Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:64][O:65][NH:66][CH3:67].Cl>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[NH:29][C@@H:25]([C:26](=[O:27])[N:66]([O:65][CH3:64])[CH3:67])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C

Procedure:
DIPEA (28.2 ml, 20.9 g, 162 mmol) was added to a stirred solution of (R)-3-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid (20.0 g, 53.9 mmol), BOP (25.00 g, 56.5 mmol) and MeONHMe.HCl (5.52 g, 56.6 mmol) in DMF (300 mL). After stirring 2 h the DMF was evaporated and the residue was dissolved in EtOAc and washed with water, 5% aqueous HCl, saturated aqueous NaHCO3 and brine, then dried with Na2SO4 and evaporated to a cream solid. This was ground to a powder (22.39 g, 100%), mp 107.1-108.7° C. (lit. mp 107-108° C.) [W. J. Thompson et al, Tetrahedron Lett, 1990, 31, 6189]. 1H NMR (CDCl3) δ 7.44-7.32 (5H, m), 7.09 (2H, d, J=8.5 Hz), 6.90 (2H, d, J=8.6 Hz), 5.15 (1H, br d, J=7.1 Hz, NH), 5.04 (2H, s, OCH2Ph), 4.91 (1H, br s, Hα), 3.17 (3H, s, NMe), 3.65 (3H, s, OMe), 3.00 (1H, dd, J=6.1, 13.6 Hz, Hβ), 2.83 (1H, dd, J=6.2, 14.2 Hz, Hβ), 1.40 (9H, s, CMe3). 13C NMR (CDCl3) δ 172.3, 157.7, 155.2, 137.1, 130.4, 128.9, 128.5, 127.9, 127.4, 114.7, 79.6, 70.0, 61.5, 51.6, 38.0, 32.1, 28.3.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](OC)=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]([NH2:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:37][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1

Procedure:
1-Cyclohexyl-6-[(5-(methoxycarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is reacted according to general operating instructions 7 with isoamylamine. 1-Cyclohexyl-6-[(5-((3-methyl-butyl)aminocarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is obtained as a solid.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH2:7]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].Cl>CCOCC>[CH2:7]([CH:12]1[CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCC1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a dispersion of 1.75 g of aluminum lithium hydride in 40 ml of dry ether, a solution of 10 g of 4-n-pentylcyclohexanecarbonyl chloride in 12 ml of ether was added dropwise below 5° C., followed by stirring overnight at room temperature. After the reaction, the reaction mixture was acidified with 5%-hydrochloric acid aqueous solution until a pH value of 1 were shown and was subjected to extraction with ether. The organic layer was washed successively with water, 5%-sodium hydroxide, and water, followed by drying with anhydrous magnesium sulfate. The resultant organic layer was subjected to filtration, followed by distilling-off of the solvent to obtain 8.2 g of 4-n-pentylcyclohexylmethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCOCC1

Procedure:
Using 3-nitro-benzoic acid (334 mg) and morpholine (209 μl) instead of 1-ethyl-piperazine, in the same manner as Step A in Example 1-D-101, the desired compound was obtained (340 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl-:17].[Cl-].IC1C=CC=CC=1>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[Cl:17]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: [Cl-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: Ic1ccccc1
Product: CC(=O)c1ccc(N)c(Cl)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
A mixture of p-aminoacetophenone (20 g), pyridine (11.7 g), and iodobenzene dichloride (40 g) in tetrahydrofuran (300 ml) was stirred for 5 hours at 0° C. The insoluble materials were filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was crystallized from ethanol to give colorless crystals of 4'-amino-3'-chloroacetophenone (20.1 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27]([C:29]1[C:34]([SH:35])=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[C:34]([S:35][C:2]2[S:6][C:5]([NH:7][C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[O:9])=[N:4][CH:3]=2)=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)c1ncccc1S
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)c1ncccc1Sc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1
Yield: 30 %

