Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[NH:7][C:8]3[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:9]=3[N:10]=2)[N:3]=[CH:2]1.[OH:16][C@:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[C:18]([OH:20])=[O:19].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[OH:16][C@:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[C:18]([NH:15][C:13]1[CH:12]=[CH:11][C:9]2[NH:10][C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[N:7][C:8]=2[CH:14]=1)=[O:19].[C:22]1([C@H:17]([CH3:21])[C:18]([NH:15][C:13]2[CH:12]=[CH:11][C:9]3[NH:10][C:6]([C:4]4[N:3]=[CH:2][S:1][CH:5]=4)=[N:7][C:8]=3[CH:14]=2)=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Reactant: Nc1ccc2nc(-c3cscn3)[nH]c2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](O)(C(=O)Nc1ccc2[nH]c(-c3cscn3)nc2c1)c1ccccc1
Product: C[C@H](C(=O)Nc1ccc2[nH]c(-c3cscn3)nc2c1)c1ccccc1
Reaction time: 3 h

Procedure:
A solution of 2-thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-6, 103 mg, 0.476 mmol), (2S)-2-Hydroxy-2-phenyl-propionic acid (79 mg, 0.48 mmol) and diisopropylethylamine (0.166 mL, 0.95 mmol) in N,N-dimethylformamide (5 mL) was reacted at the ambient temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 273 mg, 0.52 mmol). After 3 h stirring at the same temperature, the reaction mixture was concentrated under the reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and aqueous sodium bicarbonate solution (40 mL). The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The resulting crude product was triturated with ethyl acetate (3 mL), collected by filtration, and dried under the reduced pressure to afford (2S)-2-Hydroxy-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]propanamide as a white solid (3-62); 1H NMR (500 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.72 (s, 1H), 9.31 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 7.65 (d, 2H, J=8.5 Hz), 7.52 (m, 1H), 7.36 (m, 3H), 7.26 (m, 1H), 6.45 (s, 1H), 1.72 (s, 3H).
Reaction SMILES: I[C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21].C(N(CCCC)CCCC)CCC.CC(C)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[NH2:18][C:3]1[C:2](/[CH:21]=[CH:20]/[C:19]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1nccc(Oc2ccc([N+](=O)[O-])cc2)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N

Procedure:
3-Iodo-4-(4-nitrophenoxy)-2-pyridinamine (500 mg), ethyl acrylate (0.3 ml), palladium (II) acetate (30 mg), tributylamine (0.66 ml) and dimethylformaldehyde (5 ml) were stirred at 130° C. for 20 minutes. After returning the reaction solution to room temperature, water was added and extraction was performed with ethyl acetate. NH type silica gel was added to the extract, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=3:1). The solvent was distilled off under reduced pressure to obtain 330 mg of the target substance as a yellow oil.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[O:13][C:12]([CH3:23])([CH3:22])[O:11]1)C1C=CC=CC=1.C(OCC1C(C2C=CC=CC=2Cl)OC(C)(C)O1)C1C=CC=CC=1>>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:14]1[O:13][C:12]([CH3:22])([CH3:23])[O:11][C@H:10]1[CH2:9][OH:8]
Reactant: CC1(C)O[C@@H](COCc2ccccc2)[C@@H](c2ccccc2Cl)O1
Agent: CC1(C)OC(COCc2ccccc2)C(c2ccccc2Cl)O1
Product: CC1(C)O[C@@H](CO)[C@@H](c2ccccc2Cl)O1
Yield: 95 %

Procedure:
The substantially same method as described in Example 372 was conducted, except that ((4S,5R)-4-(benzyloxymethyl)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane (Preparation example 376) was used instead of that (±)-4-(benzyloxymethyl)-5-(2-chlorophenyl)-2,2-dimethyl-1,3-dioxolane (Preparation example 371), to obtain the title compound (0.58 g, 95%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].COC(C1CN(CC2C=CC(OCC3C4C=C(Cl)C=CC=4OC=3)=CC=2)C1)=O>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][N:7]4[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]4)=[CH:11][CH:12]=3)=[CH:17][CH:18]=2)[CH:24]([CH3:25])[CH3:26])=[CH:28][CH:29]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3ccc(CN(c4ccc(F)cc4)C(C)C)cc3)cc2)C1
Agent: COC(=O)C1CN(Cc2ccc(OCc3coc4ccc(Cl)cc34)cc2)C1
Product: CC(C)N(Cc1ccc(-c2ccc(CN3CC(C(=O)O)C3)cc2)cc1)c1ccc(F)cc1
Yield: 60 %

