Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:13][CH2:14][C:15]([N:17]([CH:19]([S:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1)[C:20](=O)[CH:21]([CH3:23])[CH3:22])[CH3:18])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[CH2:6]([O:13][CH2:14][C:15]1[N:17]([CH3:18])[C:19]([S:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[C:20]([CH:21]([CH3:23])[CH3:22])[N:5]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: CC(C)C(=O)C(Sc1cc(Cl)cc(Cl)c1)N(C)C(=O)COCc1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(C)c1nc(COCc2ccccc2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
In acetic acid was dissolved 2-benzyloxy-N-[1-(3,5-dichlorophenylthio)-3-methyl-2-oxobutyl]-N-methylacetamide (20), followed by addition of ammonium acetate, and the mixture was refluxed under heating. After 1 hour, the reaction mixture was concentrated under reduced pressure, neutralized with sodium hydroxide, and then, extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-methylimidazole (17a).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30]CC2C=CC(F)=CC=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39][C:40]1[C:45]([CH:46]=O)=[C:44]([F:48])[C:43]([F:49])=[C:42]([F:50])[C:41]=1[F:51]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C@H:24]([NH:30][CH2:46][C:45]2[C:40]([F:39])=[C:41]([F:51])[C:42]([F:50])=[C:43]([F:49])[C:44]=2[F:48])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1c(F)c(F)c(F)c(F)c1F

Procedure:
In the same manner as in Example 7, 433.0 mg of the title compound was obtained as colorless oil from 591.2 mg of Referential Compound 3 and 250 μL of pentafluorobenzaldehyde.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].O=[C:19]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20]([NH2:22])=[O:21].C([BH3-])#N.[Na+]>>[NH2:22][C:20]([CH:19]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: NC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1ccccc1)C(N)=O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
React 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (preparable as described in Example 1) and 2-oxo-4-phenylbutyramide and sodium cyanoborohydride to obtain the title compound as described in Example 5.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[CH3:34][C:35]([C:38]1[S:39][C:40]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][N:52]=2)=[C:41]([C:43]2[C:44]([F:50])=[C:45]([CH:47]=[CH:48][CH:49]=2)[NH2:46])[N:42]=1)([CH3:37])[CH3:36].[F:57][C:58]1[CH:59]=[C:60]([S:64](Cl)(=[O:66])=[O:65])[CH:61]=[CH:62][CH:63]=1>>[CH3:37][C:35]([C:38]1[S:39][C:40]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][N:52]=2)=[C:41]([C:43]2[C:44]([F:50])=[C:45]([NH:46][S:64]([C:60]3[CH:61]=[CH:62][CH:63]=[C:58]([F:57])[CH:59]=3)(=[O:66])=[O:65])[CH:47]=[CH:48][CH:49]=2)[N:42]=1)([CH3:34])[CH3:36]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccncn2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.213 mmol) and 3-fluorobenzenesulfonyl chloride (124 mg, 0.639 mmol), the title compound was obtained as a solid (76 mg, 73% yield). MS (ESI): 488 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1.O1CCOCC1.[H][H].[ClH:22]>CO.[Pd]>[ClH:22].[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH2:12])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C#N)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)Cc1cccc(CN)c1

Procedure:
To a solution of (3-cyano-phenyl)-acetic acid methyl ester (18.06 g, 103 mmol) in MeOH (150 mL) and 4M HCl in dioxane (30.0 mL, 120 mmol) was added 10% palladium on carbon (2 g). The mixture was placed on a Parr shaker and was hydrogenated at 50 psi hydrogen for 24 h. The catalyst was removed via filtration through Celite® and the organic solution was concentrated in vacuo. The resulting solid was stirred in EtOAc and filtered to provide the title compound as a white solid (20.42 g). 1H NMR (400 MHz, CD3OD) δ 7.42-7.32 (m, 4H), 4.09 (s, 2H), 3.69 (s, 2H), 3.67 (s, 3H); MS 180 (M+1). mg).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:21][CH2:22][OH:23])[CH2:19][C:18](=O)[NH:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH2:21][CH2:22][OH:23])[CH2:19][CH2:18][N:17]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:16]2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2(CCO)CNC(=O)C2)cc1
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].S(Cl)([Cl:25])=O>C1C=CC=CC=1>[ClH:25].[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([Cl:1])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCN(CC(O)c2ccc(F)cc2)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(CC(Cl)c2ccc(F)cc2)CC1
Temperature: 50 °C

