Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=1)[N:6]=[C:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1n[nH]c2ccc(F)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccc(F)cc12
Temperature: 25 °C
Yield: 38.2 %

Procedure:
Ethyl 2-(5-fluoro-1H-indazol-3-yl)acetate (0.48 g, 2.16 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Cesium carbonate (2.11 g, 6.48 mmol) was added, and stirred at room temperature for half an hour. Then p-nitro benzyl bromide (466 mg, 2.16 mmol) was added. After reacted for 16 hours, the solid was filtered. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a yellow solid 295 mg, at a yield of 38.2%.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH:10]=1)([O-])=O.N.[H][H]>[Ni].CO>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: CCOC(=O)N1CC=C(C[N+](=O)[O-])CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)N1CCC(CN)CC1
Yield: 98.9 %

Procedure:
A mixture of 41 parts of ethyl 3,6-dihydro-4-(nitromethyl)-1(2H)-pyridinecarboxylate and 400 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 6 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 35 parts (98.9%) of ethyl 4-(aminomethyl)-1-piperidinecarboxylate (intermediate 4).
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH2:7][C@@:8]2([CH3:33])[N:12]3[C:13]([C:16]([NH:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)[C:9]2=[O:32])=[CH:5][CH:4]=1)#[N:2].[N:36]1[NH:37][N:38]=[N:39][C:40]=1[C@@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1.CCN(CC)CC.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:35]=[CH:34][C:6]([CH2:7][C@@:8]2([CH3:33])[N:12]3[C:13]([C:16]([NH:18][C@@H:19]([CH3:23])[C:20](=[O:22])[N:43]4[CH2:44][CH2:45][CH2:46][C@@H:41]([C:40]5[N:36]=[N:37][NH:38][N:39]=5)[CH2:42]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:24]3[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=3)[C:9]2=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: C1CNC[C@H](c2nn[nH]n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](c2nn[nH]n2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
To a solution of (S)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid (60 mg, 0.117 mmol) and (R)-3-(2H-tetrazol-5-yl)-piperidine (35.8 mg, 0.234 mmol) in anhydrous DMF (1 mL) was added Et3N (33.8 μl, 0.234 mmol) at 0° C. HOAt (47.8 mg, 0.351 mmol) was then added to the reaction. After 10 min of stirring at 0° C., HATU (53.4 mg, 0.140 mmol) was added. The reaction was slowly warmed to 25° C. and stirred overnight. The crude reaction was purified by reverse phase HPLC to afford 55 mg of (3R)-3-(4-cyanobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-N-{(1S)-1-methyl-2-oxo-2-[(3R)-3-(2H-tetrazol-5-yl)piperidin-1-yl]ethyl}-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide as a white solid, m/z 647.5 [M+1]+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:22]1[N:23]=[C:24]([NH2:40])[C:25]2[N:26]=[CH:27][N:28]([C:38]=2[N:39]=1)[C@@H:29]1[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:22]3[N:23]=[C:24]([NH2:40])[C:25]4[N:26]=[CH:27][N:28]([C:38]=4[N:39]=3)[C@@H:29]3[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]3[OH:31])[CH2:5][CH2:6]2)=[O:11])=[CH:14][CH:15]=1
Reactant: C#CCC1CCN(C(=O)Oc2ccc(OC)cc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: COc1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1

Procedure:
Batch: AB-10-017. 4-methoxyphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-103 (597 g, 2.184 mmol) was added to a solution of 2-iodoadenosine (0.649 g, 1.651 mmol) according to general procedure 2. Yield: 0.294 g, 33%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.00-6.87 (2×m, 4H), 5.94 (d, 1H), 4.73 (m, 2H), 4.33-4.14 (2×m, 3H), 3.92-3.76 (2×d, 5H), 3.10-2.90 (2×bt, 4H), 2.46 (d, 5H), 1.91-1.40 (2×m, 5H). m/z MH+=539.14. HPLC rt=5.5 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21].[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(O)(=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:23]([CH3:24])=[O:25])=[CH:18][CH:19]=3)=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21]
Reactant: CC1(C)C(=O)Nc2cc(C(=O)Nc3ccc(N)cc3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(NC(=O)c2ccc3c(c2)NC(=O)C3(C)C)cc1

