Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]([NH:15][C:16]2[CH:29]=[CH:28][N:19]([C@@H:20]3[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[CH2:21]3)[C:18](=[O:30])[N:17]=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([N+:44]([O-:46])=[O:45])[C:39]=1[CH2:47][CH2:48][O:49][C:50](Cl)=[O:51].CC(O)C.N#N>C(Cl)Cl>[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([N+:44]([O-:46])=[O:45])[C:39]=1[CH2:47][CH2:48][O:49][C:50]([O:26][CH2:25][C@H:24]1[O:27][C@@H:20]([N:19]2[CH:28]=[CH:29][C:16]([NH:15][C:13]([O:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[O:14])=[N:17][C:18]2=[O:30])[CH2:21][C@@H:22]1[OH:23])=[O:51]
Reactant: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)OCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCCc1c(Cl)cccc1[N+](=O)[O-]
Agent: N#N
Solvent: ClCCl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](COC(=O)OCCc3c(Cl)cccc3[N+](=O)[O-])O2)c(=O)n1)OCCc1ccc([N+](=O)[O-])cc1
Temperature: -60 °C
Reaction time: 1.25 h
Yield: 68 %

Procedure:
N4 -(2-(4-nitrophenyl)ethoxycarbonyl)-2'-deoxycytidine (5 g, 11.9 mmol) was co-evaporated with pyridine (2×60 ml, pro analysi quality, additionally dried over molecular sieve 4 Å), dissolved in pyridine (60 ml, see above) and cooled to -60° C. (i-PrOH/N2). A solution of 2-(2-chloro-6-nitrophenyl)ethoxycarbonyl chloride (4.7 g, 17.8 mmol) in CH2Cl2 (60 ml, dist. over CaH2) was added dropwise thereto for 75 min and was stirred for 1 h 45 min in conditions of i-PrOH/N2 cooling (-40° to -25° C.). The mixture was diluted with CH2Cl2 (150 ml) and washed with H2O (100 ml). The aqueous phases were post-extracted with CH2Cl2 (100 ml). Drying the organic phases over Na2SO4, filtering, evaporating the solvent under reduced pressure and co-evaporating with toluene (3×50 ml) yielded the crude product (9.8 g) which was purified by column chromatography (440 g SiO2, 32×5.9 cm, solvent: CH2Cl2 /MeOH 100:4). 5'-O-(2-(2-chloro-6-nitrophenyl)ethoxycarbonyl)-N4 -(2-(4-nitrophenyl)ethoxycarbonyl)-2'-deoxycytidine (5.247 g, 680%) was obtained as a colourless foam.
Reaction SMILES: [C:1]([O:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl.[N:24]([O-])=O.[Na+].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[C:29]=1[OH:35].C([O-])(=O)C.[Na+]>O1CCCC1.O.CO>[OH:34][C:30]1[CH:31]=[CH:32][C:33]([N:24]=[N:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH2:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[O:9])=[N:28][C:29]=1[OH:35]
Reactant: Nc1ccccc1C(=O)OCN1C(=O)c2ccccc2C1=O
Reactant: Oc1cccnc1O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(OCN1C(=O)c2ccccc2C1=O)c1ccccc1N=Nc1ccc(O)c(O)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Phthalimidomethyl anthranilate (1.0 g) was dissolved in 20 ml tetrahydrofuran (THF), concentrated hydrochloric acid added (1 ml) and the solution cooled in an ice bath. With rapid stirring sodium nitrite (0.23 g dissolved in 1 ml water) was added and the mixture stirred for another 20 minutes. This solution was then added dropwise to an ice-cooled solution of 2,3-pyridinediol (0.4 g) and sodium acetate (2.0 g) in 50 ml of a 2:1 mixture by volume of methanol and water. On further stirring for 1 hour at 0° C. the dye precipitated. It was further diluted with 100 ml water and the mixture filtered. The precipitate was washed with water and dried. Yield 1.2 g, m.p. 196°-201° C. A thin layer chromatogram showed a single spot.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:14]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH3:29][N:27]([CH3:28])[C:25]([C@@H:15]1[CH2:14][C@@H:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:17][N:16]1[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:26]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](OCCCO[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1C[C@@H](OCCCO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
To a solution of 2.10 g of the compound obtained in Step 139-1 in THF (100 ml) was added a solution 1 mol/L TBAF in THF (10 ml) under ice cooling and the reaction mixture was stirred at room temperature for two hours. Water was poured, the solution was extracted twice with CHCl3; the combined organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=20/1 to 10/1; v/v) to obtain 1.79 g of the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.[C:22]([O:26][C:27]([N:29]1[C@H:34]([C:35](O)=O)[CH2:33][C@@H:32]2[C@H:30]1[CH2:31]2)=[O:28])([CH3:25])([CH3:24])[CH3:23].ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:35]([C@@H:34]3[CH2:33][C@@H:32]4[C@@H:30]([CH2:31]4)[N:29]3[C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[NH:21][C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(Br)cc2[nH]1
Temperature: 75 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
EDCI.HCl (2.65 g, 13.8 mmol) was added to a mixture of 4-bromobenzene-1,2-diamine 2.35 g, 12.6 mmol), (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3.00 g, 13.2 mmol) and 1-hydroxybenzotriazole (1.93 g, 12.6 mmol) in CH2Cl2 (80 mL) and stirred at ambient conditions for 16 h. The mixture was then diluted with CH2Cl2, washed with water, dried (brine; MgSO4), filtered and concentrated in vacuo to provide a brown foam. Acetic acid (80 mL) was added to the foam and the mixture was heated at 75° C. (bath temperature) for 5 h. The volatile component was removed in vacuo and the residue was dissolved in EtOAc, washed with saturated NaHCO3 solution and the organic phase was dried (brine; MgSO4), filtered and concentrated in vacuo. The resultant crude material was submitted to flash chromatography (silica gel; 50-100% EtOAc/hexanes) to provide (1R,3S,5R)-tert-butyl 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.01 g, 7.96 mmol, 63.3% yield) as a light orange foam, which was used without further purification. The reaction also yielded 847 mg of same product with lower purity. An aliquot of the collected material was purified further by preparative HPLC (C-18/30-100% CH3CN-water+0.1% NH4OAc) to achieve an analytical sample. LC-MS retention time 1.248 min; Calcd. for C17H21BrN3O2: 378.08 Found m/z 380.05 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.67 (br s, 1H), 7.43 (br s, 1H), 7.34 (d, J=8.6 Hz, 1H), 4.75 (br s, 1H), 3.62 (br s, 1H), 2.50-2.57-2.31 (m, 1H), 2.31 (dt, J=13.2, 6.7 Hz, 1H), 1.66-1.85 (m, 1H), 1.45 (br s, 3H), 1.11 (br s, 6H), 0.87 (dt, J=8.6, 5.8 Hz, 1H), 0.66 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[CH2:14][CH:15]=[C:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:28])[CH2:17]4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[CH2:14][CH2:15][C:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=[O:28])[CH:17]=4)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)CC1=CC3
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Yield: 69.9 %

