Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=O)=[N:9][NH:10][CH:11]=1)=[O:5].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12]([C:8]2[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[CH:11][NH:10][N:9]=2)=[O:14])[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(Cl)cccc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2NC(=O)c2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.6 %

Procedure:
A mixture of 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid (6.5 g, 21.6 mmol), 4-amino-1-BOC-piperidine (4.76 g, 23.8 mmol), EDC (5.0 g, 25.9 mmol) and HOBt (3.5 g, 25.9 mmol) in DMF (75 ml) was stirred at room temperature for 20 hours. The reaction mixture was reduced in vacuo and the residue partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic layer was washed with brine, dried (MgSO4) and reduced in vacuo. The residue was taken up in 5% MeOH-DCM (˜30 ml). The insoluble material was collected by filtration and, washed with DCM and dried in vacuo to give 4-{[4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (5.38 g) as a white solid. The filtrate was reduced in vacuo and the residue purified by column chromatography using gradient elution 1:2 EtOAc/hexane to EtOAc to give further 4-{[4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (2.54 g) as a white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[C:19]([OH:24])(=O)[C:20](O)=[O:21].[ClH:25]>C(O)C.C(OC(=O)C)C.[Ni]>[CH:1]1([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:25])[CH:13]=3)[NH:14][C:20](=[O:21])[C:19]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1NC1CCCCC1
Reactant: Cl
Reactant: O=C(O)C(=O)O
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2ccc(Cl)cc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
3.6 g (14.1 mmol) N-cyclohexyl-2-nitroaniline was dissolved in 50 ml ethanol and 150 ml ethylacetate. The solution was hydrogenated at atm. pressure by using Ra-Ni (1 g) as a catalyst. The reaction mixture was filtered and the filtrate was evaporated to give an oil. A mixture of the oil and 3.5 g (28 mmol) oxalic acid dihydrate in 100 ml 4N hydrochloric acid was refluxed for 2 h. After cooling to 25° C. the product was filtered off and washed with water to give 3.4 g (86%) 1-cyclohexyl-7-chlorquinoxaline-2,3(1H, 4H)-dione. M.p. (DSC) 310.6° C. 1H-NMR (DMSO-d6): 12.0 (1H, broad s), 7.7 (1H, s), 7.2 (2H, s), 4.2 (1H, broad s) 2.0-1.0 (10H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:5]=[O:6].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:6]1[CH2:21][CH2:22][O:23][CH:5]1[C:4]1[CH:7]=[CH:8][C:9]([O:10][Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])=[C:2]([F:1])[CH:3]=1
Reactant: OCCO
Reactant: CC(C)[Si](Oc1ccc(C=O)cc1F)(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[Si](Oc1ccc(C2OCCO2)cc1F)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
Into a 5 L 3-neck flask equipped with a condenser and a Dean-Stark trap add 3-fluoro-4-triisopropylsilanyloxybenzaldehyde (Example 737, Part A) (90.14 g, 0.3041 mol), ethylene glycol (188.75 g, 3.041 mol), and p-toluenesulfonic acid (0.58 g, 0.003041 mol) in toluene (3.155 L). Heat to boil and reflux until 130 mL of H2O (lower layer) is collected in the Dean-Stark trap (5 hrs). Cool to room temperature, wash with 10% aqueous potassium carbonate solution (2×1 L) and brine (2×1 L), and dry over sodium sulfate. Filter and concentrate to give the crude produce.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23]C[CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.[N:26]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[C:27]=[O:28]>CN(C=O)C.[Cl-].[Na+].O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:18]([N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:21]3)[C:27]([NH:26][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C=NC1CCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To an ice cold suspension of NaH (6 mg, 160 umol) in DMF (2.5 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (50 mg, 153 umol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at 0° C. A solution of isocyanato-cyclopentane (34 mg, 306 umol; [4747-71-1]) in DMF (0.5 ml) was added within 5 min. The reaction mixture was stirred for 1 h at ambient temperature, poured onto ice water/1 N aqueous HCl solution/brine 1/1/1 and extracted two times with iPrOAc. The combined extracts were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (20 mg, 47 umol; 21%) as yellow foam. MS: m/e=423.1 [M+H+].
