Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:17])([F:16])[C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:13]2[CH:14]=[CH:15][C:11]([C:10]([F:17])([F:16])[F:9])=[N:12]2)[N:7]=1.[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([N:13]2[CH:14]=[CH:15][C:11]([C:10]([F:17])([F:16])[F:9])=[N:12]2)[N:7]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccn(-c2ccnc(Cl)n2)n1
Product: FC(F)(F)c1ccn(-c2nccc(Cl)n2)n1

Procedure:
A mixture of 2,4-dichloropyrimidine (3.0.g, 20 mmol), 3-(trifluoromethyl)-1H-pyrazole (2.5 g, 18 mmol) and potassium carbonate (5.0 g, 36 mmol) was stirred in 25 mL of N,N-dimethylformamide at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed twice with brine, dried over magnesium sulfate, and evaporated under reduced pressure to a crude solid. Flash chromatography on silica gel (50:1 to 25:1 to 110:1 to 3:1 hexane/ethyl acetate) afforded 0.5 g of the title compound of Step A as a solid melting at 123-125° C. and 2.3 g of the isomer 2-chloro-6-[3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidine as a solid melting at 111-112° C. 1H NMR (CDCl3): δ 6.77 (d, 1H), 7.35 (d, 1H), 8.65 (d, 1H), 8.70 (d, 1H).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[O:11][C@H:10]1[S:35]C(=N)N)(=[O:7])[CH3:6].S(S([O-])=O)([O-])(=O)=O.[K+].[K+]>O>[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[O:11][C@H:10]1[SH:35])(=[O:7])[CH3:6]
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SC(=N)N)[C@@H]1OC(C)=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](S)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Yield: 80.4 %

Procedure:
Chloroform (9.0 ml.) is added to a solution of 2-S-(2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-β-D-galactopyranosyl)-2-thiopseudourea (3.4 g.) in water (10 ml.) containing potassium metabisulfite (1.38 g.). The mixture is heated with stirring under reflux for 15 minutes. The cooled solution is separated, and the organic layer is dried and evaporated in vacuo to give the title compound (2.5 g.). This material is used directly for the preparation of 6-(5-cholesten-3β-yloxy)hexyl 2,3,4-tri-O-acetyl-6-deoxy-6-ththalimido-1-thio-β-D-galactopyranoside
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:30]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([Br:30])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: COCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(OCOC)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-(4-methoxybenzoyl)-phenylacetate (490 mg, 1.2 mmol) obtained in Example 134, Step 2 was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (220 mg, 1.2 mmol) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/1) to obtain methyl 3,5-bis(methoxymethoxy)-2-bromo-6-(4-methoxybenzoyl)phenylacetate (520 mg, 89%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C(O)C.N1CCCC1>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:6]#[N:7])=[CH:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([F:9])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1cccc(F)c1
Solvent: CCO
Solvent: C1CCNC1
Product: CCOC(=O)C(C#N)=Cc1cccc(F)c1
Yield: 98.5 %

Procedure:
A solution of cyanoacetic acid ethyl ester (1.1 g), 3-fluorobenzaldehyde (1.5 g) and pyrolidine (0.043 g) in ethanol (10 mL) was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, and this obtained solid was washed with ethanol (40 mL) to give the title compound (2.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])=[C:4]([F:13])[CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:50][OH:51].CN([CH:55]=[O:56])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:13][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])([CH3:12])[CH3:10])[C:50]([O:56][CH3:55])=[O:51]
Reactant: CC(C)(O)Cc1ccc(Br)cc1F
Reactant: CO
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CC(C)(C)O)c(F)c1
Temperature: 80 °C
Yield: 85 %