Procedure:
0.83 g. (2.4 mmol) 2,3-Dihydro-3,3-dimethyl-N-(4-aminophenyl)-2-oxo-(1H)-indole-6- carboxamide (from Example 29) was stirred in 5 ml. 2N acetic acid and ml. (53.4 mmol) acetic anhydride for 3 hours at 40° C. The solvent was removed under vacuum and the residue purified by column chromatography (silica gel; isohexane:ethyl acetate:methanol 5:4:0.5 v/v/v) to give 0.6 g. (63% of theory) of the title compound; m.p. 294-295° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([NH:18][C:19](=[O:27])NC3C=CC=CC=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[C:1]1([C:7]2[S:8][C:9]3[NH:18][C:19](=[O:27])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)Nc1sc(-c2ccccc2)nc1-c1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2sc(-c3ccccc3)nc2c2ccccc12
Temperature: 300 °C
Yield: 62 %

Procedure:
15 Grams of crude 3-(2,4-diphenylthiazol-5-yl)-1-phenylurea (m.p. 240°-260° C.), prepared following substantially the procedure described in the first part of Example 5, is heated to 300° C. on a metal bath and maintained at this temperature for about 8 minutes. The reaction mass is then cooled and sludged with ethyl acetate. On crystallization from dimethylformamide, 6.95 g of the title compound is obtained. M.p. >310° C.; yield 62%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: CC1(C)C(=O)Nc2ncccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CNc2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (prepared according to B. Atkinson et al. WO201192293) (153 mg, 943 μmol, Eq: 1.00) in THF (5 mL) at rt was added lithium aluminum hydride, (2 M in THF, 0.95 mL, 1.9 mmol, Eq: 2.01) and the resulting mixture was stirred at rt for 1 h. Additional lithium aluminum hydride, (2 M in THF, 0.95 mL, 1.9 mmol, Eq: 2.01) was added and stirring was continued at rt for 1 h. The reaction mixture was quenched by adding EtOAc (˜2 mL) followed by water (˜1 mL). To the resulting slurry was added aqueous Rochelle's salt solution (20 mL) and the mixture was extracted with EtOAc (2×20 mL). The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 100% EtOAc in hexanes) to give 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (73 mg), m/z=149 (M+H).
Reaction SMILES: [O:1]([CH2:8][CH:9]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)[CH:10]([OH:21])[C:11]1[CH:20]=[CH:19][C:14]2[N:15]=[C:16]([NH2:18])[S:17][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl>[NH2:18][C:16]1[S:17][C:13]2[CH:12]=[C:11]([C:10](=[O:21])[CH:9]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:20]=[CH:19][C:14]=2[N:15]=1
Reactant: Nc1nc2ccc(C(O)C(COc3ccccc3)N3CCC(Cc4ccccc4)CC3)cc2s1
Solvent: ClCCl
Product: Nc1nc2ccc(C(=O)C(COc3ccccc3)N3CCC(Cc4ccccc4)CC3)cc2s1
Reaction time: 0.33 h

Procedure:
After stirring for 20 min., a solution of 3 g of (±) threo 1-phenoxymethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane in 30 ml of dichloromethane was slowly added dropwise and the resulting cloudy solution was stirred for 20 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 70 °C
Yield: 39.8 %

Procedure:
4-(4-Bromo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.171 g, 0.5 mmol), Na2CO3 (0.16 g, 1.5 mmol), 4-fluoro phenyl boronic acid (0.21 g, 1.5 mmol) and (PPh3)2PdCl2 (0.035 g, 0.05 mmol) were mixed in a mixture of THF/H2O (4:1, 7.5 mL) and heated at 70° C. overnight. After cooling to rt, the reaction mixture was partitioned between 50 mL ethyl acetate and 25 mL sat. NaCl solution. The separated organic layer washed with brine (10 mL), dried (MgSO4) and concentrated. The crude was purified with prep TLC (15% ethyl acetate in hexanes) to give a solid (0.071 g). M+H 356.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1.[C:18](Cl)(=[O:20])[CH3:19].O>N1C=CC=CC=1>[C:18]([NH:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
As shown in step 10-ii of Scheme 10, to Compound 1033 (10.0 g) in pyridine (80 mL) was added acetyl chloride (4.2 mL). After stirring at 50° C. for 30 min, water (200 mL) was added. The resulting solid was collected by filtration and washed with water (2×) gave tert-butyl 2-acetamido-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (Compound 1034, 10.873 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[C:9]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccc(OC)cc2)c(Nc2ccc(OC)cc2)cc1C(=O)OC

