Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][S:6]([C:9]1[CH:33]=[CH:32][C:12]([CH2:13][C:14]2[N:18]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[O:16][N:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7]>CO>[ClH:4].[CH3:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[N:18]=[C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[O:16][N:15]=2)=[CH:32][CH:33]=1)(=[O:7])=[O:8]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Cc3ccc(S(C)(=O)=O)cc3)no2)CC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cc2noc(C3CCNCC3)n2)cc1
Product: Cl
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A premixed solution of acetyl chloride (0.97 mL, 11.86 mmol) was added dropwise to methanol (10 mL), stirred for 10 minutes and tert-butyl 4-{3-[4-(methylsulfonyl)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylate (2.50 g, 5.93 mmol) was added and the mixture heated to reflux for 2 hours. The solvents were evaporated and the residue triturated with diethyl ether, filtered and dried to give the title compound as a fine white powder (2.05 g, 97%); NMR 1.97 (2H, m), 2.17(2H, dd), 3.02(2H, m), 3.31 (2H, m), 3.41 (1H, m), 4.25 (2H, s), 7.59 (2H, d), 7.89 (2H, d), 9.27(1H, br s), 9.35 (1H, br s); MS: 322 (MH+).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.BrC1C(OC)=CC2N=C[N:35](CC3C=CC4N=C(N[C@@H]5CCCC[C@H]5O)SC=4C=3)[C:34]=2C=1>>[OH:24][C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][C:15]1[S:16][C:12]2[CH:11]=[C:10]([CH2:9][N:6]3[C:5]4[CH:27]=[CH:28][C:2]([C:34]#[N:35])=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:26]=[CH:25][C:13]=2[N:14]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2cc1Br
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1
Product: N#Cc1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1

Procedure:
1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile was synthesized as a white powder (32 mg, 6%) using a procedure analogous to that described in Step 1 of Example 53, substituting (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from the previous step for (1R,2R)-2-((6-((6-bromo-5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol used in Example 53. The product was further purified by silica gel flash chromatography eluting with 5% MeOH in CH2Cl2. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.22 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.62 (m, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 5.54 (s, 2H), 4.73 (d, J=5.3 Hz, 1H), 3.51 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.88 (m, 1H), 1.56-1.67 (m, 2H), 1.10-1.35 (m, 4H); LCMS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([O:21]COC)[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10]([CH2:25][Cl:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([OH:21])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH:10]([CH2:25][Cl:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1c2c(cc3ccccc13)N(C(=O)OC(C)(C)C)CC2CCl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc1ccccc1c2O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A solution of 28 (18 mg, 47.5 μmol) in 1.5 mL of 1:1 i-PrOH/THF was treated with 12 N HCI (0.20 mL, 0.38 mmol) and the mixture was stirred at 25° C. for 6 h before the volatiles were removed in vacuo. Flash chromatography (SiO2, 1.5×15 cm, 0-20% EtOAc/hexane gradient) provided 30 (14.5 mg, 90%) as a pale yellow oil: 1H NMR (CDCl3, 250 MHz) δ7.85 (d, J=8.0 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.43-7.30 (m, 2H), 5.67 (s, 1H), 4.09-3.86 (m, 4H), 3.65 (dd, J=8.0, 10.0 Hz, 1H), 1.59 (s, 9H);13C NMR (CDCl3, 6.25 MHz) δ147.9, 135.8, 132.7, 128.8, 128.0, 126.6, 123.7, 121.2, 119.5, 119.5, 104.4, 77.2, 52.6, 46.4, 34.7, 28.5; IR (film) νmax3368, 2976, 1668, 1477, 1450, 1369, 1145, 978, 746 cm−1; FABHRMS (NBA/CsI) m/z 466.0197 (C18H20CINO3+Cs+requires 466.0186). (−)-(3S)-30: [α]D25 −54 (c 0.25, CH3OH); (+)-(3R)-30: [α]D25+51 (c 0.30, CH3OH).