Procedure:
A solution of 2.20 g cholesta-5,8-dien-3β-ol in 27 ml toluene and 6 ml cyclohexanone is refluxed for 10 minutes in a Dean-Stark apparatus. 0.57 g aluminum isopropoxide are added and the reaction mixture is refluxed for 30 minutes. After cooling and addition of sulfuric acid (2 N), the resulting mixture is extracted with ethyl acetate. The organic layer is separated, washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulphate and filtered. After evaporation of the solvent the residue is chromatographed with a mixture of hexane and ethyl acetate to give 1.53 g cholesta-4,8-dien-3-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([NH2:37])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].CO.[Li+].[OH-]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10]([NH:37][S:39]([CH3:38])(=[O:41])=[O:40])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CS(=O)(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-amine (70 mg, 0.13 mmol) in dichloromethane (2.0 mL) was added TEA (27 mg, 0.27 mmol) at 0° C. followed by slow addition of methane sulfonyl chloride (15 mg, 0.13 mmol). The reaction was warmed slowly to room temperature and stirred for 2 h. The reaction was then diluted with CH2Cl2 (70 mL) and water (10 mL). The organic layer was separated, washed with saturated brine solution (2×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in THF (1 mL), MeOH (1 mL), and H2O (0.5 mL), and then LiOH (20 mg, 0.48 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (90% EtOAc/petroleum ether). The isolated product was further purified by preparative HPLC (acetonitrile:water: 0.1% v/v trifluoroacetic acid modifier) to afford N-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-yl}methanesulfonamide (TFA salt). MS ES/APCI calc'd. for C30H36ClN6O3S [M+H]+ 595. found 595. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (bs, 1H), 8.77 (d, J=2.0 Hz, 2H), 8.23 (t, J=2.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 2H), 7.29-7.21 (m, 3H), 6.99 (s, 1H), 4.75 (t, J=5.2 Hz, 1H), 3.92-3.88 (m, 4H), 3.75-3.70 (m, 1H), 3.54-3.49 (m, 2H), 3.26 (s, 3H), 3.25-3.20 (m, 1H), 1.41-1.35 (m, 2H), 1.08-1.07 (m, 1H), 0.76-0.74 (m, 3H), 0.70 (d, J=6.8 Hz, 3H), 0.58-0.55 (m, 1H), 0.50-0.47 (m, 1H), 0.40-0.27 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:17])=[CH:4][C:3]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccncc1Oc1ccccc1
Reactant: CC(=O)OO
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc[n+]([O-])cc1Oc1ccccc1
Temperature: 60 °C

