Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@@H:23]2[CH2:27][C@H:26]([N:28]3[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]3)[C@@H:25]([OH:35])[C@H:24]2[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:15]=1)=[O:13].FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:104]([NH:106][CH:107]3[CH2:112][CH2:111][N:110]([C:113]4[CH:118]=[CH:117][CH:116]=[CH:115][N:114]=4)[CH2:109]C3)=[O:105])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1N1CC[C@@H](NC(N2C=CN=C2)=O)C1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:114]1[CH:115]=[CH:116][CH:117]=[CH:118][C:113]=1[N:110]1[CH2:111][CH2:112][C@@H:107]([NH:106][C:104](=[O:105])[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([N:28]4[CH:32]=[C:31]([CH2:33][OH:34])[CH:30]=[N:29]4)[C@@H:25]([OH:35])[C@H:24]3[OH:36])=[C:16]([NH:37][CH2:38][CH:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:15]=2)=[O:13])[CH2:109]1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Agent: O=C(N[C@@H]1CCN(c2ccccn2)C1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)N[C@@H]1CCN(c2ccccn2)C1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide trifluoroacetate (first step a) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42) replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with imidazole-1-carboxylic acid ((R)-1-pyridin-2-yl-pyrrolidin-3-yl)-amide. MS (ES+) m/e 786 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1.[N+:19]([O-])([O-:21])=[O:20].[K+].N>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([N+:19]([O-:21])=[O:20])=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1nc(N)nc(N)c1-c1cc(Cl)c([N+](=O)[O-])c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Diamino-6-methyl-5-(2,3,5-trichlorophenyl)pyrimidine (0.152 g) (Example 6) was dissolved in concentrated sulphuric acid and potassium nitrate (50 mg) was added. The solution was stirred at room temperature overnight, then poured onto ice and basified with 0.880 ammonia. The product was extracted into ethyl acetate, bulked, dried (MgSO4) and evaporated. The residue was purified by chromatography on SiO2 gel, eluting with EtOAc to 8% MeOH/EtOAc to give the desired product, 0.13 g, mp. 313°-315° C.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:16]1[CH:35]=[CH:34][C:19]([CH2:20][O:21][C:22]2[C:23]([CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)(O)=O.C(N(CC)CC)C.C(OCC)C>O1CCCC1>[NH:30]1[CH:31]=[CH:32][N:33]=[C:29]1[CH2:28][C:23]1[C:22]([O:21][CH2:20][C:19]2[CH:34]=[CH:35][C:16]([C:11](=[O:12])[NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:17][CH:18]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C(O)c1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
Phenyl sulphonyl isocyanate (1.2 g) was added to a suspension of 3-(4-carboxybenzyloxy) 2-(1-imidazolylmethyl)pyridine (1.0 g) in dry tetrahydrofuran (40 ml) containing triethylamine (0.33 g). The mixture was stirred at room temperature for 8 hours and allowed to stand at room temperature for a further 36 hours. The solvents were evaporated under vacuum and aqueous 5% sodium bicarbonate solution (100 ml) added to the residue. The mixture was extracted with dichloromethane (3×50 ml) and the combined organic extracts dried, filtered and evaporated to yield an oil which solidified on trituration with diethyl ether. Recrystallization from aqueous methanol gave 2-(1-imidazolylmethyl)-3-[4-(N-phenylsulphonylcarbamoyl)benzyloxy]pyridine (0.38 g), m.p. above 250° C. Found: C, 61.47; H, 4.40; N, 12.63. C23H20N4O4S requires: C, 61.59; H, 4.50; N, 12.49%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C1C(N=C=S)=CC=C([O:16][CH:17]2[O:22][CH:21]([CH2:23][OH:24])[CH:20]([OH:25])[CH:19]([OH:26])[CH:18]2[OH:27])C=1>CN(C)C=O>[O:16]=[CH:17][C@H:18]([C@H:19]([C@@H:20]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:25])[OH:26])[OH:27]
Reactant: OCC1OC(Oc2ccc(N=C=S)cc2)C(O)C(O)C1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 16 h

Procedure:
Synthetic glycoprotein carriers were constructed in which poly (L-lysine), average chain length 100 (Mr 20,000 Da), was glycosylated using a-D-mannopyranosyl phenylisothiocyanate dissolved in N,N-dimethylformamide. The solution was adjusted to pH 9.5 by the addition of 1M Sodium carbonate, pH 9.5. Shielded from light and incubated for 16 hours at 22∞C, the solution was dialyzed against 5 mM Sodium chloride for two days. Approximately 0.8 to 1.0% of the amine side chains in the polylysine are glycosylated, as determined by absorbance spectroscopy at 250 nm. As a control, an alternative glycoprotein carrier was synthesized by substituting a-D-mannopyranosyl phenylisothiocyanate with a-D-galactopyranosyl phenylisothiocyanate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([Cl:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH3:19])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([Cl:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc2nc[nH]c2c(OCc2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc2cc(Cl)nc(OCc3ccccc3)c21
Reaction time: 2 h