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[OH:14][CH2:15][C:16]1([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[CH:24]2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>O1CCCC1.CN(C)C=O>[OH:14][CH2:15][C:16]1([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[CH:24]2)[CH2:21][CH2:20][C:19](=[CH:3][C:1]#[N:2])[CH2:18][CH2:17]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC=C1CCC(CO)(n2cnc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (38.6 mg, 0.218 mmol) in tetrahydrofuran (0.5 mL) stirring at about 0° C. was added sodium hydride (10.5 mg, 0.262 mmol). To this was added a solution of 4-(hydroxymethyl)-4-(1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)cyclohexanone (56 mg, 0.18 mmol) in N,N-dimethylformamide (0.45 mL). The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water, causing formation of solids. The solids were filtered to give 18 mg of pure desired product. The filtrate was diluted with EtOAc, washed with water, and concentrated to give an additional 39 mg of the crude product. LCMS calculated for C17H17N4OS (M+H)+: m/z=325.1. Found: 325.0. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 8.15 (s, 1H), 7.47 (d, J=5.6 Hz, 1H), 7.18 (d, J=5.6 Hz, 1H), 5.20 (s, 1H), 4.34 (s, 2H), 2.80 (d, J=4.0 Hz, 3H), 2.59-2.29 (m, 4H), 1.26 (d, J=15.3 Hz, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:24]=[C:23]([NH:25][C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([Cl:33])[N:27]=3)[CH:22]=[CH:21][C:11]=2[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[N:6][CH:7]=1.C([O-])(=O)C.[Na+]>C1COCC1.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:24]=[C:23]([NH:25][C:26]3[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([Cl:33])[N:27]=3)[CH:22]=[CH:21][C:11]=2[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2nc(Cl)ncc2Cl)cc1/C=C/c1cncc(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2nc(Cl)ncc2Cl)cc1CCc1cncc(N)c1
Temperature: 90 °C
Yield: 61.9 %

Procedure:
To a solution of tert-butyl {2-[(E)-2-(5-aminopyridin-3-yl)vinyl]-4-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}carbamate (90.0 mg, 0.185 mmol) in THF (4 mL) was added p-toluenesulfonylhydrazide (0.515 g, 2.76 mmol). The reaction solution was heated to reflux at 90° C., then a solution of sodium acetate (0.363 g, 4.42 mmol) in water (3.7 mL, 20 mmol) was added dropwise over 4 h period. Another portion of p-toluenesulfonylhydrazide (0.343 g, 1.84 mmol) was added to reaction flask, then a solution of sodium acetate (0.242 g, 2.95 mmol) in water was added dropwise overnight under reflux. The reaction solution was diluted with ethyl acetate. Aqueous layer was extracted with ethyl acetate twice. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to yield the desired product (56 mg, 62%). LCMS for C24H29Cl2N6O2 (M+H)+: m/z=503.3, 505.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:32](=[CH:33][CH:34]=1)[C:16]1=[C:17](C3CCCCN3C(=O)C)[C:18](=[O:22])[NH:19][CH2:20][CH2:21][CH:15]1[CH2:14][CH2:13]2.O.[OH-].[Na+].[CH:38]1C=CC=CC=1>O1CCCC1>[N:3]1([CH2:6][CH2:7][C:17]2[C:18](=[O:22])[NH:19][CH2:20][CH2:21][CH:15]3[CH2:14][CH2:13][C:12]4[C:32](=[CH:33][CH:34]=[C:10]([O:9][CH3:8])[CH:11]=4)[C:16]=23)[CH2:4][CH2:5][CH2:38][CH2:2][CH2:1]1
Reactant: c1ccccc1
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(C3CCCCN3C(C)=O)=C21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CCN3CCCCC3)=C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.7 ml of 1.1 M alane-triethylamine in benzene are added dropwise to the suspension of 7.7 g of [9-methoxy-2-oxo-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-1yl]-acetyl-piperidine in 85 ml of anhydrous tetrahydrofuran at 0°. The mixture is stirred for 3 hours at 0° and at room temperature for one hour. It is cooled, 20 ml of water are added dropwise, followed by 20 ml of 3 N aqueous sodium hydroxide. The resulting mixture is extracted with 400 ml of diethyl ether, the extract dried, evaporated, the residue crystallized from petroleum ether and recrystallized from ethyl acetate-hexane to give the 1-(2-piperidinoethyl)-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 125°-128°. Its hydrochloride melts (after drying at 100°/0.01 mmHg) at 223°-225°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[O:16][CH:17]([CH3:19])[CH3:18])([O-:3])=[O:2].[CH3:20][I:21]>C(#N)C>[I-:21].[CH3:20][N+:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([O:16][CH:17]([CH3:19])[CH3:18])[CH:6]=2)=[CH:15][CH:14]=1