Procedure:
When the product of Step A was substituted for methyl-1-(4-((5-chlorobenzofuran-3-yl)methoxy)benzyl)azetidine-3-carboxylate in Example 25, Step E, the similar process afforded the title compound in 60% yield, as creamy solid. 1H-NMR (CDCl3+CD3OD) 7.66 (d, 2H, J=8.13 Hz); 7.62-7.57 (m, 4H); 7.41 (d, 2H, J=8.07 Hz); 6.95-6.85 (m, 2H); 6.85-6.75 (m, 2H); 4.44 (s, 2H); 4.39 (s, 2H); 4.39-4.2 (m, 2H); 3.5-3.45 (m, 1H); 1.26 (d, 6H, J=6.54 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[N:15][NH:16]2)=[CH:12][CH:11]=1>[Cl-].[NH+]1C=CC=CC=1>[NH:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=[C:19]1[C:14]1[C:13]2[C:17](=[CH:18][C:10]([C:4]3[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=3[OH:2])=[CH:11][CH:12]=2)[NH:16][N:15]=1
Reactant: COc1cc(O)ccc1-c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: Oc1ccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c(O)c1
Yield: 59 %

Procedure:
6-(2-methoxy-4-hydroxyphenyl)-3-1H-benzoimidazol-2-yl-1H-indazole, prepared in example 24(d), (46 mg, 0.13 mmol) was heated in pyridinium chloride (0.5 g) at 180° C. for 2 h. The reaction was allowed to cool, and was quenched with sat. NaHCO3 (15 mL) and extracted with EtOAc (2×20 mL). Organics were dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (60% THF/hexanes) gave 26 mg (59%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.49 (s, 1H), 12.94 (s, 1H), 9.49 (s, 1H), 9.39 (s, 1H), 8.43 (d, 1H, J=8.4 Hz), 7.71-7.74 (m, 2H), 7.50 (d, 1H, J=6.9 Hz), 7.43 (dd, 1H, J=8.4, 1.2 Hz), 7.16-7.23 (m, 3H), 6.45 (d, 1H, J=2.1 Hz), 6.35 (dd, 1H, J=8.4, 2.1 Hz). MS (ES) [m+H]/z calc'd 343, found 343; [m−H]/z calc'd 341, found 341.
Reaction SMILES: C12(C[O:12]C3C=CC(C#N)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[C:29]12([CH2:39][O:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=3[CH:49]3[CH2:52][CH2:51][CH2:50]3)[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>>[C:29]12([CH2:39][O:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]([NH2:46])=[O:12])=[CH:43][C:42]=3[CH:49]3[CH2:52][CH2:51][CH2:50]3)[CH2:30][CH:31]3[CH2:37][CH:35]([CH2:34][CH:33]([CH2:32]3)[CH2:38]1)[CH2:36]2
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CCC2)c1
Reactant: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Product: NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C2CCC2)c1

Procedure:
Following the procedure as described in Example 38 step 3 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with 4-(adamantan-1-ylmethoxy)-3-cyclobutylbenzonitrile, the title compound was obtained as a colorless solid (0.88 g, 88%): MS (ES+) m/z 340.3 (M+1);
Reaction SMILES: S(=O)(=O)(O)N.[CH:6]([C:8]1[CH:37]=[CH:36][CH:35]=[CH:34][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:33])[CH2:18][NH:19][C:20]([C:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][N:23]=2)=[O:21])[CH2:13][CH2:12]1)=[O:7].Cl([O-])=[O:39].[Na+].O>CC(C)=O>[C:27]1([C:25]2[NH:24][N:23]=[C:22]([C:20]([NH:19][CH2:18][C:17]([N:14]3[CH2:15][CH2:16][CH:11]([O:10][C:9]4[CH:34]=[CH:35][CH:36]=[CH:37][C:8]=4[C:6]([OH:39])=[O:7])[CH2:12][CH2:13]3)=[O:33])=[O:21])[CH:26]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2C(=O)O)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 53.5 %