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[CH:25]1([C:28]2[C:29]([O:38][CH2:39][C:40]34[CH2:50][C:44]5([F:51])[CH2:45][C:46]([F:49])([CH2:48][C:42]([F:52])([CH2:43]5)[CH2:41]3)[CH2:47]4)=[CH:30][C:31]([F:37])=[C:32]([CH:36]=2)[C:33]([OH:35])=O)[CH2:27][CH2:26]1.CS(N)(=O)=O.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1>>[CH:25]1([C:28]2[C:29]([O:38][CH2:39][C:40]34[CH2:50][C:44]5([F:51])[CH2:43][C:42]([F:52])([CH2:48][C:46]([F:49])([CH2:45]5)[CH2:47]3)[CH2:41]4)=[CH:30][C:31]([F:37])=[C:32]([CH:36]=2)[C:33]([NH:64][S:61]([CH:58]2[CH2:60][CH2:59]2)(=[O:63])=[O:62])=[O:35])[CH2:26][CH2:27]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Yield: 79 %

Procedure:
Following the procedure as described in Example 150 step 5 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoic acid and to replace methyl sulfonamide with cyclopropanesulfonamide. Purification by silica gel column chromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.10 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (br s, 1H), 7.12 (d, J=8.33 Hz, 1H), 6.94 (d, J=12.86 Hz, 1H), 3.93 (s, 2H), 3.09-2.99 (m, 1H), 2.25-2.13 (m, 3H), 2.10-1.98 (m, 4H), 1.85-1.75 (m, 6H), 1.12-1.01 (m, 4H), 0.93-0.84 (m, 2H), 0.66-0.59 (m, 2H); MS (ES+) m/z 502.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:20][NH:21][OH:22].C(N(CC)CC)C.Cl>O1CCCC1.O1CCCC1.O>[CH3:20][N:21]([C:8](=[O:9])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:22]
Reactant: CNO
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C=CC(=O)N(C)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 4-methylcinnamic acid (1.62 g, 10 mmol) and oxalyl chloride (2.0 ml, 23 mmol) in 50 ml anhydrous tetrahydrofuran (THF) was stirred at reflux for two hours, then concentrated in vacuo. The residue was redissolved in 30 ml THF, and added dropwise to a solution of N-methyl-hydroxylamine hydrochloride (1.26 g, 15 mmol) and triethylamine (5.0 ml, 36 mmol) in 50 ml of 2:1 THF-water at 0° C. The mixture was stirred for one hour at 0° C., then for one hour at room temperature, and then poured into excess 5% aqueous hydrochloric acid. The resulting mixture was extracted with ethyl ether, and the ether extract washed successively with 5% aqueous hydrochloric acid and brine, dried over sodium sulfate, and evaporated. Recrystallization of the residue from ethyl acetate provided 1.48 g (77% yield) of the titled compound, mp 142°-144° C.
Reaction SMILES: [Cl-].[NH4+].CN(C(ON1N=N[C:13]2[CH:14]=[CH:15][CH:16]=[N:17][C:12]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N([CH:33]([CH3:35])C)CC)(C)C.CN(C)C=[O:39]>O>[CH:13]1([C:12]([NH2:17])=[O:39])[CH2:14][CH2:15][CH2:16][CH2:35][CH2:33]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: NC(=O)C1CCCCC1
Temperature: 65 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
cis-4-Hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (500 mg, 1.05 mmol), ammonium chloride (112 mg, 2.09 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (795 mg, 2.09 mmol), and diisopropylethylamine (730 μl, 4.18 mmol) were taken-up in dimethylformamide (4.2 mL) under argon. The vessel was sealed and stirred at 65° C. for 4 hours. Upon cooling, the reaction mixture was diluted with water, and the resulting precipitate was collected via filtration. The solids were washed with water and diethyl ether and dried in vacuo overnight to afford cis-4-hydroxy-4-[5-(3-methyl-5-{[4-Orifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide (437.6 mg, 0.916 mmol, 88% yield) as a white solid. MS ESI: [M+H]+ m/z 478.1.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[C:27](O)=[O:28].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][C:12]=1[C:27]([N:7]1[CH2:8][CH2:9][C:10]2[O:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)=[O:28]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1c2ccccc2C(=O)c2cc(C(=O)N3CCc4occc4C3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.302 g (1.2 mmol) of anthraquinone-2-carboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=2/1); the resulting solid was washed with ethyl acetate to yield the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][C:12]([C:14]3[S:18][C:17]([C:19]([NH:21][C@@H:22]([CH2:26][NH:27][C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[O:29])[C:23]([OH:25])=[O:24])=[O:20])=[C:16]([CH3:35])[CH:15]=3)=[O:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.I[CH2:37][CH:38]([CH3:40])[CH3:39].C(N(CC)CC)C.CCOC(C)=O>CN(C=O)C>[CH2:37]([O:24][C:23](=[O:25])[C@@H:22]([NH:21][C:19]([C:17]1[S:18][C:14]([C:12](=[O:13])[NH:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[N:2][NH:1]3)=[CH:15][C:16]=1[CH3:35])=[O:20])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])[CH:38]([CH3:40])[CH3:39]