Procedure:
To 8.3 g of 1-ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-hydroxyethyl]piperazine hydrochloride were added 20 ml of benzene and 2.5 ml of thionyl chloride, followed by heating at 50° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, 25% aqueous ammonia solution and water were poured, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and, after removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. To the residue was poured 50 ml of 4M hydrogen chloride/ethyl acetate solution, the solution was concentrated under reduced pressure, and the resulting solid was washed with ether to give 8.1 g of 1-ethoxycarbonyl-4-[2-chloro-2-(4-fluorophenyl)ethyl]-piperazine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+].O=[C:24]([CH2:28][CH2:29][CH2:30][CH3:31])[C:25]([O-:27])=[O:26]>C(O)C.C(O)(=O)C.[Pd]>[CH2:8]([C:7]1[C:2]([NH:1][CH:24]([CH2:28][CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[N:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Reactant: CCCCC(=O)C(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
4-(5-amino-6-benzylpyrazin-2-yl)phenol (200 mg, 0.72 mmol) was mixed with 2-Ketohexanoic acid sodium salt (220 mg, 1.44 mmol) in ethanol (20 mL). Pd/C (10% Palladium in active carbon, 100 mg) was added with a few drops of acetic acid, and the reaction mixture heated to 65° C. Air was bubbled out by N2 gas, and a hydrogen balloon applied to the reaction flask. The reaction was continuously stirred for 4 hrs. After cooling down, it was filtered and the resulting solution was purified by flash chromatography (eluting solvent: 50% EtOAc in heptanes) to give the product as a yellow powder (130 mg, 46%). MS (ESI): m/z 392.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH3:13])=[O:11].S(Cl)([Cl:16])=O>>[C:10]([C:2]1[CH:3]=[CH:4][C:5]([C:7]([Cl:16])=[O:8])=[CH:6][N:1]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)[O-])cn1
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Cl)cn1

Procedure:
In step A, the carboxylic acid functionality of the appropriate 2,5-pyridinedicarboxylic acid, 2-methyl ester (1) (Nippon Kagaku Zasshi, 1967, 88, 563) is converted to its acid chloride using techniques and procedures well known and appreciated by one of ordinary skill in the art, using a reagent such as thionyl chloride, to provide the corresponding 6-carbomethoxynicotinoyl chloride (2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:11]([NH:15][C:16](=[O:19])[CH2:17]Cl)([CH3:14])[CH2:12][OH:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CC([O-])(C)C.[K+].O>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C@@:11]2([CH3:14])[NH:15][C:16](=[O:19])[CH2:17][O:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C[C@@](CO)(NC(=O)CCl)c1cc(Br)cc([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@]1(c2cc(Br)cc([N+](=O)[O-])c2)COCC(=O)N1
Temperature: 100 °C

Procedure:
N—[(R)-1-(3-Bromo-5-nitro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (4.45 g, 10.76 mmol) and KOtBu (2.414 g, 21.52 g) were suspended in 55 ml tert-butanol under N2 and heated 100° C. for 30 min. After completion water was added to the reaction and tert-butanol was removed under reduced pressure. The product was extracted with ethyl acetate from the remaining aqueous phase. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as tan solid. 1H-NMR (360 MHz, DMSO-d6): 8.88 (1H, NH), 8.35 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 4.16 (m, 1H), 4.06 (s, 2H), 3.74 (m, 1H), 1.50 (s, 3H); MS: 316 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc([N+](=O)[O-])cn1)N1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 155.4 %