Procedure:
Sulphamic acid (34 mg, 0.3 mmol) was added to stirred a mixture of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-formyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide (50 mg, 0.1 mmol) in acetone (1 mL). After 2 minutes, sodium chlorite (36 mg, 0.4 mmol) was added and the resulting mixture was stirred at ambient temperature for 1 hour. Water was added and the solid obtained was isolated by filtration to afford 24 mg (53% yield) of 2-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid. LC/MS [M+H]+: 449.17, 90.6%, 1H NMR (300 MHz, DMSO-d6): δ13.8 (b, 1H), 12.8 (b, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.6 (m, 1H), 7.5 (m, 3H), 7.4 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 7.0 (m, 1H), 4.8 (m, 1H), 4.2 (m, 2H), 3.7 (m, 3H), 3.5 (m, 1H), 2.0 (m, 1H), 1.7 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:7][S:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:6])[CH3:2].C(N(CC)CC)C.[Br:36][CH2:37][C:38](Br)=[O:39]>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:7][S:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:6][C:38](=[O:39])[CH2:37][Br:36])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of S-triphenylmethyl-L-cysteine ethyl ester (18 g, 46 mmol.) and triethylamine (6.4 mL, 46 mmol.) in dry THF (250 mL) under nitrogen was cooled to 0° C. A solution of bromoacetyl bromide (9.28 g, 46 mmol.) in dry THF (60 mL) was added dropwise during which time the solution turned cloudy. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give an oil. The oil was partitioned between methylene chloride and water (60 mL each), the organic layer washed with 5% HCl, NaHCO3, dried (magnesium sulfate), filtered, and the volatiles removed to give the desired product (69%).
Reaction SMILES: [C:1]1([C:7]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]1([C:7]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccccc3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepared by the method of example 3.3 using 2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (2.59 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (3.3 mmol). Chromatography on silica gel (100 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and 10% methanol in dichloromethane gave the title compound:
Reaction SMILES: [Br:1][CH:2]([CH3:12])[C:3]([O:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1)=O.O1C=CC=C1C[SH:19]>>[Br:1][CH:2]([CH3:12])[C:3](=[S:19])[O:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1
Reactant: SCc1ccco1
Reactant: CC(Br)C(=O)OCc1ccco1
Product: CC(Br)C(=S)OCc1ccco1

Procedure:
The synthetic procedure is similar to the reaction protocol for furfuryl 2 bromopropionate except that 2 furylmethanethiol (5.94 g, 0.052 mol) is used in place of 2-furylmethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.N1(CCN[C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])C=CN=N1.C([OH:39])C>N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:31]2[NH:30][C:29]([CH3:36])=[C:28]([C:26]([OH:27])=[O:39])[C:32]=2[CH3:33])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro phenyl)-2-oxo-1,2 dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3 triazol-1-yl-ethyl)-amide as a yellow solid (43.4 mg, 36%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:17]=O>CCOCC>[N:1]1([CH2:17][NH:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC1CCCCC1
Reactant: C=O
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCOCC
Product: c1ccc2c(c1)nnn2CNC1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
To a mixture of 54 g (0.45 mole) benzotriazole and 51.5 mL (0.45 mole) of cyclohexylamine in 2000 mL of ether was added dropwise 36.5 mL (0.45 mole) of 37% aqueous formaldehyde. The reaction mixture was stirred at room temperature for 18 hours. The mixture was dried over calcium chloride, filtered and concentrated under reduced pressure. 200 mL of hexanes was added to the residue and the resulting solid collected by filtration, washed with 300 mL of hexane to give 90.0 g of benzotriazol-1-ylmethyl-cyclohexylamine as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9](Cl)[CH:8]=[CH:7][C:5]=1N)([O-:3])=[O:2].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na].C[N:21](C=O)C>C(OCC)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([NH2:21])[CH:8]=[CH:7][C:5]=1[S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of 2-Nitro-4-chloro aniline (1.0 g, 5.79 mmol), sodium thiophenol (0.84 g, 6.4 mmol) in DMF (10 mL) was heated 2.5 h at 100° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer washed with water, 20% aqueous potassium hydroxide solution and aqueous 10% sodium chloride solution, then, dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent concentrated under vacuum leaving the title compound as a red solid (0.98 g, 69%).
Reaction SMILES: BrC[C:3](=[O:12])[CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8]C)=[O:6].Br>>[CH2:10]([C:4]1[C:5](=[O:6])[O:7][CH2:8][C:3]=1[OH:12])[CH3:11]
Reactant: CCOC(=O)C(CC)C(=O)CBr
Agent: Br
Product: CCC1=C(O)COC1=O
Temperature: 100 °C