Reactant: Cc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Reactant: CC(C)CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OCC(C)C
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A solution of (S)-2-({5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-methyl-thiophene-2-carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid (200 mg, 0.39 mmol), 1-Iodo-2-methylpropane (220 mg, 1.17 mmol), and triethylamine (0.16 ml, 1.17 mmol) in DMF (3 mL) was heated in a microwave at 100° C. for 30 min. The mixture was cooled to room temperature, treated with EtOAc (50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (30-100% EtOAc in hexane) to give 0.1441 g (65%) white solid. MS m/e 567.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].C(CN)O.Cl>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:16]1[NH:10][C:11](=[O:12])[NH:13][C:14]1=[O:15]
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: NCCO
Product: O=C1NC(=O)C(=Cc2ccccc2Cl)N1
Reaction time: 4.25 h

Procedure:
A mixture of o-chlorobenzaldehyde (2.50 g.) and hydantoin (1.78 g., 1 molar ratio) was treated with water (15 ml) and heated to 70°. Monoethanolamine (1.63 g., 1.5 molar ratio) was added and the mixture was stirred magnetically at 90°-92° (bath temperature) for 4.25 hours. The mixture was cooled in an ice-bath, acidified with concentrated HCl, refrigerated overnight, filtered, washed with water and dried at 55°/10 mm. The title compound was obtained as a pinkish solid (2.63 g.), m.p. 266°-270° decomp.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][C:52]1[CH:60]=[CH:59][C:55]([CH:56]([OH:58])[CH3:57])=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][C:52]([CH3:51])=[CH:53][CH:54]=2)[CH3:57])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(C)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccc(C)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 80.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (111 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methyl-α-methylbenzyl alcohol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (97 mg, yield 75%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([NH2:31])([CH3:30])[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:30][C:21]([NH:31][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:20])[CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: CC(C)(N)CCN1CCOCC1
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Product: CC(C)(CCN1CCOCC1)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and 1,1-dimethyl-3-morpholin-4-yl-propylamine as starting materials, MS (EI): 417.2 [M+H]+.
Reaction SMILES: N[C:2]1[C:3]([CH:12]([CH3:14])[CH3:13])=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:15]([O-:18])([O-])=O.[K+].[K+].[C:21]([CH2:23]OS(C1C(C)=CC=CC=1)(=O)=O)#[N:22].O>CN(C=O)C>[CH:12]([C:3]1[CH:2]=[C:7]([O:18][CH3:15])[C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[O:11][CH2:23][C:21]#[N:22])([CH3:14])[CH3:13]
Reactant: Cc1ccccc1S(=O)(=O)OCC#N
Reactant: CC(C)c1c(N)cc([N+](=O)[O-])cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c(OCC#N)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 76.1 %

Procedure:
A mixture of 3-amino-2-isopropyl-5-nitrophenol (9.94 g, 47 mmol), K2CO3 (13.00 g, 94 mmol) and toluenesulfonic acid cyanomethyl ester (10.93 g, 52 mmol) in 500 mL DMF was warmed to 50° C. After 16 h the mixture was cooled, poured into 500 mL H2O and extracted with toluene/ethyl acetate (1:1). The combined organics were washed with H2O, washed with brine, filtered and concentrated in vacuo. The crude solid was recrystallized from EtOH to afford (2-isopropyl-4-methoxy-5-nitro-phenoxy)-acetonitrile (8.95 g, 76%) as a yellow crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([OH:23])=O)[C:17]=3[CH:24]=2)[C:3]1=[O:25].C(Cl)(=O)C(Cl)=O.[Cu](C#N)C#N.[CH2:37]([Li])[CH2:38][CH2:39][CH3:40]>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:9])[F:10])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](=[O:23])[CH2:37][CH2:38][CH2:39][CH3:40])[C:17]=3[CH:24]=2)[C:3]1=[O:25]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(=O)O)c3c2)c1=O