Procedure:
A mixture of 4-(benzyloxy)-6-chloro-3H-imidazo[4,5-c]pyridine 2.24 (1.00 g, 3.85 mmol) and K2CO3 (1.06 g, 7.70 mmol) were suspended in DMF and iodomethane (0.312 mL. 5.01 mmol) was added dropwise. The reaction was stirred for 2 hours and judged to be complete by LC and TLC. The reaction was concentrated, diluted with NaHCO3 (30 mL) and EtOAc (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (3×50 mL), dried, filtered, and concentrated under reduced pressure to afford a mixture of regioisomers. Purification via flash chromatography (2→5% THF in CH2Cl2) afforded 4-(benzyloxy)-6-chloro-3-methyl-3H-imidazo[4,5-c]pyridine 2.25 as the first eluting isomer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:48])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:48])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCOCC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCOCC4)c(NS(C)(=O)=O)c3)cc12
Yield: 19.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-morpholino phenyl)methanesulfonamide (150 mg, 0.205 mmol) was hydrolyzed with lithium hydroxide (43.2 mg, 1.02 mmol) in THF/Methanol/water (2/3/1 ml). This yielded 23 mg (19.49% yield) of pure compound. 1H NMR (CDCl3, 300 MHz): δ 9.17 (s, 1H), 8.55 (s, 1H), 7.86 (s, 2H), 7.75 (s, 1H), 7.32 (s, 3H), 6.99-6.97 (m, 2H), 6.90-6.80 (d, 1H), 5.31 (s, 2H), 3.91-3.88 (m, 4H), 3.10 (s, 3H), 2.92-2.89 (m, 4H), 2.26 (s, 3H), 2.17 (s, 3H). MS: m/z=575.1 (M+1), HPLC Purity: 98.92% Method: B.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([OH:20])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=C(S(O[CH2:34][C@:35]2([CH3:38])[CH2:37][O:36]2)(=O)=O)C=CC=1)([O-])=O>CN1CCCC1=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([O:20][CH2:34][C@:35]2([CH3:38])[CH2:37][O:36]2)[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: CC(=O)Nc1ccc(OC(=O)c2ccccc2)cc1O
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(OC(=O)c2ccccc2)cc1OC[C@]1(C)CO1
Yield: 39 %

Procedure:
This compound was prepared from 4-(acetylamino)-3-hydroxyphenyl benzoate (2.71 g, 10 mmol) and [(2S)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate using the standard procedure and 1-methylpyrrolidin-2-one as a solvent. Flash chromatography on silica gel (ethyl acetate/n-heptane) afforded the subtitled compound as a colourless solid (1.31 g, 3.9 mmol, 39%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]1[CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1>[Pd].CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH:7]1[CH2:16][CH2:15][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:9][CH2:8]1
Reactant: C1=CCC(C2CCC3(CC2)OCCO3)OC1
Agent: [Pd]
Solvent: CO
Product: C1CCC(C2CCC3(CC2)OCCO3)OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-(3,6-dihydro-2H-pyran-2-yl)-1,4-dioxaspiro[4.5]decane (190 mg, 0.847 mmol), as prepared in Example 2 step C, and Palladium on Carbon (118 mg, 0.055 mmol, 5%, “Degussa, wet”) was carefully added methanol (24 mL). The reaction flask was evacuated, backfilled with hydrogen via balloon and stirred at room temperature overnight. The catalyst was removed by filtration and the filtrate concentrated in vacuo to afford the product.
Reaction SMILES: O=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][C:11]2[NH:36][C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[CH3:35])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>>[S:46]=[C:2]1[NH:8][CH:7]([CH2:9][CH2:10][C:11]2[NH:36][C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[CH3:35])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1ccccc1NS(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Yield: 85.9 %

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 88 mg of 4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide (compound B9) and 77 mg of Lawesson's reagent. Purification by chromatography on LiChroprep-NH2® (eluents: i. neat dichloromethane, ii. dichloromethane/ethanol 20:1 parts by volume) affords 78 mg of the title compound as a waxy solid. ESI-MS: 520.4 (MH+). TLC: Rf=0.44 (LiChroprep-NH2® HPTLC, dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]([CH3:16])[CH2:10][C:11](OCC)=[O:12].C[O-].[Na+]>CO>[CH3:16][CH:9]1[CH2:10][C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8]1
Reactant: CCOC(=O)CC(C)Nc1ccccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1CC(=O)Nc2ccccc2N1
Yield: 40.6 %