Reactant: CI
Reactant: CC(C)Oc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Solvent: CC#N
Product: CC(C)Oc1cc(-c2cc[n+](C)cc2)ccc1[N+](=O)[O-]
Product: [I-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of 7.35 g of 4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridine and 16.1 g of methyl iodide in 150 ml of acetonitrile is heated at 50° C. (bath) for 1 h. 2.5 ml of methyl iodide are added and the heating is continued for 1 h 50. The mixture is then concentrated under vacuum, so as to obtain 11.1 g of 1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].N1C=CC=CC=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21](Cl)=[O:22]>C(Cl)Cl>[OH:3][CH2:2][CH2:1][O:4][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)=[O:22]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: OCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCO)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
15.6 g (252 mmol) of ethylene glycol (manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD.) was dissolved in 100 mL of dehydrated methylene chloride (manufactured by Kanto Chemical Co., Inc.) and 3.49 g (44.0 mmol) of pyridine was added to the solution followed by cooling down with ice water. To this solution, a solution in which 8.00 g (42.0 mmol) of 2-naphthalene carbonyl chloride (manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD.) was dissolved in 80 mL of methylene chloride was dripped in one hour while being stirred. Subsequent to two hour stirring, the resultant was stirred for six hours at room temperature. The reaction solution was rinsed with water and thereafter the organic phase was isolated followed by drying with magnesium sulfate (manufactured by Kanto Chemical Co., Inc.) and the solvent was distilled away. The remainder was refined by silica gel column chromatography with a solvent mixture of a methylene chloride (manufactured by JUNSEI CHEMICAL CO., LTD.) and methanol (manufactured by Kanto Chemical Co., Inc.) with a volume ratio of 97:3 serving as an eluent to obtain 6.88 g of 2-naphthoic acid 2-hydroxyethyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]12[O:15][CH:11]([CH2:12][NH:13][CH2:14]1)[CH2:10][N:9]([CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:8]2.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(O)(=O)C.C(O)=O>C(#N)C>[C:21]([O:20][C:19](=[O:25])[NH:18][CH2:17][CH2:16][N:9]1[CH2:10][CH:11]2[O:15][CH:7]([CH2:14][N:13]([CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[CH2:12]2)[CH2:8]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O=CO
Product: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Temperature: 25 °C
Yield: 99 %

Procedure:
Potassium carbonate (3.82 g, 27.6 mmol) was added to a mixture of tert-butyl [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamate (5.00 g, 18.4 mmol) and 4-(bromomethyl)benzonitrile (3.61 g, 18.4 mmol) in acetonitrile (150 mL). The mixture was heated to reflux over night, cooled to room temperature, filtered and evaporated. The residue was dissolved in dichloromethane (100 mL), washed with water and dried over MgSO4. Purification by preparative HPLC gave 7.04 g (78%) of the sub.title compound as a salt with one equivalent of acetic acid and one equivalent of formic acid.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: CC(C)(C)N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-3-nitrobenzoic acid (500 mg, 2.03 mmol) in DMF (3 mL) was added tert-butylamine (0.22 mL, 2.04 mmol), 1,1′-dimethyltriethylamine (0.71 mL, 4.1 mmol) and (1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (1.27 g, 2.44 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 0 to 100% gradient of EtOAC:DCM (1:1) in DCM as eluent to give 2-bromo-N-tert-butyl-3-nitrobenzamide: 1H NMR (400 MHz, CDCl3) δ 7.74 (1H, dd, J=8.0, 4.0 Hz), 7.62 (1H, d, J=8.0 Hz), 7.51 (1H, t, J=8.0 Hz), 5.62 (1H, br), 1.52 (9H, s); LC-MS (ESI) m/z 301.0 [M+H]+.