Procedure:
A reaction vessel charged with 1-(4-bromo-2-fluoro-phenyl)-2-methyl-propan-2-ol (2.35 g, 9.51 mmol), palladium acetate (214 mg, 0.95 mmol), 3-diphenylphosphanylpropyl-diphenyl-phosphane (404 mg, 0.95 mmol) and triethylamine (4.24 mL, 30.4 mmol) in DMF (26 mL) was added MeOH (20 mL). The reaction vessel was charged to 50 psi with CO gas and heated at 80° C. for 15 hours. The reaction mixture was allowed to cool, partitioned between EtOAc and brine solution. The layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organics were washed with brine (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo to an orange oil. The residue was purified by silica gel column chromatography using 0-30% EtOAc-hexanes as eluent to yield methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.83 g, 85%). ESI-MS m/z calc. 226.1. found 227.5 (M+1)+; Retention time: 1.29 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J=7.9, 1.7 Hz, 1H), 7.71 (dd, J=10.3, 1.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 3.92 (s, 3H), 2.88 (d, J=1.3 Hz, 2H), 1.26 (s, 6H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1>>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:23])=[CH:17][CH:16]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Product: CC(Cc1ccc(O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 4-hydroxyphenyl-propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol=9:1 as eluant.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].[NH2:13][NH2:14].C1COCC1.C(N(CC)C(C)C)(C)C>>[Cl:12][C:5]1[N:4]=[N:3][C:2]([NH:13][NH2:14])=[C:7]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=1.[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: NN
Reactant: C[Si](C)(C)c1cc(Cl)nnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(Cl)nnc1NN
Product: C[Si](C)(C)c1cc(NN)nnc1Cl
Yield: 67 %
Yield: 13 %

Procedure:
To a solution of 3,6-dichloro-4-(trimethylsilyl)pyridazine (9.67 g, 43.7 mmol) (Turck et al., J. Heterocycl. Chem., 1990, 27, 1377: prepared using the method described by Trecourt et al., J. Heterocycl. Chem., 1995,, 32, 1057) in a 1.0 M solution of hydrazine in THF (131 ml, 131 mmol) was added N,N-diisopropylethylamine (7.5 ml, 43.8 mmol) and the mixture was stirred at reflux under nitrogen for 68 h. The mixture was allowed to cool, silica gel was added and the solvent was evaporated in vacuo. The residue was then purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give 1.24 g (13%) of 6-chloro-3-hydrazino-4-(trimethylsilyl)pyridazine and 6.34 g (67%) of the title compound as a yellow-brown solid; 1H NMR (360 MHz, CDCl3) δ0.39 (9H, s), 3.96 (2H, br s), 6.24 (1H, br s), 7.08 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@H:21]([OH:28])[CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:31].[N:32]1[CH:37]=C[CH:35]=[CH:34][CH:33]=1.ClC(OC1C=CC=CC=1)=[O:40].C1(N)CC1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:31][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@H:21]([OH:28])[CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH:29]=[CH:30][C:2]=1[NH:1][C:37]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:40]
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1C#N
Agent: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C#N
Reaction time: 1 h
Yield: 53.5 %

Procedure:
After dissolving (4-(4-amino-3-chlorophenoxy)-6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline) (96.9 mg, 0.22 mmol) in dimethylformamide (1 ml) under a nitrogen atmosphere, pyridine (0.027 ml, 0.33 mmol) and phenyl chloroformate (0.035 ml, 0.28 mmol) were added dropwise at room temperature, and the mixture was stirred for 1 hour. Cyclopropylamine (0.10 ml) was added dropwise, and the mixture was further stirred overnight. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was subjected to silica gel column chromatography (eluent—ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (61.6 mg, 0.118 mmol, 53.5%) as light yellow crystals.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@H:14](O)[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N(CC)CC)C.CS([Cl:28])(=O)=O.CO>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][O:10][C@H:11]1[CH2:15][C@@H:14]([Cl:28])[CH:13]=[CH:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CO[C@@H]1C=C[C@@H](O)C1)OCC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOP(=O)(CO[C@@H]1C=C[C@H](Cl)C1)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trans-1-diethylphosphonomethoxycyclopent-2-en-4-ol (220 mg, 0.88 mmol) was dissolved in CH2Cl2 (2 mL) and cooled to 0° C. under nitrogen. Triethylamine (192 mg, 192 mmol) was added followed by methanesulphonyl chloride (220 mg, 192 mmol) and the reaction mixture leftto stir for 0.5 hrs at 0° C. The reaction mixture was allowed to warm to room temperature and MeOH was added. The aqueous solution was diluted with CH2Cl2 (10 mL) and washed with water, saturated NaHCO3 and brine. The solution was dried (MgSO4), filtered, concentrated and then purified by flash column chromatography with 5% MeOH/95% CH2Cl2 (144 mg, 62%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:25]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:24]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)[CH2:25]4)[C:12]=3[C:14]([F:15])([F:16])[F:17])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 58 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylic acid (1.05 g, 3.5 mmol) and 4-(3-pyrrolidinyl)-pyridine, a procedure analogous to that given in Example 1 provided the title compound (0.93 g, 58%) as a beige solid, mp 244°-245° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[C:9]2[NH:8][C:7]3[C:13]4[C:18]([CH2:19][C:6]=3[C:5]=2[CH:4]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4.O1CCN(B)CC1.Cl.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[C:9]2[NH:8][C@@H:7]3[C:13]4[C:18]([CH2:19][C@@H:6]3[C:5]=2[CH:4]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4
Reactant: COc1cc(C)c2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: BN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c2c(c1)[C@H]1Cc3ccccc3[C@H]1N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.4 %