Procedure:
An round bottomed flask was charged with ethyl 3-(2-aminophenylamino)butanoate (684 mg, 3.08 mmol) and a stirbar. MeOH (15 mL, 0.1 M) was added, followed by sodium methoxide (249 mg, 4.62 mmol), and the solution was stirred at reflux for 48 h. The mixture was concentrated with celite and purified by silica gel chromatography (eluting with hexanes/ethyl acetate) to yield 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one as an off-white amorphous solid (0.22 g, 1.25 mmol, 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1>C(#N)C>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: OCc1cccc(Br)n1
Solvent: CC#N
Product: OCc1cccc(Nc2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.35 g (14.3 mmol) of 4-aminopyridine and 1.34 g (7.1 mmol) of (6-bromopyridin-2-yl)methanol are stirred at 150° C. for 4 h. After cooling to RT, 50 ml of acetonitrile are added to the reaction mixture, and the mixture is stirred for 20 min. The precipitate formed is filtered off with suction at 0° C. and washed with 10 ml of acetonitrile.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)([OH:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H].C>CO>[ClH:1].[NH:20]1[C:21]2[C:17](=[C:16]([C:12]3([OH:15])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: [H][H]
Reactant: OC1(c2cccc3[nH]ccc23)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: OC1(c2cccc3[nH]ccc23)CCNCC1
Yield: 78.2 %

Procedure:
A mixture of 13.7 g of the hydrochloride of Example 2 in 600 ml of methanol was subjected to hydrogen at 40° C. in the presence of 4.7 g of palladized charcoal and the mixture was then filtered. The filtrate was evaporated to dryness under reduced pressure at 40° C. and the residue was triturated in ether, filtered and dried at 20° to 25° C. under reduced pressure to obtain 7.9 g of 4-(1H-indol-4-yl)-4-piperidinol hydrochloride melting at 270° C.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:12][C@H:11]([CH3:13])[C@@:9](C(=O)C)([OH:10])[C@H:8]2[F:17])[C:5]2[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)C.O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:12][C@H:11]([CH3:13])[C@@H:9]([OH:10])[C@H:8]2[F:17])[C:5]2[CH:18]=[C:19]([Cl:23])[C:20]([Cl:22])=[CH:21][C:4]=2[N:3]=1
Reactant: CC(=O)[C@@]1(O)[C@@H](C)O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H]1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: C[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](F)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-5,6-dichloro-1-(3-acetyl-2,5-dideoxy-2-fluoro-beta-D-ribofuranosyl)-1H-benzimidazole (0.42 g, 1.0 mmoles) was dissolved in methanol and ethanol (17 mL each). Sodium carbonate (0.22 g, 2.1 mmoles, 2 eq.) was dissolved in 4.2 mL water and added to the starting material solution. The reaction was stirred at room temperature overnight. The solution was diluted with water (40 mL). The product was extracted with ethyl acetate (2×). The ethyl acetate solution was dried with MgSO4, filtered, and the solvent removed in vacuo. The residue purified by chromatography on 75 g of silica gel eluted with ethyl acetate/hexane (1:4, v/v) followed by (1:2, v/v). The product containing fractions were combined and the solvents removed in vacuo. The yield was 0.3 g, 75%. MS (FAB(+): m/z, 383; 1H NMR (DMSO-d6) δ7.97 (s, 1H, Ar—H), 7.88 (s, 1H, Ar—H), 6.20 (d, 1H, H-1′, J=19 Hz), 5.77 (d, 1H, OH-3′, J=5 Hz), 5.40 (d, 1H, H-2′, J=53 Hz), 4.0 (m, 2H,), 1.40 (d, 3H, H-5′, J=6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16]2)=[O:10])=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1
Reactant: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2C(F)(F)F)C1
Temperature: 115 °C
Yield: 17.9 %

