Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(N[CH:8]([CH3:10])[CH3:9])=O)(C)C.[C:11](O)(=O)[CH2:12][C:13](O)=O.[CH:18]([N:21]1[C:26](=[O:27])[CH2:25][C:24](=[O:28])[N:23]([CH:29]([CH3:31])[CH3:30])[C:22]1=[O:32])([CH3:20])[CH3:19]>C(OC(=O)C)(=O)C>[CH:29]([N:23]1[C:24](=[O:28])[CH2:25][C:26](=[O:27])[N:21]([CH:18]([CH3:20])[CH3:19])[C:22]1=[O:32])([CH3:31])[CH3:30].[CH2:9]1[CH2:8][CH2:10][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)NC(=O)NC(C)C
Agent: CC(C)N1C(=O)CC(=O)N(C(C)C)C1=O
Solvent: CC(=O)OC(C)=O
Product: C1CCCCC1
Temperature: 90 °C
Yield: 70 %

Procedure:
1,3-Diisopropyl-2,4,6-(1H,3H,5H)-pyrimidinetrione was prepared by the dropwise addition of acetic anhydride (40 ml) over three hours to a solution of 1,3-diisopropylurea (7.5 g, 0.05 mole) and malonic acid (5.2 g, 0.05 mole) at 65° C. After the addition was completed, the temperature was raised to 90° C. and maintained for three hours. The solvent was evaporated under reduced pressure and the residue solidified upon cooling. 1,3-Diisopropyl-2,4,6-(1H,3H,5H)-pyrimidinetrione recrystallized from cyclohexane as colorless needles (7.3 g, 70% yield), m.p. 79°-82°.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:29][CH2:28][C:27]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:25]([F:24])[CH:26]=2)([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCc2cc(F)cc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 3-fluoro-5-trifluoromethyl-benzylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H25F4NO5 [M−H]−: 470.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[S:35])[NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: C1COCCO1
Product: S=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Temperature: 85 °C
Yield: 116 %

Procedure:
A solution of 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (10 g, 0.023 mol) in anhydrous 1,4-dioxane (400 mL) was treated with Lawesson's reagent (7.44 g, 0.018 mol) and heated at 85° C. for 4 h. The orange solution was cooled to room temperature and concentrated in vacuo. The crude product was washed with CH2Cl2 and then dried to give 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbothioamide as a yellow solid (9.41 g, yield 91%). ESI-MS: 449.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]([C:22]3[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]([OH:28])=[C:20]([O:19][CH2:17][CH3:18])[CH:21]=3)[NH:32][C:33](=[O:34])[NH:35][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccc(Br)cc1)c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccc(Br)cc2)cc([N+](=O)[O-])c1O
Yield: 16.9 %

Procedure:
To a solution of 2-(4-bromophenyl)-1-phenylethanone (Intermediate 8) (140 mg, 0.5 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (108 mg, 0.5 mmol), and urea (69 mg, 1.5 mmol) in 20 mL of ethanol was added 0.2 mL of concentrated HCl, the mixture was stirred at reflux for 3 days. After the solvent was removed under reduced pressure, the residue was purified by HPLC (46-76% acetonitrile+0.1% trifluoroacetic acid in water, over 15 min.) to give Compound 25 (43 mg, yield 16.5%). 1H NMR (CD3OD 400 MHz): δ 7.52 (s, 1H), 7.20-7.17 (m, 5H), 7.11-7.08 (m, 3H), 6.69 (d, J=8.4 Hz, 2H), 5.23 (s, 1H), 3.40-3.95 (m, 2H), 1.30 (t, J=6.8 Hz, 3H); MS (ESI): m/z 510.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:25]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([I:25])=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cn3cccc(OCc4ccccc4)c3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3c(OCc4ccccc4)cccn3c2I)cc1
Reaction time: 2.5 h

