Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:5]=C(S([O-])(=O)=O)C=[CH:8][CH:9]=1)([O-])=O.[Na+].[N:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH:18]=[CH:17][CH:16]=1.C(=O)/C=C/C.[OH-].[Na+]>OS(O)(=O)=O.O=S(=O)=O.O>[CH3:8][C:9]1[CH:4]=[CH:5][C:21]2[C:20](=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:15]=[CH:16][CH:17]=[CH:18]3)[N:25]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Nc1cccc2ncccc12
Agent: C/C=C/C=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: Cc1ccc2ccc3ncccc3c2n1
Temperature: 105 °C
Yield: 84.5 %

Procedure:
To a mixture of sodium 3-nitrobenzenesulfonate (2.88 g, 12.8 mmol) in oleum (12 mL) and water (12 mL) was added quinolin-5-amine (3.09 g, 21.4 mmol). The mixture was stirred and heated to 105° C. Crotonaldehyde (3.00 g, 42.8 mmol) was added dropwise over 15 min. The resulting mixture was stirred at 105° C. for 16 h. The mixture was then poured into ice (50 g), and the pH value was adjusted to 11 with 1 N aqueous sodium hydroxide solution. The mixture was extracted with EtOAc (3×60 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford 2-methyl-1,7-phenanthroline as a yellow solid (2.10 g). MS (ESI) m/z 195.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[CH2:22]([O:21][C:19]([NH:7][CH2:6][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: NCCc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1cccc(Br)c1

Procedure:
A solution of m-bromophenethylamine (6.71 g, 33.55 mmol) and Et3N (7 mL, 50.32 mmoL) in CH2Cl2 (100 mL) is cooled to 0° and ethyl chloroformate (4 mL, 50.32 mmoL) is added. After addition is complete the resulting mixture is allowed to come to room temperature and the solvent is removed in vacuo. The residue is then dissolved in EtOAc (200 mL) and the organic phase washed with 2N HCl (1×250 mL), H2O (1×200 mL), saturated NaHCO3 solution (1×200 mL), saturated NaCl solution (1×200 mL), dried over MgSO4 and concentrated in vacuo to give N-ethoxycarbonyl-m-bromophenethylamine.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(=O)([O-])O.[Na+].[C:12]1([CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:23]3[C:24]([NH2:27])=[N:25][O:26][C:22]=3[CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O1CCCC1>O>[C:12]1([CH2:18][O:19][C:20]2[CH:29]=[CH:28][C:23]3[C:24]([NH:27][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[N:25][O:26][C:22]=3[CH:21]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1noc2cc(OCc3ccccc3)ccc12
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1noc2cc(OCc3ccccc3)ccc12
Reaction time: 18 h

Procedure:
8.8 ml (0.092 mol) of ethyl chloroformate and 10.6 g (0.126 mol) of sodium hydrogen carbonate are added to a solution of 10.1 g (0.042 mol) of 6-(phenylmethoxy)-1,2-benzisoxazol-3-amine in 100 ml of a 9:1 mixture of tetrahydrofuran and water. The mixture is stirred for 18 hours and then the solvent is evaporated off and the residue is treated with dichloromethane and water. The organic phase is decanted off, dried over sodium sulphate and concentrated under reduced pressure. After crystallization from isopropyl alcohol and recrystallization from n-butanol, 11.5 g of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][C:14]=3[O:22][CH3:23])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([O:29][CH3:30])[C:27]#[CH:28].O>C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:28]#[C:27][CH2:26][O:29][CH3:30])=[CH:15][C:14]=3[O:22][CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCOC
Reactant: COc1cc(I)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: O
Product: COCC#Cc1cc(OC)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 46 %