Procedure:
A solution of 25 g of 4-methyl-3-phenoxypyridine, [J.Med.Chem., 18, 1 (1975)] in 90 ml of glacial acetic acid is treated with 30 ml of 40% peracetic acid in acetic acid and the mixture is stirred and heated at 60° C. for 12 hours. Two further 10 ml portions of 40% peracetic acid are added and the mixture heated 4 hours at 60° C. 100 ml of isopropanol is added and the mixture is heated at 90° C. for 4 hours. The mixture is stripped at reduced pressure and dissolved in 500 ml of dichloromethane. The organic layer is washed with an excess of 25% sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered, concentrated, and distilled to yield 4-methyl-3-phenoxypyridine-1-oxide. B.P. 150°-152° C./0.3 mm
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]12([CH2:22][NH2:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:6]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ccc1Cl
Yield: 84 %

Procedure:
Prepared according to the method described in Example 22 from 2,5-dichlorobenzoic acid (0.319 g), 1-adamantanemethylamine (0.25 g), 4-dimethylaminopyridine (0.204 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.321 g) in dichloromethane (30 ml). The crude product was purified by silica gel chromatography eluting with dichloromethane to give the title compound as a white solid (0.43 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([I:31])=[C:25]([CH:30]=1)[CH2:26][N:27]=[N+]=[N-].O>C1COCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([I:31])=[C:25]([CH:30]=1)[CH2:26][NH2:27]
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
PPh3 (1.46 g, 5.58 mmol) was added to a stirred solution of 5-chloro-2-iodobenzylazide (0.55 g, 1.86 mmol) in THF (17.5 mL), and water (3.5 mL) were combined and stirred at room temperature. After 16 hr, the mixture was warmed to 80° C. for 3 h. The reaction was then concentrated and the residue was partitioned between ether and 1N HCl. The aqueous layer was adjusted to pH=8 with NaHCO3, saturated with NaCl and then extracted into CH2Cl2. The CH2Cl2 layer was washed with brine, dried (Na2SO4) and evaporated to give 5-chloro-2-iodobenzylamine (428 mg): 1H NMR (CDCl3, 400 MHz) δ 3.83 (s, 2H), 6.95 (dd, J=2.6, 8.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[O-]CC.[Na+].[Na].[CH:14]([C:16]([CH3:18])=[O:17])=[CH2:15]>C(O)C.C(Cl)(Cl)Cl>[O:17]=[C:16]([CH3:18])[CH2:14][CH2:15][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: C=CC(C)=O
Reactant: CCOP([O-])OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCC(C)=O)OCC
Temperature: 15 °C

Procedure:
To 243 grams (1.76 moles) of diethyl phosphite stirred under nitrogen and protected by a drying tube was added a solution of sodium ethoxide prepared from 5.07 grams (0.22 mole) of sodium in 100 ml of anhydrous ethanol. Methyl vinyl ketone, 112 grams (1.60 moles), was then added at such a rate as to keep the temperature at 35°-40° C. The addition required about one hour. The reaction mixture was stirred for one-half hour after the addition was completed and was stripped to dryness in vacuo at 60° C./16 mm. The residue was taken up in 600 ml of chloroform, and the solution cooled to 15° C. and washed successively with dilute acid, water and saturated sodium chloride solution. After drying, the chloroform solution was distilled to yield 112 grams of diethyl 3-oxobutylphosphonate as a colorless liquid, B.P. 106° C./0.05 mm, nD 25 1.4340. VPC indicated that the product was 90% pure.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A mixture of 2-chloro-1H-indole-3-carboxaldehyde (2.2 g, 12.25 mmol), 4-t-butylphenylboronic acid (4.36 g, 24.49 mmol), copper acetate (4.45 g, 24.50 mmol), 4A molecular sieve (2.5 g), pyridine (3.0 mL) and dichloromethane (40 mL) is stirred overnight at room temperature. The reaction mixture is diluted with dichloromethane (100 mL), washed with water (50 mL), with 3N aqueous hydrochloric acid (10 mL), the precipitate removed by filtration and the dichloromethane layer is washed again with water (50 mL), aq sodium bicarbonate, with brine, dried and filtered. The filtrate is concentrated to give a solid. The crude is crystallized from dichloromethane-methanol to afford 1-(4-tert-butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde (3.09 g, 81% yield) as a yellow solid. TLC (silica gel, 20% ethyl acetate/heptane) Rf 0.50; ESI/MS 312 (M+H), RT 4.32 min; NMR: 10.12 (1H, s); 8.20 (1H, d, J=6 Hz); 7.71 (2H, d); 7.53 (2H, d); 7.38 (2H, m); 7.11 (1H, d); 1.38 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 120 °C