Procedure:
3-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-pyridine-2-carboxylic acid methyl ester (149 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 3-mercapto-pyridine-2-carboxylic acid methyl ester (340 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:8]([CH3:19])=[CH:7]2.[Br:20]N1C(=O)CCC1=O.C(OCC)C.C(OCC)(=O)C>CN(C)C=O>[Br:20][C:8]1([CH3:19])[CH2:7][C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[C:10](=[O:12])[N:9]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc2cccc(F)c2c(=O)n1-c1cccnc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(Br)Cc2cccc(F)c2C(=O)N1c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
8-Fluoro-3-methyl-2-pyridin-3-yl-2H-isoquinolin-1-one (550 mg, 2.2 mmol) and N-bromosuccinimide (396 mg, 2.23 mmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 50° C. for 60 minutes and poured into diethyl ether (50 mL) and ethyl acetate (20 mL). A white solid precipitated, which was removed by filtration. The filtrate was washed with diluted brine (water/sat. NaCl (aq.)=1:1; 4×20 mL), dried over MgSO4 and rotavaped. 1H NMR (500 MHz, CDCl3): 2.27 (s, 3H, Me), 7.2 (dd, J=8.4 Hz, J=10.7 Hz, 1H), 7.52 (dd, J=4.9 Hz, J=7.9 Hz, 1H), 7.64 (d (d of unresolved m), J=8 Hz, 1H), 7.72 (td, J(d)=5 Hz, J(t)=8.1 Hz, 1H), 7.84 (d, J=8.2 Hz), 8.53 (d, J=1.8 Hz, 1H), 8.74 (d, J=4.3 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Product: O=C(Cc1ccccc1)N(c1ccc([N+](=O)[O-])cc1)c1cncnc1

Procedure:
Starting compounds: 5-[N-(4-nitrophenyl)amino]pyrimidine and phenylacetyl chloride
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[N:5]=[C:6]([CH3:13])[C:7]=1[CH2:8][OH:9]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)c(CO)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a mixture of ethyl 4-chloro-2,6-dimethylnicotinate (1.5 g) and THF (50 mL) was added diisobutylaluminum hydride (1M in toluene, 42.0 mL) at 0° C. After stirring at room temperature for 1 h, sodium sulfate decahydrate (13.5 g) and THF were added to the mixture and the mixture was stirred at room temperature for 3 h. The mixture was passed through Celite®. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (0.920 g). The obtained crystals were recrystallized from EtOAc-hexane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([C:11](=[CH2:20])[C:12]3[C:18]([CH3:19])=[CH:17][S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH:11]([CH3:20])[C:12]3[C:18]([CH3:19])=[CH:17][S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1c2c(C)csc2C2CN(Cc3ccccc3)CC12
Agent: [Pd]
Solvent: CO
Product: Cc1csc2c1C(C)C1CN(Cc3ccccc3)CC21
Reaction time: 16 h