Reaction SMILES: Cl.C([O:6][C:7](=[O:19])[C@H:8]([CH2:17][NH2:18])[NH:9]C(OC(C)(C)C)=O)(C)(C)C.[NH2:20][C:21]1[C:22]([OH:32])=[C:23]([S:28]([OH:31])(=[O:30])=[O:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[NH2:9][C@@H:8]([CH2:17][NH:18][C:34](=[O:36])[NH:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([S:28]([OH:31])(=[O:30])=[O:29])[C:22]=1[OH:32])[C:7]([OH:6])=[O:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)OC(C)(C)C
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N[C@@H](CNC(=O)Nc1cc(Cl)cc(S(=O)(=O)O)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
297 mg (1 mmol) of 3-amino-N-(tert-butoxycarbonyl)-L-alanine tert-butylester hydrochloride, 223 mg (1 mmol) of 3-amino-5-chloro-2-hydroxybenzenesulfonic acid and 100 mg (0.33 mmol) of triphosgene were suspended in methylene chloride (3 ml), added with 0.8 ml of pyridine, and stirred at room temperature overnight. The solvent was distilled away, and the resultant residue was purified by employing purification step A to obtain the title compound in protected form. To the resulting protected form, 3 ml of trifluoroacetic acid was added, and the resultant was stirred for 5 hours. Subsequently, the solvent was distilled away and the obtained residue was purified using purification step A to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][CH:9]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[O:11])=[CH:44][CH:45]=1
Reactant: COC(=O)/C=C/c1ccc(C(=O)OCCCCCCOC(=O)C(Cc2ccc([N+](=O)[O-])cc2)Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Zn]
Product: COC(=O)/C=C/c1ccc(C(=O)OCCCCCCOC(=O)C(Cc2ccc(N)cc2)Cc2ccc(N)cc2)cc1
Yield: 75.3 %

Procedure:
Preparation can be carried out analogously to Example 1 using 2.84 g (4.59 mmol) 6-({4-[(1E)-3-methoxy-3-oxoprop-1-enyl]benzoyl}oxy)hexyl 2-(4-nitrobenzyl)-3-(4-nitrophenyl)propanoate, 7.44 g (27.52 mmol) Ferric chloride hexahydrate and 3.00 g (45.89 mmol) Zinc powder yielded 1.93 g (72%) 6-({4-[(1E)-3-methoxy-3-oxoprop-1-enyl]benzoyl}oxy)hexyl 2-(4-aminobenzyl)-3-(4-aminophenyl)propanoate as yellow powder.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].Cl.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1)#[N:8]>C(O)(=O)C>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH:16][C:1](=[O:4])[CH3:2])=[CH:11][CH:10]=1)#[N:8]
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)NNc1ccc(C#N)cc1
Temperature: 80 °C
Yield: 92.9 %

Procedure:
2.7 g of sodium acetate are added to a solution of 5 g of 4-cyanophenylhydrazine hydrochloride in 40 ml of acetic acid and the mixture is then heated at 80° C. for 20 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water, the product is extracted with EtOAc, the organic phase is washed with a saturated NaCl solution and dried over MgSO4, and the solvent is evaporated off under vacuum. The residue is triturated in a PE/EtOAc (90/10; v/v) mixture and the precipitate formed is filter-dried. 4.8 g of the expected compound are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:21][N:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27]Cl)=[O:23])[CH2:19][C:17]=2[N:18]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C)C=O.ClCCl>[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[NH:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:21][N:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)=[O:23])[CH2:19][C:17]=2[N:18]=1
Reactant: c1c[nH]cn1
Reactant: O=C(OCCCCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OCCCn1ccnc1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Reaction time: 16 h
Yield: 30 %

Procedure:
