Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:31]([O:30][C:26]1[C:25]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][C:27]=1[CH:14]=[O:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc(COc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Kolonits, P. et al., Acta Chim. Hung. 113:367 (1983). POCl3 (155 mL, 1.66 mol) was slowly added to N-methylformanilide (175 mL, 1.4 mol) at room temperature under Ar which resulted in formation of a yellow solid. After 2 h, the solid was treated with a solution of 1,2,3-tribenzyloxybenzene 8 (20 g, 51 mmol) in anhydrous DMF (40 mL) and heated to 60° C. After 3 h, the resulting crimson solution was cooled to room temperature and then poured into ice water (3 L) with vigorous stirring for 12 h. The resulting brown precipitate was filtered, washed with hexanes (3×100 mL) and finally recrystallized from MeOH to afford 10 (19.8 g, 93%) as a white powder. mp 73-74° C. 1H NMR (CDCl3): δ10.11 (s, 1 H), 7.57 (d, J=9 Hz, 1 H), 7.44-7.28 (m, 15 H), 6.83 (d, J=9 Hz, 1 H), 5.21(s, 2 H), 5.16 (s, 2 H), 5.08 (s, 2 H); 13C NMR (CDCl3): δ188.8, 158.5, 155.9, 141.1, 136.9, 136.2, 135.8, 128.6, 128.5 (2), 128.3 (2) 128.2, 127.5, 124.0, 109.1, 76.8, 75.5, 70.9. Anal. Calcd for C28H24O4: C, 79.22; H, 5.70. Found: C, 79.17; H, 5.80. HRMS (FAB) calcd for C28H24O4 (M+H+): 424.1675. Found: 424.1669.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C1(C)[C:12]([NH2:19])=[C:13]([CH3:18])[C:14](N)=[CH:15][CH:16]=1.C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:27]([CH2:26][NH:23][C:24]3[CH:25]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH:18]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(N)c(C)c1N
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NCc2cccc(CNc3ccc([N+](=O)[O-])cc3)c2)cc1
Temperature: 60 °C

Procedure:
1.73 g of para-fluoronitrobenzene (2 eq.) were dissolved in 5 ml of DMSO. 1.2 equivalents of m-xylenediamine and 4 equivalents of triethylamine were added to the solution. The reaction mixture was heated at 60° C. for 20 hours. The mixture was then poured onto crushed ice and a precipitate formed. The latter was filtered, washed with water, and then dried.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C1COCC1>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in THF (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in THF was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15]OC1C(C)=CC(C)=CC=1C.[C-:26]#[N:27].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][C:26]#[N:27]
Reactant: COc1ccccc1C1CCCCC1COc1c(C)cc(C)cc1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1C1CCCCC1CC#N
Temperature: 100 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
Combine 2-[2-(2-methoxy-phenyl)-cyclohexylmethoxy]-1,3,5-trimethyl-benzene (0.810 g, 2.71 mmol), sodium cyanide (2.13 g, 43.4 mmol), and d6-DMSO (10.0 mL) at rm temperature. Heat and stir at 100° C. under nitrogen for 18 hours. Cool to room temperature and add ethyl acetate then add water and wash 5× with brine. Separate layers and dry over anhydrous sodium sulfate. Concentrate and flash chromatography using 0 to 30% ethyl acetate/hexanes to yield the titled compound (0.346 g, 56%). TLC Rf=0.43 in 20% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.2 (m, 1H), 7.0 (m, 1H), 6.9 (m, 2H), 3.8 (s, 3H), 3.3 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 2.1 (m, 1H), 1.8 (m, 6H), 1.4 (m, 2H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:1](=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: C(=Nc1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
Benzaldehyde (0.20 mole) was treated with aniline (0.20 mole) with vigorous stirring in a 1 liter Erlenmeyer Flask. After 15 mins. 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 5 minutes. The reaction mixture was left standing at room temperature for 10 min.; then it was placed in an ice-bath for 0.5 hours. The crystals which formed were collected, washed with 95% ethanol, and air-dried. Recrystallization from 85% ethanol gave N-benzylideneaniline. m.p. 50°-51.5° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33].ClC(OCC)=[O:38]>>[CH3:30][N:31]([CH3:35])[C:32]([N:25]1[CH2:26][CH2:27][CH:22]([NH:21][S:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([C:8](=[O:9])[NH:7][CH:1]3[CH2:6][CH2:5][O:38][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)(=[O:28])=[O:29])[CH2:23][CH2:24]1)=[O:33]