Procedure:
A solution of product from step g) (3.1 g) in MeOH (55 ml) was treated with 10% Pd/C (4.65 g) and a balloon of H2 at 40° C. for 16 hours. The reaction mixture was filtered through a pad of celite, evaporated in vacuo and the residue purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 50% ethyl acetate) to give 948 mg (49% over two steps) of the subtitle product. MS calculated for C18H21NS+H 284, observed 284.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C@@H:11]3[C@@H:6]([N:7]([C:15]([C:17]4[CH:25]=[CH:24][C:20]5[NH:21][CH:22]=[N:23][C:19]=5[CH:18]=4)=[O:16])[CH2:8][CH2:9][CH2:10]3)[CH2:5][C:4]=2[C:3]=1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:39](OCC)(OCC)[O:40]CC>CO>[NH:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:15]([N:7]3[C@H:6]4[C@H:11]([C:12]5[CH:13]=[C:14]6[O:40][CH:39]=[N:1][C:2]6=[CH:3][C:4]=5[CH2:5]4)[CH2:10][CH2:9][CH2:8]3)=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: Nc1ccc2c(c1O)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3cc4ocnc4cc3C[C@H]21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of (cis-7-amino-8-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-(1H-benzoimidazol-5-yl)-methanone (100 mg), 4-toluenesulfonic acid hydrate (5 mg), triethyl orthoformate (40 μL), and methanol (1 mL) is stirred at 60° C. for 2 h. After cooling to room temperature, the mixture is concentrated and the residue is dissolved in ethyl acetate. The resulting solution is washed with 1 M NaOH solution, dried (Na2SO4), and concentrated to give the title compound. Yield: 50 mg (49% of theory); LC (method 1): tR=2.24 min; Mass spectrum (ESI+): m/z=359 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[N:18]2)=[CH:13][CH:12]=1>CO.[Pd]>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18]2)=[CH:13][CH:12]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(N)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
To a solution of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4-nitro-1H-pyrazole obtained in Example 28 (0.67 g) in methanol (10 mL), 10% palladium on carbon (0.067 g) was added and stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: hexane:ethyl acetate=3:1 to 1:1) to give the titled compound (0.258 g) as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][N:5]=1)[CH2:2][CH3:3].[C:12](Br)(Br)([Br:14])[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][C:12]([Br:14])=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([CH2:1][CH2:2][CH3:3])=[N:5][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1ccc(C=O)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1ccc(C=C(Br)Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
6-Propylnicotinaldehyde (0.2 g, 0.00134 mol) was dissolved in DCM (4 mL). Carbon tetrabromide (0.887 g, 0.00268 mol) and triphenylphosphine (1.4 g, 0.00536 mol) were added to the solution followed by stirring at RT overnight. After insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography (3% ethylacetate:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (0.05 g).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:40])[C:23](=[O:39])[O:24][CH2:25][CH:26]4[C:38]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:32]5[C:27]4=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1>O1CCOCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:40])[C:23](=[O:39])[O:24][CH2:25][CH:26]4[C:38]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:32]5[C:27]4=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCO1
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 40.5 %

Procedure:
In a manner similar to that of Example 1(g), starting with 500 mg (0.9 mmol) of 9H-fluoren-9-ylmethyl [4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate in 10 ml of dioxane, 200 mg (40%) of the desired product, with a melting point of 94° C., are obtained.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>C(OCC)C>[CH:17]1[C:21]2[C:21](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:20]=[CH:19][C:18]=1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:24]([OH:23])=[O:33])=[CH:27][CH:28]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethane sulfonic anhydride (32.2 mmol) was added dropwise over 5 minutes to a −40° C. pyridine (70 mL) solution of (4-hydroxy-phenyl)-acetic acid methyl ester (5.35 g, 32.2 mmol). The reaction was stirred at −40° C. for 10 minutes and then at 0° C. for 2 hours. The reaction was diluted with diethyl ether and washed with water and 2N hydrochloric acid. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on a Biotage Flash 40M column eluting with ethyl acetate/hexanes (1:4) to provide the title compound as a clear, colorless oil, which crystallized upon standing 9.27 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.37-7.34 (m, 2H), 7.24-7.21 (m, 2H), 3.70 (3H), 3.64 (2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:24].C(N(CC)CC)C.Cl.[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=2)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=1
Reactant: COC(=O)CCN
Reactant: Cc1cc(OC(CC(C)(C)C)c2ccc(C(=O)O)cc2)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(Cl)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(6-chloro-5-methyl-pyridin-3-yloxy)-3,3-dimethyl-butyl]-benzoic acid (414 mg, 1.19 mmol) in methylene chloride (12 mL) is added triethyl amine (0.5 mL, 3.6 mmol), DMAP (5.0 mg), 3-Amino-propionic acid methyl ester hydrochloride (250 mg, 1.8 mmol) and EDCI (688 mg, 3.6 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (400 mg).
Reaction SMILES: [NH+:1]1([O-])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][NH+]1C=Cc2cccnc21
Product: Clc1ccnc2[nH]ccc12