Procedure:
To a mixture of 2-chloro-5-nitropyridine (476 mg, 3.0 mmol) and 4-piperidine acetic acid methyl ester (471 mg, 3.0 mmol) in tetrahydrofuran (10 mL) was added diisopropylethylamine (1.0 mL, 5.74 mmol). The mixture was heated in a microwave at 120° C. for 30 minutes. The mixture was evaporated to dryness and extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid methyl ester as a yellow solid. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][SH:20])[CH3:15].O>CN(C=O)C>[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][S:20][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1)[CH3:15]
Reactant: Nc1ncc(Br)s1
Reactant: CCOC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCSc1cnc(N)s1
Yield: 49.3 %

Procedure:
5-Bromo-2-aminothiazole (25 g, 96 mmol) in DMF (150 mL) was added K2CO3 (26.5 g, 192 mmol) and the mixture was purged with N2 for 5 min. The mixture was cooled to 0° C. on an ice bath before 3-mercaptopropionic acid ethyl ester (12.9 g, 96 mmol) was added dropwise over the course of 30 min. The reaction mixture was stirred for 13 Hours before water (400 mL) was added. The aqueous mixture was extracted with Et2O (1×500 mL, 2×250 mL). The combined organic phases was washed with saturated NH4Cl (3×150 mL), dried (MgSO4). The solvent was removed in vacuo to give a dark residue which was purified by column chromatography (SiO2, EtOAc-heptane (1:1)). The solvent was removed in vacuo to give 11 g (49%) of 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19].C1C([N+]([O-])=O)=CC=C([Cl-][C:30]([O-])=[O:31])C=1.C(N(CC)CC)C.[Cl:40][C:41]1[C:49]2[NH:48][C:47](=[O:50])[N:46]([CH:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[C:45]=2[CH:44]=[CH:43][CH:42]=1>O1CCCC1>[Cl:40][C:41]1[C:49]2[NH:48][C:47](=[O:50])[N:46]([CH:51]3[CH2:56][CH2:55][N:54]([C:30]([NH:1][C@@H:2]4[CH2:8][CH2:7][C@@H:6]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=5)[CH2:5][N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]4=[O:19])=[O:31])[CH2:53][CH2:52]3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: O=c1[nH]c2c(Cl)cccc2n1C1CCNCC1
Reactant: COCCN1C[C@H](c2ccccc2)CC[C@@H](N)C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCN1C[C@H](c2ccccc2)CC[C@@H](NC(=O)N2CCC(n3c(=O)[nH]c4c(Cl)cccc43)CC2)C1=O
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A solution of (3R,6S)-3-amino-1-(2-methoxyethyl)-6-phenylazepan-2-one (0.015 g, 0.057 mmol) and 4-nitrophenylchloroformate (0.012 g, 0.057 mmol) in dry tetrahydrofuran (2 mL) was cooled to 0° C. under argon. Triethylamine (0.006 g, 0.057 mmol) was added and the reaction stirred for 1 h. Solid 4-chloro-1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.057 mmol) followed by triethylamine (0.055 g) were added. The reaction was allowed to come to room temperature and stirred for 1 h. The reaction was diluted with dicholoromethane and extracted with 1N NaOH until the yellow color of the organic layer disappeared. The organic layer was dried over sodium sulfate, concentrated and purified by normal phase chromatography (silica gel, 0 to 7% methanol in methylene chloride gradient elution), which gave the title compound (9 mg). MS 540.2370 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:29]([C:27]1[S:28][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[CH:25][CH:26]=1)(=[O:30])=[O:31])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccn2)s1
Yield: 40 %

Procedure:
According to the method described in example S20a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol) was reacted with 5-(pyridin-2-yl)thiophene-2-sulfonyl chloride to yield the title compound as a white solid (16 mg, 40%). MS ESI 460.2 [M+H]+, calcd for [C22H25N3O4S2+H]+ 460.13