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCOC(=O)Cl
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)NC3CCOCC3)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid (tetrahydro-pyran-4-yl)-amide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and dimethylcarbamyl chloride for ethyl chloroformate. Wt.: 125 mg (78%). 1H NMR (300 MHz, CDCl3) δ 8.8.59 (m, 1H), 8.29 (m, 1H), 8.23 (d, 1H), 7.69 (m, 2H), 7.58 (d, 1H), 6.17 (d, 1H), 4.82 (d, 1H), 4.32 (m, 1H), 4.03 (m, 2H), 3.57 (m, 2H), 3.40 (m, 2H), 3.25 (m, 1H), 2.73 (s, 6H), 2.64 (m, 2H), 2.10 (m, 2H), 1.61 (m, 4H), 1.27 (m, 2H); LC/MS m/z 489 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][CH:47]1[CH2:50][CH2:49][O:48]1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[N:13]([CH2:46][CH:47]2[CH2:50][CH2:49][O:48]2)[C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2
Reactant: BrCC1CCO1
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(CC3CCO3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 150 mg (1.08 mmol) of 2-(bromomethyl)oxetane were added and the mixture was stirred at RT for 18 h, at 40° C. for 18 h and at 100° C. for 4 h. After cooling, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. 581 mg (53% of theory, purity 63%) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([OH:22])=O)=[CH:16][C:11]2=[N:10][N:9]=1.S(Cl)(Cl)=O.[CH3:31][N:32]1[C:36]([NH2:37])=[CH:35][CH:34]=[N:33]1.C(N(CC)CC)C>C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([NH:37][C:36]3[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=3)=[O:22])=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Reactant: Cn1nccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Temperature: 95 °C

Procedure:
A mixture of 3-(3-(2-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzoic acid (2.44 g, 6.7 mmol) and thionyl chloride (30 ml, 411 mmol, Aldrich) was heated to 95° C. for 2 h. The volatiles were removed in vacuo. The solids were re-dissolved in CH2Cl2 (30 ml). A 10 ml aliquot of this solution (860 mg, 2.2 mmol) was treated with 1-methyl-1H-pyrazol-5-amine (656 mg, 6.7 mmol, Maybridge), followed by triethylamine (939 μl, 6.7 mmol, Aldrich). The mixture was diluted with 10% Na2CO3 and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated over silica gel. The residue was purified using column chromatography (Acetone/Hexanes=0-50%). The mixture was dissolved in MeOH and loaded onto an Agilent AccuBOND II SCX solid phase extraction column. After washing with MeOH, the title compound was eluted with 2M NH3 in MeOH. The residue was recrystallized from MeOH yielding the title compound as a white solid. HRMS (TOF) Calcd for C24H20ClN6O+: 443.1382, found: 443.1389.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][C:6]=1[O:5]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CS(C)=O>[OH:17][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][C:2]([O:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[CH:15][CH:14]=3)[O:5][C:6]=2[CH:7]=[C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: O=c1c2ccc(F)cc2oc2cc(N3CCOCC3)cc(O)c12
Reactant: OCc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2ccc(OCc3ccccn3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 80 °C

Procedure:
6-Fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one (15 mg, 0.05 mmol) and 2-pyridylmethanol (8 mg, 0.07 mmol) were dissolved in DMSO (0.25 mL) and KHMDS (0.5 M in toluene, 0.24 mL) was added. The reaction mixture was heated to 80° C. for 16 hours. The reaction was quenched with sat. NH4Cl/water (1:1, 2 mL) and the solids were filtered. The crude solid was purified via flash chromatography eluting with CH2Cl2/MeOH (98:2) to produce 4.9 mg (25%). 1H NMR (CDCl3, 400 MHz) δ: 12.80 (s, 1H), 8.63 (d, 1H), 8.13 (d, 1H), 7.76 (dd, 1H), 7.52 (d, 1H), 7.27-7.24 (m, 1H), 7.02 (d, 1H), 6.88 (s, 1H), 6.27 (s, 1H), 6.23 (s, 1H), 5.31 (s, 2H), 3.86-3.83 (m, 4H), 3.37-3.35 (m, 4H). LRMS (APCI, positive): Da/e 405.1 (m+1).