Procedure:
N-(4-chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide (469 mg) from Example No. 117, copper (I) iodide (57 mg), and bis(triphenylphosphine)-palladium (II) chloride (35 mg) are suspended in diethylamine (15 mL). Methyl propargyl ether (101 μL) is added and the mixture is allowed to stir at rt for 64 h. The reaction mixture is poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer is washed with saturated aqueous ammonium chloride (3×10 mL) and brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The combined organic layers are dried (MgSO4) and concentrated. The crude product is purified by column chromatography (heptane/2-propanol, 12/1; 10/1; 5/1) to afford 188 mg (46%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[CH:17]\I)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[CH:17][C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH3:13]
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)C=CC#Cc1ccc([N+](=O)[O-])cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-nitro-benzene and (Z)-ethyl-3-iodoacrylate to the title product except using 1.6 mmol of acetylene and 1.8 mmol vinyl iodide. Purification by flash chromatography (20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a yellow solid (350 mg, 89% yield). 1H NMR (400 MHz, CDCl3) δ 8.22-8.19 (d, J=8.9, 2H), 7.68-7.65 (d, J=8.9, 2H), 6.38-6.35 (d, J=11.4, 1H), 6.26-6.23 (d, J=11.4, 1H), 4.29-4.24 (q, J=7.1, 2H), 1.35-1.31 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.38, 147.48, 132.66, 130.32, 129.41, 123.57, 121.67, 97.99, 90.64, 60.64, 14.23. Anal. Calcd. for C13H11NO4: C, 63.67; H, 4.52; N, 5.71; Found C, 63.45; H, 4.44; N, 5.65. m.p.: 76.0°-78.0° C.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:61][N:56]4[CH2:57][CH2:58][CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CO.O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:61][N:56]4[CH2:57][CH2:58][CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 62.9 %

Procedure:
A solution of 0.148 g of (Cis)-2-butyl-6-(hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4yl]methyl]-4(3H)-quinazolinone in 5.0 ml of methanol and 1.0 ml of tetrahydrofuran is heated at reflux for 4 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 99:1 to 9:1 chloroform-methanol to give 0.065 g of the desired product as a solid. FAB mass spec 562 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[CH2:23]([O:22][C:20]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)/[C:7]1=[O:11])=[O:21])[CH3:24]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)/C(=C\C2CCCCC2)c2ccc(Cl)cc21
Yield: 95.1 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one (2.71 g, 10.4 mmol) was reacted with ethyl chloroformate (1.47 mL, 15.6 mmol) and triethylamine (2.89 mL, 20.7 mmol) in dichloromethane to give E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a brown solid (Yield 3.3 g, 95%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]([OH:17])=O)[C:10]2=O)=[CH:5][CH:4]=1.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([N:26]2[C:15](=[O:17])[CH2:14][CH:9]3[C:10]([C:11]4[CH:12]=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=[CH:5][C:6]=4[CH2:7][CH2:8]3)=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)CC1CCc2ccc(C(F)(F)F)cc2C1=O
Solvent: CCO
Product: O=C1CC2CCc3ccc(C(F)(F)F)cc3C2=NN1c1ccccc1

Procedure:
After a mixture of 7-trifluoromethyl-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid and phenylhydrazine in ethanol is refluxed under heating for 10 hours, the ethanol is distilled off. To the residue is added acetic acid and the mixture is refluxed under heating for 7 hours. After the acetic acid is distilled off, the residue is extracted with chloroform and the extract is washed with water and dried over magnesium sulfate anhydride. The chloroform is distilled off to give 2-phenyl-9-trifluoromethyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:13][C@H:12]2[CH2:14][CH2:15][OH:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>C1COCC1>[Si:21]([O:16][CH2:15][CH2:14][C@@H:12]1[CH2:13][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: O=S(=O)(c1ccc(F)cc1)N1C[C@H]1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1CN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To the 2-{(2R)-1-[(4-fluorophenyl)sulfonyl]aziridin-2-yl}ethanol from Step 3 dissolved in THF (0.2 M) was added TBSCl (1.1 equiv.) followed by imidazole (2.2 equiv.). The reaction mixture was stirred 1 h at rt, then filtered with washing of the solids with MTBE. The combined organics were washed (2×) with 1M HCl, brine (2×), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with EtOAc/Hex (1:9) to give the title compound (85%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:12][C:11]([NH:13]C(=O)C)=[N:10][C:9]=1[CH3:17])(=[O:7])=[O:6]>Cl>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[CH3:17])(=[O:6])=[O:7]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)NCCO)s1
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)NCCO
Temperature: 80 °C
Yield: 63.2 %