Procedure:
To a 0° C. solution of 8-(benzyloxy)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine (0.25 g, 0.79 mmol) in N,N-dimethylformamide (8.0 mL) was added dropwise a solution of N-iodosuccinimide (0.17 g, 0.79 mmol) in N,N-dimethylformamide (4 mL). The reaction was stirred for 2.5 hours and concentrated to a volume of 2 mL The mixture was diluted with ethyl acetate, washed twice with 1M aqueous sodium hydroxide, and concentrated. The residue was purified by silica gel chromatography, eluting with 5% acetone in dichloromethane to yield 0.23 (67%) of 8-(benzyloxy)-2-(4-fluorophenyl)-3-iodoimidazo[1,2-a]pyridine. 1H NMR (CDCl3): δ 8.10 (dd, 2H), 7.90 (d, 1H), 7.53 (d, 2H), 7.40 (m, 3H), 7.19 (t, 2H), 6.81 (t, 1H), 6.61 (d, 1H), 5.46 (s, 2H); MS m/z 445 (M+1).
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[NH:17])=[CH:14][CH:13]=1.O>C(Cl)(Cl)Cl>[OH:6][C:1]1[N:18]=[C:16]([C:15]2[CH:19]=[CH:20][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:17]=[C:3]([CH3:5])[CH:2]=1
Reactant: COc1ccc(C(=N)N)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2nc(C)cc(O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Under N2, a solution of ethyl acetoacetate (7.15 g, 0.053 mol) in CHCl3 (200 ml) was added dropwise to a suspension of 4-methoxybenzamidine in CHCl3 (200 ml). After stirring at room temperature overnight, water was added to the solution. The aqueous phase was separated and extracted with CHCl3 and the organic layers were combined, dried (Na2SO4), filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 2% CH3OH--CHCl3 to yield 8.58 g (75%) of product, m.p. 198°-199° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[C:45]1([NH:44][C:22](=[O:24])[CH2:21][CH2:20][C@H:19]([C@@H:18]2[C@:26]3([CH3:34])[C:15]([C:14]4[CH2:13][CH2:12][C@@H:11]5[C@:30]([C:29]=4[CH2:28][CH2:27]3)([CH3:33])[CH2:31][CH2:32][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:10]5([CH3:36])[CH3:35])=[CH:16][CH2:17]2)[CH3:25])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: Nc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](CCC(=O)Nc1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Temperature: -15 °C
Reaction time: 8 h

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (0.50 g) is dissolved in 15 ml of dry dichloromethane. After cooling to −15° C., 0.188 ml of N-methylmorpholine and 0.153 ml of isobutylchloroformiate is added and the mixture is stirred at −15° C. for 20 minutes, whereupon 0.44 ml of aniline is added. The mixture is stirred overnight and the temperature is slowly elevated to room temperature. After aqueous work-up and crystallization from methanol, 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid-N-phenyl amide (0.431 g) is obtained. H-NMR (CDCl3, 400 MHz): δ=7.53 (2H, d); 7.34 (2H, t); 7.17 (1H, s); 7.12 (1H, t); 5.35 (1H, s); 3.21 (1H, m); 0.9 (9H, s); 0.04 (6H, m).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH2:14]([O:22][C:23](N1C=CC=CC1=O)=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:23]([O:22][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24])[C:6]([OH:8])=[O:7]
Reactant: O=C(OCCc1ccccc1)n1ccccc1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@@H](NC(=O)OCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 104.8 %

Procedure:
To a stirred mixture of D-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing phenethyl-2-pyridyl-carbonate and phenethyl-2-oxopyridine 1-carboxylate (0.459 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.35 g, 89%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 268 [M−H]+; (ESI) m/z: 266 [M−H]−. 1H NMR (DMSO-d6): δ 1.09 (d, J=6.4 Hz, 3H), 2.89 (t, J=6.9 Hz, 2H), 3.94 (dd, J=3.4, 9.0 Hz, 1H), 4.04-4.11 (m, 1H), 4.13-4.24 (m, 2H), 6.75 (d, J=9.0 Hz, 1H), 7.20-7.33 (m, 5H) 11.95 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][N:21]([CH2:20][CH2:19][C:18]2[CH:29]=[CH:30][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)CC1CC1

Procedure:
The title compound was prepared as described in Example 102 using tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) and cyclopropylmethyl bromide and isolated as a clear oil (0.155 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.16-8.07 (m, 2H), 7.84-7.77 (m, 2H), 7.39 (dq, J=8.0, 0.9 Hz, 2H), 7.31 (s, 2H), 3.50 (t, J=7.6 Hz, 2H), 3.17-2.86 (m, 4H), 1.48 (s, 9H), 0.87 (ddd, J=11.2, 9.0, 6.7 Hz, 1H), 0.49 (d, J=8.0 Hz, 2H), 0.21 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 503 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8].C(N(CC)CCN[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:29]=[O:30])=[O:19])C>C(Cl)(Cl)Cl>[OH:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[CH2:4][CH2:3][CH2:2][NH:1][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:29]=[O:30])=[O:19]
Reactant: NCCCN(CCO)CCO
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCCN(CCO)CCO
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 41.2 %