Reaction SMILES: Cl.[OH:2][C@H:3]([C:11]1[C:12]([CH3:21])=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][CH2:14]2)[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1>>[OH:2][C@H:3]([C:11]1[C:12]([CH3:21])=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[O:15][CH2:14]2)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[CH2:7][CH2:6]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCN(c3ccc(C#N)cn3)CC2)ccc2c1COC2=O

Procedure:
(R)-6-(4-(2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 10 starting from (R)-5-(1-hydroxy-2-(piperazin-1-yl)ethyl)-4-methylisobenzofuran-1 (3H)-one hydrochloride (INTERMEDIATE 12) and 6-chloropyridine-3-carbonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17](=[O:24])[CH2:18][C:19](OCC)=[O:20])[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:31]O.Cl>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([C@H:11]2[CH2:16][C@@H:15]([C:17]3[O:24][NH:31][C:19](=[O:20])[CH:18]=3)[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 23.9 %

Procedure:
Methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3.14 g, 8.06 mmol) was dissolved in MeOH (50 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.322 g, 8.06 mmol) dissolved in water (5.00 mL) was added during 5 min and the colourless mixture continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.494 mL, 8.06 mmol) was added during 8 min. The resulting solution was stirred at −55° C. for 6 h 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (60 mL, 360.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown oil. The crude was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 40-85% Acetonitrile in H2O/MeCN/HOAc 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (690 mg, 24%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.29 (s, 9H), 1.81-1.88 (m, 1H), 2.14-2.21 (m, 1H), 2.22-2.31 (m, 1H), 2.35-2.42 (m, 1H), 3.03-3.10 (m, 1H), 3.37-3.44 (m, 1H), 3.66 (s, 3H), 4.16-4.22 (m, 1H), 5.12-5.16 (m, 1H), 5.48 (s, 1H), 6.97-7.01 (m, 1H), 7.17 (s, 1H), 7.21-7.25 (m, 2H). MS m/z 359 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:14][O:15][C:16](=[O:28])[C@@H:17]([OH:27])[C@@H:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:28])[C@@H:17]([OH:27])[C@@H:18]([NH:26][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: COC(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 170 mg, 0.86 mmol) and (3S,2S)-3-amino-2-hydroxy-4-phenylbutyric acid methyl ester (Preparation 21A, 174 mg, 0.83 mmol) were coupled under similar conditions to EXAMPLE 43 using HOBt (142 mg, 0.93 mmol), EDCI (200 mg, 1.04 mmol), DIPEA (0.32 ml, 1.87 mmol) in DMF (10 ml). The crude product was purified by chromatography on silica gel eluting with hexane/ethyl acetate (25:75) to give the title compound as a colourless oil. δH (CDCl3): 3.04 (4H, 2dd), 3.74 (3H, s), 4.36 (1H, br s), 4.63 (1H, m), 4.98 (1H, ddd), 6.66 (1H, s), 6.96 (1H, d), 7.18–7.35 (5H, m), 7.48 (1H, s), 8.63 (1H, s).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:11].O>CO>[OH:3][N:2]=[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[NH2:11]
Reactant: N#Cc1cccnc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=NO)c1cccnc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
Hydroxylamine hydrochloride (1.3 g) and sodium carbonate (2.0 g) were added to a mixed solution of 3-cyanopyridine in methanol (10 ml)/water (10 ml) and the mixture was stirred at 100° C. for 2.5 hours. After distilling off the solvent under reduced pressure, water was added to the residue and extracted with tetrahydrofuran, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain N′-hydroxypyridine-3-carboximidamide (1.3 g) as a colorless oily substance.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH-].[Li+].C(O)(C(F)(F)F)=O>O.C(#N)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC(CC(=O)OCC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NN=Cc1ccc(NC(=O)CCC(=O)NC(CCC(=O)O)CC(=O)O)cc1
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Diethyl 3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]hexanedioate (700 mg) prepared in Example 19, Step 2 was added to water/acetonitrile (20 ml) followed by lithium hydroxide (150 mg) at 25° C. The mixture was stirred for 30 min. The course of the reaction was monitored by RPHPLC. After satisfactory product was formed the reaction was neutralized with TFA and purified by reverse phase chromatography (0.05% TFA water/acetonitrile) to result in 350 mg of a white solid: H NMR (d6 -DMSO) δ1.55 (m, 1H), 1.7 (m, 1H), 2.3 (m, 2H), 2.57 (m, 2H), 2.67 (m, 2H), 4.03 (m, 1H), 7.79 (s, 4H), 7.99 (d, 1H, J=8 Hz), 8.86 (bs, 2H), 9.17 (bs, 2H), 10.2 (s, 1H); MS (FAB) m/z 379.2 (MH+).