Procedure:
To a solution of 5-nitropicolinic acid (CIII) (500 mg, 2.97 mmol) in DMF (15 mL) was added pyrrolidine (244 μl, 2.47 mmol) and DIPEA (1.03 mL, 5.95 mmol). The reaction was cooled at 0° C. before adding HATU (1.13 g, 2.47 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was concentrated under vacuum and then dissolved in a mixture of water and 10% iPrOH/CHCl3. The organic layer was separated and the aqueous phase was washed again with 10% iPrOH/CHCl3. The combined organic phases were washed with brine, dried over MgSO4 and evaporated to yield (5-nitropyridin-2-yl)(pyrrolidin-1-yl)methanone (CIV) as a red solid (849 mg). ESIMS found for C10H11N3O3 m/z 222.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[S-:11][C:12]#[N:13].[Na+].BrBr.O>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 15 °C
Yield: 91.8 %

Procedure:
A stirred mixture of o-nitroaniline (82.5 g.), dry sodium thiocyanate (180 g.) and acetic acid (1 liter) was treated at 11°-12° C. with a solution of bromine (96.5 g.) in acetic acid (100 ml.). The stirring was continued for a further hour at 11°-12° C. and the mixture was then allowed to warm to 15° C. and poured into water (3.5 liters). The yellow solid was filtered off, washed with water, and dissolved in acetone (1 liter). The solution was filtered and the filtrate was evaporated to give 2-nitro-4-thiocyanato-aniline (107 g.), m.p. 110°-112° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=[N:31][CH2:32][CH2:33][CH2:34][N:35](C)C.Cl.C1C=CC2N(O)N=NC=2C=1.NCCC#N>C1COCC1>[Cl:26][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[C:10]([NH:35][CH2:34][CH2:33][C:32]#[N:31])=[O:11])=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CCCN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)NCCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(3′-chlorobiphenyl-4-yl)propanoic acid (1 g, 2.66 mmol) in THF (30 ml) at room temperature was added EDC.HCl (1.020 g, 5.32 mmol) and HOBT (0.815 g, 5.32 mmol). The reaction was stirred at room temperature for 10 minutes then was added 3-aminopropionitrile (0.389 ml, 5.32 mmol) and TEA (0.742 ml, 5.32 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 2 to 4% EtOH/DCM) and gave the title compound: 1.1 g (yield: 97%). LCMS (condition B): 428.2 (M+1); retention time=1.20 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(F)c1

Procedure:
Into a 2000-mL round-bottom flask maintained with a nitrogen atmosphere, was placed a solution of methyl 3-fluoro-4-nitrobenzoate (98 g, 492.46 mmol, 1.00 equiv) in ethyl acetate:methanol=1:1 (1000 mL). Then Pd/C (10 g, 10 wt %, Degussa type) was added. The flask was fitted with a balloon of hydrogen, and the heterogeneous reaction mixture was stirred fo(16 h under a hydrogen atmosphere at 30°C. The catalyst solids were filtered off and the filtrate was concentrated under vacuum to give the deisred product methyl 4-amino-3-fluorobenzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])=O.[NH4+:16].C(O)(=O)C>[Ir].CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [NH4+]
Agent: [Ir]
Agent: O=C[O-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
826 mg (5.0 mmol) of 4′-nitroacetophenone (MW: 165.15), 946 mg (15.0 mmol) of ammonium formate (MW: 63.06) and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube, and subjected to argon-gas replacement. To this, 5 mL of dehydrated methanol and 286 μL (5.0 mmol) of acetic acid were added and stirred while heating at 60° C. for 3 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product DL-1-(4′-nitrophenyl)ethylamine. Its conversion rate was 100% based on NMR measurement, with 96% of DL-1-(4′-nitrophenyl)ethylamine, 1% of 1-(4′-nitrophenyl)ethanol, and 3% of other by-products. Since no compound in which reduction of nitro groups occurred was generated, we confirmed that reductive amination reaction was carried out in a functional-group-selective manner.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18](=[O:19])[CH2:17][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1CC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of ethyl 4-nitro-1H-pyrrole-2-carboxylate (884 mg, 4.8 mmol) in DMF (11 ml) was added NaH (60% dispersion in mineral oil, 190 mg, 4.8 mmol) at 0° C. After 5 min the reaction mixture was added to a solution of 2-bromo-1-(4-methoxy-phenyl)-ethanone (1 g, 4.4 mmol) at 0° C. and the resultant mixture was allowed to warm to room temperature. After one hour the LCMS analysis showed the presence of the desired product and the complete consumption of the bromo-ketone stating material was confirmed by TLC (EtOAc/Hexanes 1:1). An aqueous solution of HCl (1M) was then added until a white precipitate appeared. Water was added and the white solid filtrated, rinsed with water and dried in vacuo to give ethyl 1-[2-(4-methoxyphenyl)-2-oxoethyl]-4-nitro-1H-pyrrole-2-carboxylate as a white solid (1.32 g, yield 83%). 1H-NMR (400 MHz, CDCl3): δ 1.29 (t, 3H, J 7.1 Hz), 3.90 (s, 3H), 4.22 (q, 2H, J 7.2 Hz), 5.77 (s, 2H), 6.98-7.20 (m, 2H), 7.50 (d, 1H, J 1.8 Hz), 7.63 (d, 1H, J 1.8 Hz), 7.95-8.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:18][O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:18][O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]4[N:36]=[N:37][NH:38][N:25]=4)=[CH:22][C:21]=3[CH3:29])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C#N)cc(C)c1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nn[nH]n2)cc(C)c1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzonitrile (example 51) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as brown solid. MS: m/e=527.4 [M+H+].
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1CO1
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 39 %