Procedure:
A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-amide (0.95 g, 3.4 mmol) in 6N hydrochloric acid (13 ml) was heated for 2 h at 80° C., evaporated, and saturated NaHCO3 solution (20 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (50 ml) and dried (MgSO4). The crude product was further purified by crystallization (dichloromethane/MeOH/hexane) to yield the title compound (0.51 g, 63%) as a white solid. MS (ISP) 236.0 [(M−H)−]; mp 151° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cc1cnn(-c2ccc(C=O)cc2)c1
Product: Cc1cnn(-c2ccc(/C=C/C=O)cc2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 4) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[O:5]=O>O>[C:1]([OH:5])(=[O:2])[CH:3]=[CH2:4].[CH:1]([CH:3]=[CH2:4])=[O:2]
Reactant: O=O
Agent: C=CC=O
Solvent: O
Product: C=CC(=O)O
Temperature: 280 °C

Procedure:
A stainless-steel reaction tube having an inner diameter of 10 mm and a length of 300 mm was filled with 5 ml of the above catalyst for oxidation reaction. A mixed gas containing 3 volume % of acrolein obtained in Example 1, 3 volume % of oxygen, 30 volume % of water vapor and 64 volume % of nitrogen was introduced into the reaction tube at a space velocity of 3000/hour. The reaction tube was heated to 280° C. in an electric furnace, thereby subjecting the mixed gas to oxidation reaction. The outlet of the reaction tube was cooled and the resulting reaction gas was condensed and collected. Gas chromatograph analysis of the collected liquid showed that the acrolein conversion was 98% and the acrylic acid yield on the basis of acrolein was 90%.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21]>CCN(CC)CC>[CH3:16][C@H:3]([CH2:2][N:29]1[CH:24]2[CH2:25][CH2:26][CH:27]1[CH2:28][CH:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23]2)[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Solvent: CCN(CC)CC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccccc21
Yield: 63.4 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.083 g, 0.25 mmol) and 3-pentyl-8-aza-bicyclo[3.2.1]octane (104KS32-2) (0.051 g, 0.28 mmol) in Et3N (½ mL) were reacted according to GP15 to give the title compound (108LM39-36) (0.061 g, 63%). 1H NMR (CDCl3) δ 7.33-7.29 (m, 1H), 7.03-6.96 (m, 3H), 4.60 (ABq, J=14.8 Hz, J=37.1 Hz, CH2), 4.14-4.00 (m, 2H), 3.13 (bs, 1H), 3.05 (bs, 1H), 2.63-2.50 (m, 1H), 2.17-2.03 (m, 3H), 2.00-1.80 (m, 3H), 1.72-1.53 (m, 3H), 1.42-1.15 (m, 10H), 0.93-0.85 (m, 6H); 13C NMR (CDCl3) δ 165.0, 145.7, 128.9, 123.7, 122.6, 117.1, 116.1, 67.9, 60.9, 58.9, 58.2, 45.3, 38.4, 37.0, 36.8, 32.2, 31.7, 28.5, 28.3, 27.2, 22.9, 17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=385.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[C:24](C)(C)[O:25][SiH2]C(C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1C(C)(C)O[SiH2]C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To 30 g of 2-(tert-butyl-dimethyl-silanyloxymethyl)-4-(3-fluoro-5-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5) in 240 mL MeOH at 0° C. was added 2.6 mL of 1N HCl, dropwise. The reaction mixture was warmed up to room temperature and stirred for an additional 4 hours. After cooling to 0° C., to the reaction mixture was added 5 g of NaHCO3 and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to afford 22.7 g of 4-(3-fluoro-5-nitro-phenoxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tertbutyl ester (6).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OC(C)(C)C)CC3
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OC(C)(C)C)CC3
Yield: 70 %

Procedure:
To a stirred solution of 3-vinyl-N-(tert-butyloxycarbonyl)morphinan, 44 (10 mg, 0.028 mmol) in dry methanol (1 mL) was added Pd/C (4 mg) and the flask was charged with hydrogen gas in a balloon. After starting material disappeared on TLC, solvent was evaporated and column chromatography of the residue gave 7 mg (70%) of product: 1H NMR (300 MHz, CDCl3) δ7.06˜7.36 (3H, m); 4.37 (0.5H, s); 4.19 (0.5H, s); 3.88 (1H, dd); 3.11 (1H, m); 2.63 (2H, m); 2.59 (2H, m); 2.44 (1H, m); 1.60˜1.80 (4H, m); 1.40˜1.60 (9H, d); 0.90˜1.40 (9H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:18][O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:2][C:3]2[S:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:25][C:24]=1[CH3:30]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1C
Temperature: 50 °C