Procedure:
To a solution of 5.0 g (0.020 mol) of 5,10-dihydro-8-methoxy-6-methylindeno[1,2-b]indole in 50 ml of tetrahydrofurane was added 8.1 g (0.080 mol) of morpholino borane and dropwise 6.3 ml of conc. hydrochloric acid. The initially exothermic reaction mixture was stirred at room temperature for 72 hour. An additional 6.3 ml of conc. hydrochloric acid was then added and the mixture stirred over night. 25 ml of water was then added and the mixture evaporated. The residue was suspended in 200 ml of water and 5 ml of conc. hydrochloric acid and the mixture was heated on a water bath until most of the solid material had dissolved. The solution was then filtered hot and the filtrate cooled and alkalinized by addition of 10M sodium hydroxide solution. Filtration and washing with water gave 1.93 g (38.4%) of the title compound 1H NMR (CDCl3) δ: 2.08 (3H,s), 3.15-3.25 (1H,dd), 3,42-3.55 (1H,dd), 3.7 (3H,s), 4.1-4.22 (1H,t), 5.22-5.28 (1H,d), 6.42-6.46 (1H,d), 6.6-6.65 (1H,d), 7.14-7,25 (3H,m), 7.3-7.4 (1H,m).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C1C(O)=CC=C(C)C=1.CS(O[CH:30]([C:44]#[N:45])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)(=O)=O>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH:30]([C:44]#[N:45])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:32]=3)=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: Cc1ccc(OC2C(C(=O)O)C2(C)C)cc1
Agent: Cc1ccc(O)cc1
Product: Cc1ccc(OC2C(C(=O)OC(C#N)c3cccc(Oc4ccccc4)c3)C2(C)C)cc1

Procedure:
Following the procedure of Example 2, 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylic acid is prepared from 4-cresol, which is then reacted with α-cyano-m-phenoxybezyl methanesulfonate to yield α-cyano-m-phenoxybezyl 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:31])[N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([N:24]([CH2:28][CH2:29][OH:30])[CH2:25][CH2:26][OH:27])=[O:31])=[CH:17][CH:16]=1
Reactant: O=C(NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Yield: 67.4 %

Procedure:
To a degassed solution of [4-(4-{[N,N-bis-(2-hydroxyethyl)carbamoyl]methoxy}phenyl)-butyl]carbamic acid benzyl ester 25 (0.19 g, 0.43 mmol) in ethanol (4 mL) was added 10% palladium on activated carbon (0.1 g, 50% wet). The mixture was hydrogenated overnight at atmospheric hydrogen. The catalyst was filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 20-5:1:0.1-1 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 26 (0.09 g, 72%) as a colorless oil. 1H NMR (300. MHz, CD3OD) δ 1.56 (m, 4H), 2.56 (t, 2H), 2.65 (t, 1H), 3.29 (m, 1H), 3.55 (m, 4H), 3.72 (m, 4H), 4.90 (s, 2H), 6.86 (d, 2H), 7.09 (d, 2H). m/z (ESI): 311 [C16H26N2O4+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([OH:14])(C#C)[CH3:11].[N+]([C:18]1C=C(C=C[CH:25]=1)C=O)([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:9][CH:10]([CH3:11])[OH:14].[NH2:5][C:4]1[CH:3]=[C:2]([C:18]#[CH:25])[CH:8]=[CH:7][CH:6]=1
Reactant: C#CC(C)(C)O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(N)c1
Product: CC(C)O
Temperature: 80 °C