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[C:20]([CH:22]=1)[NH2:21].N1C=CC=CC=1>ClCCl>[I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:21][C:20]2[CH:22]=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=2[O:23][CH3:24])(=[O:13])=[O:12])[CH:3]=1
Reactant: COc1ccc(C)cc1N
Reactant: O=S(=O)(Cl)c1cc(I)c2occc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C)cc1NS(=O)(=O)c1cc(I)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-iodo-1-benzofuran-5-sulfonyl chloride (10.75 g, 31 mmol; Intermediate 56) in dichloromethane (200 mL) was added 5-methyl-2-methoxyaniline (4.25 g, 31 mmol) and pyridine (7.4 mL, 93 mmol) and allowed to stir at ambient temperature overnight. The dark red solution was washed with water, separated, dried and filtered through a plug of silica to remove most of the red impurity, and finally concentrated. Yield: 13.51 g (99%) red solid. HPLC 90% RT=2.58 min (System A; 30-80% MeCN over 3 min), 1.75 min (System C; 2-95% MeCN over 2 min). 1H NMR (400 MHz, CDCl3) δ ppm 2.23 (m, 3H) 3.52 (s, 3H) 6.54 (d, J=8.30 Hz, 1H) 6.79 (dd, J=8.42, 1.59 Hz, 1H) 6.86 (d, J=2.20 Hz, 1H) 6.96 (s, 1H) 7.31 (d, J=1.71 Hz, 1H) 7.71 (d, J=2.20 Hz, 1H) 7.95 (d, J=1.71 Hz, 1H) 8.04 (d, J=1.71 Hz, 1H). MS (ESI) for C16H14INO4S m/z 444 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].P([O-])([O-])([O-])=O.C(OCC)C>C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
350 g of 1,4-dioxa-spiro[4.5]decan-8-one were suspended in 2000 ml of ethanol, and 28.1 g of sodium borohydride were added in portions while cooling with an ice bath. After stirring overnight at room temperature, first 750 ml of phosphate buffer (pH 7, Merck-Darmstadt) and then 1000 ml of diethyl ether were added, with stirring, and precipitated solids were filtered and then washed with diethyl ether. The filtrate was dried over sodium sulfate, filtered and concentrated. 345 g of 1,4-dioxa-spiro[4.5]decan-8-ol were obtained in the form of a white solid.
Reaction SMILES: CC(N=C=O)(C1C=CC=C(C([N:13]=C=O)(C)C)C=1)C.COC1C=CC(O)=CC=1.[C:28]([O:33][CH2:34][CH:35](O)C)(=[O:32])[C:29]([CH3:31])=[CH2:30].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2])CCC>>[C:28]([OH:33])(=[O:32])[C:29]([CH3:31])=[CH2:30].[C:28]([OH:33])(=[O:32])[C:29]([CH3:31])=[CH2:30].[NH2:13][C:28]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CC(C)(N=C=O)c1cccc(C(C)(C)N=C=O)c1
Reactant: C=C(C)C(=O)OCC(C)O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]
Agent: COc1ccc(O)cc1
Product: C=C(C)C(=O)O
Product: CCOC(N)=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
244 Parts of m-tetramethylxylene diisocyanate and 0.3 part of hydroquinone monomethyl ether were charged in a three necked flask and thereto was added dropwise a mixture of 302 parts of 2-hydroxypropyl methacrylate and 0.3 part of n-butyl tin dilaurate over a period of 3 hours with stirring at 60° C. After completion of the addition, reaction was allowed to proceed for 8 hours at 70° C. to obtain urethane dimethacrylate UDM1.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:26]([CH3:34])([CH3:33])[O:27][SiH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:20].Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[C:29]([SiH2:28][O:27][C:26]([CH3:34])([CH3:33])[CH:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19]([C:10]1[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=1[N:8]=[C:36]=[O:38])=[O:20])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Reaction time: 2 h

Procedure:
A solution of triethylamine (1.35 eq.) in anhydrous toluene was added to the amine (5)(1 eq.) and triphosgene (0.36 eq.) in anhydrous toluene under a N2 atmosphere. The reaction was finished after 2 hours. (monitored by IR, ξNCO 2265 cm1). The product was used without further purification.