Procedure:
A mixture of ethyl 4-bromo-2-ethyl-3-oxobutanoate and hydrogen bromide (48%, 0.037 mL, 0.327 mmol) was heated at 100° C. for 20 h. After cooling to rt, the solid was collected by filtration followed by diethyl ether washing to give 3-ethyl-4-hydroxyfuran-2(5H)-one. LC/MS: (M+1)+: 129.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:5][C:4]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=2[O:2][CH3:1])=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccc(OC)c(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 77.2 %

Procedure:
Using 2,5-dimethoxyaniline (2.53 g, 16.5 mmol) and 4-nitrobenzoic acid (2.51 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 3.50 g (77.2%) of the title compound in the form of orange needle crystals.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].Cl.[N:9](OCCC(C)C)=[O:10]>COC(C)(C)C.COCCOC>[CH3:1][CH:2]([CH3:3])[C:4](=[O:7])[C:5](=[N:9][OH:10])[CH3:6]
Reactant: CC(C)CCON=O
Reactant: CCC(=O)C(C)C
Agent: Cl
Solvent: COCCOC
Solvent: COC(C)(C)C
Product: CC(=NO)C(=O)C(C)C

Procedure:
100 g (948 mmol) of 2-methylpentan-3-one were dissolved in 400 ml of tert-butyl methyl ether. 50 g (274 mmol) of solution of hydrochloride in ethylene glycol dimethyl ether (20%) were added. Subsequently, a solution of 117 g (949 mmol) isoamyl nitrite in 150 ml of tert-butyl methyl ether was added dropwise within 60 minutes. The solvent was removed fully under reduced pressure. The residue was taken up in 300 ml of n-heptane and concentrated again under reduced pressure. After 200 ml of n-heptane had been added, extraction was effected with 522 ml of sodium hydroxide solution (2 molar). After phase separation, the aqueous phase was washed with n-heptane. The aqueous phase was acidified by adding conc. hydrochloric acid. The product was isolated by filtration with suction, washed with water and dried at elevated temperature under reduced pressure.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[CH3:13][CH2:14]OCC>C(O)(=O)C.C(Cl)Cl>[NH:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13]1
Reactant: CCOCC
Reactant: NNc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc2[nH]ccc2c1
Temperature: 50 °C
Yield: 275.1 %

Procedure:
To a solution of 1 (90 mg, 0.27 mmol) in acetic acid (2 mL) was added a solution of phenylhydrazine (0.026 mL, 0.27 mmol) in acetic acid (1 mL) and the mixture heated at 50° C. for 1 hour. The reaction was cooled to room temperature then boron trifluoride etherate (0.060 mL, 0.46 mmol) added and the reaction heated at 80° C. for 16 hours. The mixture was diluted with CH2Cl2 (25 mL) and washed with satd NaHCO3 (3×15 mL, caution: vigorous gas evolution). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel, eluted with 40% EtOAc/hexanes, to give 2 (87 mg, 78% yield) as an off-white solid. Rt=1.96 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=411.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].C(O)C.O.N>O1CCOCC1.[Ni].O>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: Cc1ccc(-c2ccccc2)cc1C#N
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
4.46 g (23.1 mmol) of 2-methyl-5-phenylbenzonitrile was dissolved in 26 ml of 1,4-dioxane and to this was added 5 ml of ethanol. To this solution was added 9 ml of 28 wt % ammonia water, and 3 g of a suspension of Raney nickel W2 (manufactured by Aldrich; 50 wt % in water). This mixture was stirred for 8 hours at room temperature under hydrogen atmosphere. To this mixture was further added 2 g of a suspension of Raney nickel W2 (manufactured by Aldrich; 50 wt % in water), 8 ml of 28 wt % ammonia water and 20 ml of ethanol, and the mixture was stirred for 4.5 hours at room temperature under hydrogen atmosphere. The reaction mixed was filtrated through celite, and the filtrate was concentrated. The residue was distilled by using Kugelrohl distillation apparatus (0.5 mmHg, set temperature: 216° C.), to obtain 4.25 g of 2-methyl-5-phenylbenzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([NH2:10])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]
Reactant: COC(=O)C1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C

Procedure:
A solution of 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (838 mg, 2.2 mmol), THF (10 ml) and P(Ph)3 (1.15 g, 4.4 mmol) and water (0.08 ml, 4.4 mmol) was refluxed for 6 hours and then concentrated in vacuo. The residue was dissolved in Et2O and treated with HCl (0.1N, 20 ml). The aqueous layer was extracted with Et2O, washed with Na2CO3 (10% aq.), dried over anhydrous MgSO4 and concentrated to afford the amine as colorless oil which was used in next step without further purification.