Procedure:
N-(3-Aminopropyl)diethanolamine (0.89 g) was added to the intermediate (a) (2.62g) obtained in Example 28. After being stirred for 2.5 hours at 70° C., the reaction mixture, with chloroform added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then filtrated. The solvent was evaporated out and the residue was purified by silica gel column chromatography (silica gel 70 g, chloroform:methanol=50:1-30:1), thereby yielding 1.17 g of the aimed compound as white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][O:7][C:8](=[O:10])[CH3:9])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:11])([CH2:6][O:7][C:8](=[O:10])[CH3:9])[C:3]([Cl:15])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OCC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: CC(=O)OCC(C)(C)C(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Intermediate 73, 2,2-dimethyl-3-acetyloxypropionic acid (11.76 g, 80 mmol) was dissolved in benzene (100 mL), and the reaction solution was cooled to 0° C. Oxalyl chloride (15.0 g, 120 mmol) was added dropwise. After being stirred for 3 h, the solvent was removed in vacuo, and the residue was distilled in vacuo to give the title compound.
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].CCN(CC)CC.[C:23](ON1C(=O)CCC1=O)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl.CCOC(C)=O>[CH2:26]([O:25][C:23]([C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[OH:15])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)OCc2ccccc2)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.6 %

Procedure:
To a stirred mixture of Compound 249A (1.40 g, 6.47 mmoL) in 10 mL of CH2Cl2 was added Et3N (1.08 mL, 7.76 mmoL), followed by Cbz-OSu (1.69 g, 6.80 mmoL). The reaction mixture was stirred at room temperature for 16 hrs and then diluted with 300 mL of EtOAc. The organic layer was washed with 5% citric acid solution (2×40 mL), 5% K2CO3 solution (2×40 mL) and brine (40 mL) and dried (MgSO4). The residue was filtered and concentrated in vacuo to afford 2.25 g (yield: 99%) of Compound 262A. It had an analytical HPLC retention time=3.02 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=351.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[O:8][C:7]([CH2:12][N:13]1[CH:21]=[N:20][C:19]3[C:14]1=[N:15][CH:16]=[N:17][C:18]=3[N:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:6]2.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCOCC1>[CH2:37]([NH:44][C:9]([C:10]1[N:5]([NH:6][C:7](=[O:8])[CH2:12][N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][C:23](=[O:24])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:4]=[CH:3][C:2]=1[Cl:1])=[O:11])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1ncn2Cc1nn2ccc(Cl)c2c(=O)o1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2CC(=O)Nn1ccc(Cl)c1C(=O)NCc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution di-tert-butyl 9-((5-chloro-4-oxo-4H-pyrrolo[1,2-d][1,3,4]oxadiazin-2-yl)methyl)-9H-purin-6-ylimidodicarbonate (100 mg, 0.2 mmol) in 2 mL of dry 1,4-dioxane under argon atmosphere 127 μL of benzylamine (1.16 mmol) were added and the mixture was stirred at 30° C. during 2 hours. At the end of this period, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography silica (dichloromethane/methanol). After purification were obtained 95 mg of tert-butyl 9-(2-(2-(benzylcarbamoyl)-3-chloro-1H-pyrrol-1-ylamino)-2-oxoethyl)-9H-purin-6-ylcarbamate (92% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15].ClCCl.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([OH:29])(=[O:1])=[O:28].[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15]
Reactant: CS(=O)(=O)Cl
Agent: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred solutions of 18.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane are added 11.9 parts of N,N-diethylethanamine. Then there are added dropwise (slowly) 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is washeed with water, dried, filtered and evaporated. The solid residue is crystallized from 4-methyl-2-pentanone, yielding 15 parts (58%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one methanesulfonate; mp. 125° C.
Reaction SMILES: N([O-])=[O:2].[Na+].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:10](N)[CH:9]=1)(=[O:7])[CH3:6]>O.S(=O)(=O)(O)O>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:10]([OH:2])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2)c(N)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(F)cc2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (12.0 g.) in water (40 ml.) was added to a stirred solution of 4-acetyl-2-amino-4'-fluoro-biphenyl, (36.6 g.) in 5N sulphuric acid (480 ml.), whilst maintaining the temperature of the reaction mixture at 0°-5° C. The reaction mixture was stirred at 0°-5° C. for a further 1 hour. The resulting cold solution of diazonium salt was poured slowly into stirred refluxing 5N sulphuric acid (400 ml.). When the addition was complete, refluxing was continued for 0.5 hour. The resulting solution was poured into ice/water, causing the precipitation of a solid which was collected, dried and dissolved in ether. The ethereal solution was extracted with dilute aqueous sodium hydroxide and the extract was acidified to precipitate a product which was extracted into ether. The ethereal extract was washed with water, dried over anhydrous sodium sulphate, and evaporated to give a product which was recrystallized from light petroleum (b.p. 80°-100° C.) to give the novel intermediate 4 -acetyl-4'-fluoro-2-hydroxybiphenyl, m.p. 152°-154° C. A mixture of this compound (36.5 g.), dimethyl sulphate (25.2 g.) and potassium carbonate (25 g.) in anhydrous acetone (200 ml.) was refluxed with stirring overnight. Acetone was removed by evaporation, the residue poured into water, and the resulting mixture extracted with ether. The ether extract was washed with dilute sodium hydroxide solution, then with water and dried over anhydrous sodium sulphate. Ether was removed by evaporation and the residue was distilled in vacuo to give a product, b.p. 142°-144° C./0.2 mm. which solidified on cooling. This solid was recrystallized from light petroleum (b.p. 62°-68° C.) to give the novel intermediate 4-acetyl-4'-fluoro-2-methoxybiphenyl, m.p. 75°-77° C.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]#[N:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([O:29][CH2:30][CH2:31][CH2:32][Br:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br-:33].[C:9]([C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][N+:1]([CH2:32][CH2:31][CH2:30][O:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:10]
Reactant: BrCCCOc1ccccc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Product: N#CC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccccc3)(CC1)C2
Product: [Br-]
Yield: 44.1 %