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 3.0 g (24 mmol) of 4-anisidine in 24 ml ofglacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel withethyl acetate/hexane 1:1 and the product fractions are concentrated by evaporation, yielding the title compound in the form of a yellow foam, FAB-MS: 437 [M+ +H].
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:23])(=[O:22])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH:7]=1.CO>>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][S:12]([C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:24])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:22])=[O:23]
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2OC)c1
Solvent: CO
Product: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)O)c1
Yield: 92.5 %

Procedure:
To a suspension of 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acrylic acid methyl ester (14c) (0.42 g, 1.20 mmol) in methanol (5.5 ml) 1N NaOH solution (3.6 ml, 3.60 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and extracted with ethyl acetate. The extract was washed with saturated NaCl and dried (Na2SO4). The solvent was removed and the residue was dried in desiccator over P2O5 to give the title compound as a white solid (0.37 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:22]([O-])=O>[Pd].C(OCC)(=O)C.CO>[CH3:21][O:20][CH2:19][CH2:18][NH:17][C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:5]3[CH:4]=[C:3]([NH2:22])[C:2]([NH2:1])=[CH:7][CH:6]=3)=[N:9][C:10]=2[CH:16]=1
Reactant: COCCNc1ccc2[nH]c(-c3ccc(N)c([N+](=O)[O-])c3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCNc1ccc2[nH]c(-c3ccc(N)c(N)c3)nc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-(2-methoxy-ethyl)-amine (0.5 g, 1.5 mmol) in 4:1 ethyl acetate/methanol (50 ml) under nitrogen, was added 5% palladium on carbon (120 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL), and the combined filtrate and washings were concentrated to give the crude 4-[5-(2-methoxy-ethylamino)-1H-benzoimidazol-2-yl]-benzene-1,2-diamine which was used in the next step without any purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:12]3[C:13]4[N:14]([CH:25]=[CH:26][N:27]=4)[CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](Cl)=[O:37])=[CH:31][CH:30]=1.CN(C=O)C.C(OCC)C>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:16]3[N:17]=[C:12]([N:8]4[CH:9]=[CH:10][N:11]=[C:7]4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:13]4[N:14]([CH:25]=[CH:26][N:27]=4)[CH:15]=3)[CH:19]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(-n3ccnc3-c3ccccc3)n2)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1)Nc1cccc(-c2cn3ccnc3c(-n3ccnc3-c3ccccc3)n2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Solid 3-[8-(2-Phenyl-imidazol-1-yl)-imidazo[1,2-a]Pyrazin-6-yl]-phenylamine (50 mg) (7) is added to an anhydrous 0.2 M solution of (4-Chloro-phenyl)-acetyl chloride in toluene (0.7 mL) at room temperature, and 0.25 ml of anhydrous DMF is subsequently added to solubilize the reagents. The reaction is warmed to 50° C. and stirred under N2 for 3 hours. The reaction is cooled to room temperature. Diethyl ether (15 ml) is then added slowly and the resulting tan solid 2-(4-Chloro-phenyl)-N-{3-[8-(2-phenyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-acetamide (60 mg) (8) is filtered and washed with diethyl ether and dried under vacuum.
Reaction SMILES: [OH:1][CH2:2][C:3](=[N:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][OH:5].B.C1COCC1>C1COCC1>[OH:1][CH2:2][CH:3]([NH:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][OH:5]
Reactant: CC(C)(C)OC(=O)NN=C(CO)CO
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(CO)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.9 %