Procedure:
A mixture of 3-bromoaniline (1.72 g, 10 mmol), 2-methyl-3-butyn-2-ol (1.1 g, 13 mmol), 3-nitrobenzaldehyde (0.5 g, 3.3 mmol), triethylamine (5 g), dichlorobis(triphenylphosphine)palladium (15 mg) and triphenylphosphine (80 mg) was deaerated by bubbling nitrogen. The reaction mixture was heated to 80° C. and treated with CuI (10 mg). After 7 hr at reflux thin-layer chromatography showed nearly complete conversion of the 3-bromoaniline to a mixture of 3-aminophenylacetylene dimethylcarbinol and N-(3-nitrobenzylidene) aminophenyl acetylene dimethylcarbinol.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.C(OC(N[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=O)(C)(C)C.[N+:46]([C:49]1[CH:62]=[CH:61][C:52]([CH2:53][O:54][C:55]([NH:57][C:58](=[NH:60])[CH3:59])=[O:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:43]2[CH2:44][CH2:45][CH:40]([NH:60][C:58](=[N:57][C:55]([O:54][CH2:53][C:52]3[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:62][CH:61]=3)=[O:56])[CH3:59])[CH2:41][CH2:42]2)=[O:29])[CH2:10]1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Yield: 97.3 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 446 mg of (2S,4S)-4-(4-methoxy-benzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidine-carboxylic acid, 220 mg of 4-t-butoxycarbonylamino-piperidine and 119 mg of N-(4-nitrobenzyloxycarbonyl)-acetamidine, 307 mg of the title compound were obtained as a powder.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=1[C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[C:21]([C:13]1[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1OCCO[Si](C)(C)C(C)(C)C
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(N)cc1OCCO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of tert-butyl-[2-(2-tert-butyl-5-nitro-phenoxy)-ethoxy]-dimethylsilane (353 mg, 1.0 mmol) and calcium chloride (131 mg, 1.16 mmol) in ethanol (5 mL) and water (1 mL) add iron powder (660 mg, 11 mmol). Heat the solution at reflux for 2 hours, cool and filter through Celite. Concentrate under reduced pressure, re-dissolve in ethyl acetate and wash with brine (200 mL). Concentrate under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:22])[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=[O:58])C>>[Cl:1][C:2]1[C:3]([CH:8]([NH:22][C:41]([CH:46]2[CH2:42][CH2:43][CH2:44][CH2:45]2)=[O:58])[C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
In a 10 mL flask were added C-(3-chloropyrazin-2-yl)-C-(4-phenoxyphenyl)-methylamine (75 mg, 0.24 mmol), DIEA (0.38 mL, 0.0022 mol), TBTU (0.12 g, 0.00036 mol) and DMF (4 mL, 0.05 mol) and the reaction mixture is stirred at rt overnight. Reaction mixture was concentrated in vacuo and washed with sat NaHCO3, brine extracting with DCM. The organic layer was concentrated to give a dark yellow solid. Purification by prep TLC using 50% EtOAc: hexanes afforded 80 mg of the title compound as an off white solid. MS (ES+): m/z 407.86 (50)[MH+]. HPLC: tR=3.75 min (Open Lynx, polar—5 min).
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH2:64]([CH2:66][NH2:67])[OH:65].O>ClCCl>[CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44]([NH:67][CH2:66][CH2:64][OH:65])=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2]
Reactant: NCCO
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)NCCO)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)NCCO)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBt (2 mg) were added. After 20 min, ethanol amine (1 mg) was added. The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated. The reaction mixture was extracted with dichloromethane (3×5 mL). The combined organic layer was washed with water (2×5 mL). The organic layer was dried over sodium sulphate, and was concentrated. The crude product was purified by preparative HPLC [Eurospere-100, C18 column (250 mm×8 mm), mobile phase: acetonitrile-water (1:1 isocratic)] to obtain the title compound.