Procedure:
Following the general procedure outlined in Example 24, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)acetonitrile (0.19 g, 0.658 mmol) and 3-bromopropyl phenyl ether (0.17 mL, 1.07 mmol) in 2CH3CN/3CHCl3 (15 mL) were reacted to give the desired product (0.146 g, 45%). EI-MS m/z 423 (M+), 1H NMR (400 MHz, CD3OD) δ 7.5 (m, 4H), δ 7.35 (m, 3H), δ 7.3-7.2 (m, 4H), δ 6.9 (m, 4H), δ 4.07 (m, 3H), 3.8-3.7 (m, 2H), δ 3.62 (m, 5H), δ 3.6-2.5 (m, 2H), δ 2.4-2.3 (m, 2H), δ 2.3-2.1 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]([C:18]#[N:19])([CH3:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:29][OH:30]>C(O)C>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]([C:18](=[NH:19])[NH:29][OH:30])([CH3:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)(CS(C)(=O)=O)NC(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(CS(C)(=O)=O)(NC(=O)OCc1ccccc1)C(=N)NO
Temperature: 60 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
To a solution of (1-Cyano-2-methanesulfonyl-1-methyl-ethyl)-carbamic acid benzyl ester (Example 109a, 3.07 g, 10.4 mmol) in dry ethanol (58 ml) were added triethylamine (2.17 mL, 15.5 mmol) and hydroxylamine hydrochloride (936 mg, 13.5 mmol). The reaction mixture was then stirred at 60° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a ethyl acetate/heptane gradient to yield the title compound (2.04 gr, 60%) as a white powder. MS (ESI, m/z): 330.6 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([OH:21])=O)=[CH:13]3)[CH2:5]1)([CH3:3])[CH3:2].Cl.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]([N:4]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])=[CH:13]3)[CH2:5]1)([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)N1CC[C@H](Oc2ccc3[nH]c(C(=O)O)cc3c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CC[C@H](Oc2ccc3[nH]c(C(=O)N4CCCC4)cc3c2)C1

Procedure:
According to the procedure described for the synthesis of Example 1 the title compound was synthesized from 5-((S)-1-isopropyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid 1:1 hydrochloride and pyrrolidine under coupling conditions employing TBTU and DIPEA in DMF. The crude product was purified over silica eluting with a gradient formed from DCM/MeOH(2 N NH3) 98/2 to 94/6. The product fractions were evaporated to yield the title compound as off-white solid. (m/e): 342.3 (MH+, 100%).