Add sodium hydride (0.068 g; 2.25 equiv; 1.70 mmoles) to a solution of: 3-chloropropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (0.283 g; 1.0 equiv; 0.76 mmoles), and 1H-imidazole (0.105 g; 2.0 equiv; 1.54 mmoles) in dimethylformamide (2.4 mL). Stir the reaction mixture for 16 hours, then dilute with dichloromethane and wash with water. Extract the aqueous layer with dichloromethane twice. Concentrate the combined organic extracts and then purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford of 3-(1H-imidazol-1-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (0.0922 g; 30%) as a yellow solid: MS (m/z): 405(M+1).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C@H:4]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:8][O:7][C@@H:6]([CH3:20])[O:5]1.[H-].[Na+].[C:23]1([CH:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[C:23]1([CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:1]/[N:2]=[CH:3]/[C@H:4]2[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:8][O:7][C@@H:6]([CH3:20])[O:5]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1/C=N/O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1/C=N/OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R,5S)-(E)-4-hydroxyiminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (100 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (14 mg 60% in oil) at 5° C. After being stirred at the same temperature for 30 minutes, to the solution was added diphenylmethyl bromide (86.6 mg) and the mixture was stirred in an ice bath for additional 2 hours. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo and the crude residue was purified with preparative TLC with a mixture of n-hexane and ethyl acetate (4:1) as an eluent to give (2R,4R,5S)-(E)-4-diphenylmethoxyiminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl.CN1C(=O)N(C)CCC1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][O:15][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1
Reactant: COCCOCOc1cccc(CO)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCOc1cccc(COCc2ccccn2)c1
Reaction time: 0.17 h

Procedure:
To a cooled solution (0° C.) of [3-(2-methoxy-ethoxymethoxy)-phenyl]-methanol (212 mg, 1 mmol, example 72) in THF (3 mL) is added 60% NaH (80 mg, 2 mmol) and the mixture stirred 10 min. Added 2-picolyl chloride hydrochloride (164 mg, 1 mmol) and DMPU (0.8 mL), removed cold bath and let reaction mixture stir for 2 hrs. Quenched reaction with sat NH4Cl soln. and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 70% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. MS (ESI) 304 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C>[Fe].CO>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc(Cl)c(CC(=O)OC)n1Cc1ccc(N)cc1
Yield: 98.5 %

Procedure:
A mixture of methyl 2-butyl-4-chloro-1-(4-nitrobenzyl)imidazole-5-acetate (5.00 g, 13.7 mmol, 1 eq), iron (2.67 g, 47.8 mmol, 3.5 eq), glacial acetic acid (5.47 mL, 95.3 mmol, 7 eq), and methanol (250 mL) was refluxed for 5.5 hours. The solvent was removed by rotary evaporation. The residue was diluted with water (300 mL) and extracted five times with 300 mL portions of ethyl acetate. The organic layers were dried and concentrated. The residue was flash chromatographed in 75:25 hexane/ethyl acetate over silica gel to give 4.53 g of a golden yellow oil which crystallized after standing for several days. NMR (200 MHz, CDCl3) δ 6.72 (d, 2H, J=7 Hz); 6.60 (d, 2H, J=7 Hz); 4.99 (s, 2H); 3.61 (s, 3H); 3.47 (s, 2H); 2.60 (t, 2H, J=7 Hz); 1.68 (m, 2H); 1.35 (m, 2H); 0.86 (t, 3H, J=7 Hz). Mass spectrum shows M+=335/337. Mass Calcd. for C17H22N3O2Cl: 335.1400. Found: 335.1407.