Procedure:
To a 0 THF solution of tert-butyl 2-[2-hydroxy-1-(hydroxymethyl)ethylidene]hydrazine carboxylate (1.0 g, 4.897 mmol) was added a solution of 1M BH3-THF (10 mL) dropwise. The reaction mixture was stirred at rt for 30 min, after which time the mixture was quenched by slowly adding 5 mL of methanol. The mixture was concentrated under reduced pressure and dried to give the desired product (1.12 g, 100%). 1H-NMR (DMSO-d6) δ 8.38 (s, 1H), 7.15 (s, 1H), 4.62 (s, 1H), 4.39 (t, 1H), 3.38 (q, 4H), 3.10 (s, 1H), 1.38 (s, 9H); LCMS RT=1.16 min; [M+H]+=206.9.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:28])[CH:22]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: O=C(O)c1cc(Br)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)ccn1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 52.6 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (200 mg, 0.680 mmol) in DMF (10 ml) was added 4-bromo-2-pyridinecarboxylic acid (137 mg, 0.680 mmol), HOBT.H2O (104 mg, 0.680 mmol), HBTU (258 mg, 0.680 mmol) and DIPEA (0.356 ml, 2.039 mmol) and the reaction mixture was stirred at room temperature for 2.5 hours. The DMF was evaporated under vacuo then 10 ml of DCM were added and washed with 2M aq. HCl solution (10 ml) saturated aq. NaHCO3 solution (10 ml) and brine (10 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was purified by silica chromatography using a gradient isohexane/EtOAc [100/0] to [50/50] then to [0/100]). The desired fractions were then collected and concentrated to dryness to give the title compound (171 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO>[CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCc2ncccc2OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CCc2ncccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methyl 4-[2-(3-benzyloxy-2-pyridyl)ethyl]benzoate (0.1 g, 0.3 mmol) in EtOH (1 ml) was treated with aqueous NaOH solution (0.6 ml 1N). The reaction was stirred at ambient temperature for 18 hours and then treated with HCl soltuion (0.6 ml, 1N). The resulting precipitate was filtered and recrystallised from isopropanol to give the title product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@H:8]2[C@H:13]3[O:14][C@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:15]([O:17]C)=O)=[CH:4][CH:3]=1.[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:37](=[O:38])[C:36]([C:31]3[NH:30][C:29]4[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=4[S:33](=[O:35])(=[O:34])[N:32]=3)=[C:15]([OH:17])[C@H:9]3[C@@H:8]2[C@H:13]2[O:14][C@@H:10]3[CH2:11][CH2:12]2)=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H]1[C@@H](NCc2ccc(F)cc2)[C@@H]2CC[C@H]1O2
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@H]3[C@H]([C@@H]4CC[C@H]3O4)N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a stirred solution of methyl (1R,2S,3R,4S)-3-[(4-fluorobenzyl)amino]-7-oxabicyclo[2.2.1]heptane-2-carboxylate (0.056 g, 0.21 mmol) in anhydrous N,N-dimethylformamide (3 mL) under a nitrogen atmosphere, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.070 g, 0.21 mmol) was added followed by N-methylmorpholine (0.046 mL, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21 mmol). The mixture was stirred at 25° C. for 1 h, triethylamine (0.88 mL, 0.63 mmol) was added and the resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was allowed to cool to 25° C., diluted with ethyl acetate, washed with 1.0M aqueous hydrochloric acid solution and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[(1S,2R,7S,8R)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-11-oxa-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (48 mg, 0.085 mmol, 41%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.51-1.71 (4H, m), 3.05 (3H, s), 3.30 (1H, m), 3.79 (1H, d, J=8.4 Hz), 4.40 (1H, d, J=15.6 Hz), 4.70 (1H, d, J=4.8 Hz), 4.76 (1H, d, J=4.8 Hz), 5.04 (1H, d, J=14.8 Hz), 7.15 (2H, t, J=8.4 Hz), 7.33 (2H, m), 7.49 (1H, dd, J=8.4, 2.4 Hz), 7.55 (2H, m). LC-MS (ESI) calcd for C24H23FN4O7S2 562.1, found 563.5 [M+H+]. Anal. calcd for C24H23FN4O7S2: C, 51.24; H, 4.12; N, 9.96; found: C, 51.10; H, 4.51; N, 9.98. ee>98% [HPLC-analysis: Chiralpak AS-RH 4.6×250 mm, 5 micron, 0.8 mL/min, 310 nm].