Procedure:
1H-Pyrrolo[2,3-b]pyridine-N-oxide (Reference Example 65) (10.0 g) in phosphorous oxychloride (75 mL) was heated at reflux for 8 hours. The excess phosphorous oxychloride was evaporated and the residue was taken up in water and the solution was brought to a pH=8–9, the resultant precipitate was filtered and air-dried to give the title compound as an off-white solid (10.2 g). MS: 152 (MH+). 1H NMR (CDCl3): δ 8.2 (d, 1H), 7.5 (d, 1H), 7.2 (d, 2H), 6.6 (d, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:4])=[O:2]
Reactant: c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccccc1

Procedure:
Aniline (C6H5NH2) is mainly produced in industry in two steps from benzene. First, benzene is nitrated using a concentrated mixture of nitric acid and sulfuric acid at 50 to 60° C., which gives nitrobenzene. In the second step, the nitrobenzene is hydrogenated, typically at 200-300° C. in presence of various metal catalysts.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1
Reactant: NCCc1cccc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: NCCc1cccc(O)c1
Yield: 95.4 %

Procedure:
10% Palladium-carbon catalyst (water content 50%, 86 mg) was added to a solution of 2-(3-benzyloxyphenyl)ethylamine (434 mg, 1.91 mmol, 1.0 eq) in THF (10 ml), and the mixture was stirred at room temperature for 3 hours in a stream of hydrogen. The reaction ma ire was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 2-(3-hydroxyphenyl)ethylamine (250 mg, 95.5%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:24])=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:23]=3)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:24])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1cccc(-c2ncccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1cccc(-c2ncccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A306 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-6-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[NH4+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>>[CH2:1]([N:8]1[C:12]([CH2:20][C:19]2[CH:20]=[CH:19][C:18]([C:22]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:22][CH:18]=2)([OH:13])[CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C1CCC(=O)N1Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: O=C1CCC(O)(Cc2ccc(-c3ccccc3)cc2)N1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
9.5 g N-Benzylsuccinimide is added to 120 ml THF and the mixture is then cooled to −78° C. A solution of 4-methylbiphenylmagnesium chloride in THF (1.3 eq) is then added. The subsequent mixture is then stirred for 2 h at −78° C. The mixture is then warmed to 10° C. and 100 ml saturated ammonium chloride solution is added. The phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are washed with water then brine and then concentrated in vacuo. The crude material is crystallized from toluene to give 1-Benzyl-5-biphenyl-4-ylmethyl-5-hydroxy-pyrrolidin-2-one. 1H NMR (DMSO): 1.72 (1H), 1.91 (1H), 2.27 (2H), 2.72 (1H), 2.97 (2H), 4.40 (1H), 4.55 (1H), 7.21-7.66 (14H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1
Yield: 78 %

Procedure:
(S)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.051 mol) and 5-chloro-1H-indole-2-carboxylic acid (0.051 mol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 50%, 75%, 80% and 100% ethyl acetate-hexanes giving a foam (yield 78%), HPLC (60/40) 4.21 minutes (99%). A portion of this material was recrystallized by dissolving in hot ethyl acetate (approximately 5-7 mL/g), and adding an approximately equal volume of hexanes at reflux, followed by slow cooling of the solution to 25° C. The solid was filtered and washed with 1:4 ethyl acetate-hexanes and dried (70-90% recovery): mp 175-177° C.;
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1>N1C=CC=CC=1.CCOCC>[C:7]1([CH3:8])[CH:9]=[CH:10][C:4]([S:1]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 8 h

Procedure:
57.2 g (300 mmol) of tosyl chloride are added to a solution of 39.6 g (300 mmol) of (2,2-dimethyl[1,3]dioxolan-4-yl)methanol in 170 ml of pyridine at 0° C. The mixture is stirred overnight, diluted with ether, washed with a 1N hydrochloric acid solution until the aqueous phase is at acid pH, and then washed with a saturated sodium hydrogen carbonate solution.