Reactant: [Li]CCCC
Agent: N#C[Cu]C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: -78 °C
Yield: 63.9 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (0.200 g, 0.000540 mol) in methylene chloride is added N,N-dimethylformamide (one drop) followed by oxalyl chloride in methylene chloride (2.0 M, 0.540 ml, 0.00108 mol). The resultant mixture is stirred at room temperature for 90 minutes and concentrated in vacuo to a white solid, which is saved. To a suspension of copper cyanide (0.061 g, 0.000675 mol) in tetrahydrofuran, is added dropwise n-butyllithium (2.5 M in hexanes, 0.540 ml, 0.00135 mol) at -78° C. The reaction mixture is allowed to warm for 5 minutes and then cooled back to -78° C. The mixture is then treated with a solution of the white solid from the first step in tetrahydrofuran, and the resultant mixture stirred one hour at -78° C. The reaction mixture is quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic layer is washed sequentially with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a yellow syrup. Chromatography of the syrup on silica gel using hexanes:ethyl acetate gives the title compound as a colorless syrup (0.142 g, 64.0%) which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(N[C@H](C(O)=O)CCC(=O)N)=O)CC(C)C.N[C@H](C(N[C@H](C(O)=O)CCC(=O)N)=O)CC1CCCCC1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: NC(=O)CC[C@H](NC(=O)[C@@H](N)CC1CCCCC1)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
A10, Leu, Leu-Gln, or Cha-Gln;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:13])[C:11]=1[OH:12])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2.[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:13])[C:11]=1[O:12][CH2:18][CH2:19][CH2:20][Cl:21])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: ClCCCBr
Reactant: O=C1CCc2cc(Cl)c(O)c(Br)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C1CCc2cc(Cl)c(OCCCCl)c(Br)c2N1
Reaction time: 1 h

Procedure:
5 grams of 6-chloro-8-bromo-7-hydroxy-3,4-dihydrocarbostyril and 3 g of sodium hydroxide are mixed with 120 ml of isopropanol and stirred at 50°-60° C. for 1 hour. Then 10 ml of 3-bromo-1-chloropropane are added thereto and stirred at 70°-80° C. for 6 hours. The reaction mixture is concentrated under reduced pressure to dryness and the residue thus obtained is extracted with chloroform. The chloroform layer is washed with water and dried. Then chloroform is removed by distillation and the residue thus formed is recrystallized from ethanol to obtain 6.2 g of 6-chloro-8-bromo-7-(3-chloropropoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 87°-88° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>CO.O>[NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[CH3:13][OH:14].[C:17]([C@@H:15]([C@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: O
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Racemic cis-1-amino-2-indanol (66.6 g, water wet, content 81.1%) was dissolved in 390 ml of methanol with 10 ml of water. 65 g of (R,R)-tartaric acid were added in portions at 60° C. Stirring of the mixture was continued for one hour at reflux and then it was cooled down again to 20° C. The solid was isolated by filtration and washed twice with 120 ml of methanol. After drying, 56.2 g of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate were obtained with an e.e. of 97.2%.
Reaction SMILES: OC(C1CCN(CC2C=CC([N+]([O-])=O)=C(N[C@@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([OH:27])=O)[CH2:21][CH2:20]3)C=2)CC1)(C)C.C1N=C[N:33](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[CH:22]1([C:25]([NH2:33])=[O:27])[CH2:23][CH2:24][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)O)CC3)c2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132.6 %

Procedure:
To a solution of cis-4-(5-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexanecarboxylic acid (0.53 g, 1.263 mmol) in DMF (7 mL) was added CDI (0.410 g, 2.53 mmol) and aqueous ammonium hydroxide (100 μL, 2.53 mmol). The reaction was stirred overnight at RT. After 16 hours, the reaction mixture was partitioned between water and DCM and the aqueous layer was extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM, to provide cis-4-(5-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2-nitrophenylamino)cyclohexane-carboxamide as an orange foam (0.213 g, 40.3% yield). MS, m/z (C22H34FN4O4): calcd, 418.3. found, 419.1 [M+H].