Procedure:
To a solution of 2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-thiophene (0.210 g, 0.760 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.147 g, 0.760 mmole) in acetonitrile (5 mL), is added cesium carbonate (0.248 mL, 0.760 mmole) in one portion. The reaction is heated at 50° C. overnight, then concentrated. The residue is loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][C:11]#[CH:12])=[O:7])([CH3:4])[CH3:3].O.ON1C2C=CC=CC=2N=N1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][CH2:37][CH2:38][NH2:39].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][CH2:37][CH2:38][NH:39][C:13](=[O:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:10][C:11]#[CH:12]
Reactant: NCCNc1nc2ccccc2o1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A cold mixture of Boc-L-propargyl-glycine (128.2 mg, 0.602 mmol), N-hydroxybenzotriazole hydrate (84.5 mg, 0.625 mmol) and the hydrochloride salt of N1-(benzo[d]oxazol-2-yl)ethane-1,2-diamine (152.3 mg, 0.609 mmol) in dichloromethane (6 mL) was cooled in an ice bath, then treated with triethylamine (0.34 mL, 2.44 mmol) and 1-[3-dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride (119.6 mg, 0.624 mmol). The resulting mixture was stirred for 40 h at room temperature, then diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated to yield a residue The residue was purified by flash column chromatography, eluting with 8% methanol in chloroform to yield (S)-tert-butyl 1-(2-(benzo[d]oxazol-2-ylamino)ethylamino)-1-oxopent-4-yn-2-ylcarbamate as a solid.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:19][CH3:20])=[N:16][C:17]#[N:18])[N:9]=1)[C:2]([NH2:4])=[NH:3].[ClH:21].C[OH:23]>>[ClH:21].[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:19][CH3:20])=[N:16][C:17](=[O:23])[NH2:18])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CO
Reactant: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Agent: Cl
Product: CNC(=NC(N)=O)NCCSCc1csc(NC(=N)N)n1

Procedure:
A mixture of 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (1.0 g.), and 2.5 N hydrochloric acid (12 ml.) was heated for four minutes on the steam bath. On cooling a white solid precipitated which was applied to Merck 60 F-254 preparative thin layer chromatography plates and eluted with chloroform/methanol/ammonia (s.g. 0.880) 7:3:0.5 v/v/v. The yellow foam obtained was dissolved in methanol and methanolic hydrogen chloride added. The solution was evaporated to dryness and the residue crystallized from methanol to give 2-guanidino-4-[2-(2-carbamoyl-3-methylguanidino)ethylthiomethyl]thiazole hydrochloride, m.p. 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([CH:19]=[O:20])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1.[CH2:21]([Mg]Br)[CH3:22]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([CH:19]([OH:20])[CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1
Reactant: CC[Mg]Br
Reactant: O=CC1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Solvent: C1CCOC1
Product: CCC(O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1

Procedure:
2.32 g of the compound obtained in Step A of Example 115 in 150 ml of tetrahydrofuran are stirred for 4 hours at −30° C., under an inert atmosphere, in the presence of 15 ml of a 1M solution of ethylmagnesium bromide in tetrahydrofuran. After returning to ambient temperature, the mixture is worked up in conventional manner, then concentrated under reduced pressure, enabling the expected product to be isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[N:16]1([CH:13]2[CH2:14][CH2:15][N:10]([C:6]3[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=3)[CH2:11][CH2:12]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(N2CCC(N3CCOCC3)CC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N2CCC(N3CCOCC3)CC2)c1
Yield: 42.9 %

Procedure:
4-[1-(3-Nitro-phenyl)-piperidin-4-yl]-morpholine (1.60 g, 0.00549 mol) was dissolved in Methanol (45 mL) and the solution was carefully added to Palladium on Carbon 10% (90.10, carbon black. Palladium, 0.750 g) in a Parr vessel under nitrogen. The mixture was then placed on a Parr hydrogenator and was allowed to shake until uptake of hydrogen had ceased (˜3 hours). The catalyst was then removed via filtration and the filtrate was reduced to afford 615 mg of 3-(4-Morpholin-4-yl-piperidin-1-yl)-phenylamine without further purification. 1H NMR (400 MHz, DMSO, d6) δ 6.81 (t, 1H, J=7.88 Hz), 6.14 (m, 1H), 6.11 (m, 1H), 6.00 (m, 1H), 4.80 (s, 2H), 3.57 (m, 6H), 2.46 (m, 5H), 1.82 (m, 2H), 1.43 (m, 2H).