Procedure:
A mixture of (R)-tert-butyl-dimethyl-(3-oxiranyl-propoxy)-silane (13 g, 60 mmol; prepared according to Org. Lett. (2005), 7, 3997) and 6-amino-4H-benzo[1,4]oxazin-3-one (9.9 g) in EtOH/H2O (9:1, 325 mL) was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue purified by CC (Hept/EA 1:1) to give the desired intermediate as a brown oil (8.9 g, 39% yield).
Reaction SMILES: BrCCCCCCOC1C=CC(C2C=CC(C#N)=CC=2)=CC=1.O[C:24]1[CH:25]=[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[C:28]([CH:34]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].CC(C)=O>O>[C:29]([O:31][CH2:32][CH3:33])(=[O:30])[C:28]1[CH:34]=[CH:24][CH:25]=[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)c1
Agent: N#Cc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(C(=O)OCC)c1
Yield: 90 %

Procedure:
0.08 mol (28.8 g) of 4-(6-bromohexyloxy)-4′-cyanobiphenyl, 0.08 mol (16.6 g) of diethyl 5-hydroxyisophthalate, 0.12 mol (19.2 g) of potassium carbonate anhydride and 400 ml of acetone were placed in a 1 l three-neck flask and the mixture was reacted under reflux for 24 hours by using a water bath. After the reaction solution was allowed to cool, it was poured into about 4 l of purified water to take out a precipitate, which was to be a crude subject product, by filtration and the precipitate was dried under reduced pressure (yield: 90% (37 g)). The resulting precipitate was recrystallized from acetone to obtain diethyl isophthalate carrying cyanobiphenyl through a hexyl group as a target product (yield: 73% (30 g)). The resulting compound was subjected to nuclear magnetic resonance (NMR) measurement. The results of measurement are shown below. Also, the compound was subjected to mass spectrometry, with the result that a peak corresponding to a molecular weight of 515.6 was confirmed.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([OH:12])=O)=[CH:4][C:3]=1[Cl:13].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)=[O:12])=[CH:4][C:3]=1[Cl:13]
Reactant: COc1nc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.4 %

Procedure:
A mixture of 6-amino-5-chloro-2-(methyloxy)-3-pyridinecarboxylic acid (Y. Hirokawa et al., Bioorg. Med. Chem. Lett., 1998, 12, 1551–1554, 500 mg, 2.47 mmol) and 1,1′-carbonyldiimidazole (440 mg, 2.71 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 45 min. A solution of 1,1-dimethylethyl 4-(aminomethyl)-1-piperidinecarboxylate (529 mg, 2.47 mmol) in N,N-dimethylformamide (5 ml) was added and the resulting mixture was stirred at room temperature for 5 h. The mixture was poured into water (200 ml) and extracted with ethyl acetate/toluene (2:1, 200 ml×3). The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was chromatographed on a column of silica gel eluting with methanol/dichloromethane (1:25) to give 703 mg (71%) of the title compound as a pale yellow amorphous solid.