nc(-c3ccco3)nn12

Procedure:
A solution of 7-amino-5-[(4-benzyloxyphenyl)methyl]amino-2-(2-furyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine (2.37 g) in ethyl acetate (150 ml) and methanol (150 ml) was treated with 10% palladium on carbon (3.0 g) and hydrogenated at atmospheric pressure for 2.5 hours. The catalyst was filtered through diatomaceous earth and the liquors evaporated. The residue was purified by chromatography on silica (100 g) eluting with dichloromethane containing methanol 3-30% v/v, and gave 7-amino-2-(2-furyl)-5-[(4-hydroxyphenyl)methyl]amino-[1,2,4]-triazolo[1,5-a][1,3,5]triazine, m.p. 268-270; NMR: 4.39 (d, 2H, CH2N), 6.64 (d of d, 1H, furyl-4H), 6.68 and 7.13 (A2B2 pattern, 4H, phenyl-H), 7.03 (d, 1H, furyl-3H), 7.8 (t, 1H, NH), 7.84 (d, 1H, furyl-5H), 8.13 (br s, 2H, NH2) and 9.19 (s, 1H, OH); m/e 324 (M+H)+.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Na+].[CH2:14]([O:21][C:22]([NH:24][CH:25]([CH2:29][CH2:30][P:31]([OH:34])([OH:33])=[O:32])[C:26]([O-:28])=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][CH:25]([CH2:29][CH2:30][P:31]([OH:33])([OH:34])=[O:32])[C:26]([O:28][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: O=C(NC(CCP(=O)(O)O)C(=O)[O-])OCc1ccccc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: O=C(NC(CCP(=O)(O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
Next, 226 mL of benzyl alcohol was cooled to 0° C. and 19.5 g (164 mmol) of thionyl chloride was added dropwise. After stirring for 15 minutes, 21.2 g (62.4 mmol) of 2-(N-benzyloxycarbonylamino)-4-phosphonobutanoic acid monosodium salt was added and stirred at room temperature for 20 hours after the ice bath was removed. Completion of the reaction was confirmed by TLC (BuOH/AcOH/H2O=5:2:2, 254 nm). Benzyl alcohol was removed by vacuum distillation at 70° C. using a vacuum pump. The obtained oily residue was extracted by 300 mL of ethyl acetate and insoluble sodium chloride was removed by filtration. After being washed with 50 mL of water three times, the filtrate was dried over anhydrous sodium sulfate. After the solvent was removed by vacuum distillation, 300 mL of diethyl ether was added, seed crystals were added and the mixture stirred vigorously, and the product was crystallized from product mixture was partially dissolved in the ether, benzyl 2-(N-benzyloxycarbonylamino)-4-phosphonobutanoate (21.2 g, yield 84%) was obtained as white powder-like crystals.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][CH2:49][CH2:50][OH:51]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][CH2:49][CH2:50][OH:51])=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: NCCO
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCCO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-amino-ethanol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H47Cl2N6O4 [(M+H)+] 709.3031, observed 709.3029.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32](O)=[O:33])[CH2:29][N:30]=1)=[CH:9]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:57][NH:58][CH2:59][CH2:60][OH:61]>O.CN(C)C=O>[OH:61][CH2:60][CH2:59][N:58]([CH3:57])[C:32](=[O:33])[CH2:31][CH:28]1[S:27][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[N:30][CH2:29]1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Reactant: CNCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)N(C)CCO)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.3 %

Procedure:
A mixture of (2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (250 mg), 1H-1,2,3-benzotriazol-1-ol (100 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (140 mg), 2-(methylamino)ethanol (60 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-95:5, volume ratio) to give colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (140 mg, yield 50%) as colorless crystals. melting point 94-96° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COc1cccc(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of 2-methyl-3-(methyloxy)phenol (Intermediate 59, 1.3 g) in DMF (50 mL) was added sodium hydride (60% in mineral oil, 480 mg, 0.012 mol at 0° C. and the mixture was stirred for 30 minutes. 2-Chloro-5-nitropyridine (1.9 g, 0.012 mol, Aldrich) was added and the mixture was heated at 60° C. for 3 hours. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (4 times 100 mL). The combined ethyl acetate phases were dried over sodium sulphate and concentrated under vacuum to give a residue which was purified by column chromatography on silica gel (PE:EtOAc=10:1) to afford the title compound (2.3 g) as a liquid.