Procedure:
To a round bottom flask were added N-[4-bromo-2-(trifluoromethyl)phenyl]-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (1025 mg, 2.148 mmol) and potassium carbonate (1203 mg, 8.70 mmol). The mixture was suspended in water (100 mL) and refluxed for 16 h at 115° C. Analysis by LCMS indicated consumption of starting material and formation of desired product and by-products related to the starting material. The solution was neutralized to pH=7 with 1N aq HCl and diluted with 150 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. This material was purified by silica gel chromatography (0-20% isopropanol/ethyl acetate), to afford the title product (177 mg, 18%). MS(ES)+ m/e 459.2, 461.2 M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([O-])([O-])=O.[K+].[K+].[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C.O>[I:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:21][CH:20]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a stirred solution of phthalimide (0.6 g, 4.0 mmol) in DMF (5 ml) was added K2CO3 (2.25 g, 16.00 mmol), followed by 4-iodobenzyl bromide (1.33 g, 4.4 mmol) at 0° C. and the reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was washed with diethyl ether to get the desired compound as a white solid (700 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.84 (m, 4H), 7.70-7.66 (m, 2H), 7.12 (d, J=8.3 Hz, 2H), 4.72 (s, 2H).
Reaction SMILES: C([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=[O:25])[CH2:8][CH2:7]1)=O)C.Cl[C:27](OCC)=O.C(OC(=O)C)(=O)C>>[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=[O:25])[CH2:8][CH2:7]1)(=[O:3])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1

Procedure:
3-[3-(4-Acetyl-piperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde was prepared as described for 4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazine-1-carboxylic acid ethyl ester in Example 8 but substituting ethyl chloroformate with with acetic anhydride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>O1CCOCC1.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[CH:5]=[O:6])=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=Cc1cc(-c2ccncc2)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To 3-bromo-5-(trifluoromethyl)benzaldehyde (1.0 g, 3.95 mmol) in 1,4-dioxane (15 ml), pyridine-4-boronic acid) (583 mg, 4.74 mmol), sodium carbonate (2M aqueous solution) (1.67 gms in 7.9 ml water) and Pd(PPh3)4 450 mg, 0.39 mmol) was added and heated at 90° C. for 5 h. Then reaction mixture was diluted with ether, washed with water, brine and dried. Volatiles were removed under vacuum and the crude residue was column chromatographed (50% ethylacetate/50% hexanes) to yield 250 mg of 3-(pyridin-4-yl)-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16](OC2C=CC=CC=2Cl)=[O:17])[CH2:12][C:11](=[O:26])[N:10]([CH2:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][C:31]([O:36][CH3:37])=[CH:30][C:29]=2[O:38][CH3:39])[CH2:9]1.CN(C)C=O.Cl.[C:49]([O:53][C:54]1[CH:58]=[C:57]([CH:59]([NH2:62])[CH2:60][CH3:61])[O:56][N:55]=1)([CH3:52])([CH3:51])[CH3:50].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:41][CH3:42])=[C:6]([CH:40]=1)[CH2:7][C@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:62][C@@H:59]([C:57]2[O:56][N:55]=[C:54]([O:53][C:49]([CH3:50])([CH3:52])[CH3:51])[CH:58]=2)[CH2:60][CH3:61])=[O:17])[CH2:12][C:11](=[O:26])[N:10]([CH2:27][C:28]2[C:29]([O:38][CH3:39])=[CH:30][C:31]([O:36][CH3:37])=[CH:32][C:33]=2[O:34][CH3:35])[CH2:9]1
Reactant: CCC(N)c1cc(OC(C)(C)C)no1
Reactant: COc1cc(OC)c(CN2C[C@@H](Cc3cc(Cl)ccc3OC)C(=O)N(C(=O)Oc3ccccc3Cl)CC2=O)c(OC)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@@H](NC(=O)N1CC(=O)N(Cc2c(OC)cc(OC)cc2OC)C[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1cc(OC(C)(C)C)no1
Reaction time: 15 h
Yield: 43 %

Procedure:
To the compound S141C described in WO 06-059801A, that is, (6R)-2-chlorophenyl 6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxylate (395 mg) in an N,N-dimethylformamide (0.64 ml) solution, the compound S94 described in WO 06-059801A, that is, 1-(3-tert-butoxyisoxazol-5-yl)propylamine hydrochloride (150 mg), 4-dimethylaminopyridin (78 mg) and N,N-diisopropylethylamine (0.111 ml) were added at 0° C., and the mixture was stirred at that temperature for 15 hours. To the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The extract was combined, successively washed with saturated aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution, and brine, dried over sodium sulfate, then concentrated. The residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate=50/50 to 35/65) to obtain (6R)-6-(5-chloro-2-methoxybenzyl)-N-[(1R)-1-(3-tert-butoxyisooxazole-5-yl)propyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxamide (189 mg) (compound S49a) and (6R)-6-(5-chloro-2-methoxybenzyl)-N-[(1S)-1-(3-tert-butoxyisooxazol-5-yl)propyl]-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepane-1-carboxamide (compound S49b).