Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:25].C(=O)(O)[O-].[Na+]>O>[Cl:25][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Clc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 60 °C
Yield: 63 %

Procedure:
A mixture of 5,6-diphenylfuro[2,3-d]pyrimidin-4(3H)-one (3 g) and POCl3 (30 mL) was heated at 55-65° C. for 3 h. Water was then added followed by sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (95:5) to give the title compound as a white solid (2 g, 63%). 1H NMR (300 MHz, CDCl3): δ 8.77 (s, 1H), 7.61-7.58 (m, 2H), 7.52-7.46 (m, 5H), 7.35-7.32 (m, 3H). LC-MS (ESI) m/z 307.0 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([OH:29])[CH3:28].N(C(OCC)=O)=NC(OCC)=O.[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([N:52]2[CH:56]=[N:55][C:54]([NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:53]2)=[CH:49][C:50]=1O)=[O:45]>C1COCC1.CN(C=O)C>[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([N:52]2[CH:56]=[N:55][C:54]([NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:53]2)=[CH:49][C:50]=1[O:29][CH:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH3:28])=[O:45]
Reactant: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1O
Reactant: CC(O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
Triphenyl phosphine (124 mg, 0.47 mmol, 1.5 Eq.) was added to a stirred solution of 1-(2-Chloro-phenyl)-ethanol (74 mg, 0.47 mmol, 1.5 Eq.) in anhydrous THF (5 mL) at 0° C. under nitrogen. The reaction was stirred at this temperature for 30 minutes, then diethyl azodicarboxylate (75 μL, 0.47 mmol, 1.5 Eq.) was added dropwise and the reaction stirred at 0° C. for a further 1 hour. 3-Hydroxy-5-(3-phenylamino-[1,2,4]triazol-1-yl)-thiophene-2-carboxylic acid methyl ester (100 mg, 0.32 mmol, 1.0 Eq.) in anhydrous DMF (2 mL) was added and the reaction stirred for a further 1 hour at 0° C. then allowed to warm to ambient temperature overnight. The crude reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (2×20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (88 mg, 0.19 mmol, 73%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.93 (3H, s), 5.84 (1H, q), 6.70 (1 h, br s), 6.74 (1H, s), 7.02 (1H, t), 7.21-7.40 (5H, m), 7.51 (1H, d), 7.63 (1H, d), 8.12 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=S)[NH:7][CH:8]=1.ClCC(O)=[O:14].Cl>O>[CH3:1][O:2][C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:14])[NH:7][CH:8]=1
Reactant: O=C(O)CCl
Reactant: COc1c[nH]c(=S)[nH]c1=O
Agent: Cl
Solvent: O
Product: COc1c[nH]c(=O)[nH]c1=O
Yield: 93.5 %

Procedure:
A mixture of 5-(methoxy)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (21.5 g; 0.137 moles), chloroacetic acid (21.5 g; 0.227 moles), and water (585 mL) was refluxed for 2 h. Concentrated HCl (85 mL) was added and the mixture was then refluxed for 16 h. Upon cooling, a solid formed and was collected by filtration, washed with water and dried to yield the desired product (18.2 g; 94% yield). MS: (M+H)+=143.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:4]([N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)[C:3](=[O:10])[C:2]([CH3:12])([CH3:11])[CH3:1])=[CH:16][CH:15]=1
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Yield: 12.1 %

Procedure:
167 g (1 mol) of 3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one and 140.5 g (1 mol) of 4-chlorobenzaldehyde were dissolved in 700 ml of toluene and 1.2 g (0.02 mol) of glacial acetic acid and 1.8 ml (0.02 mol) of piperidine were added. The reaction mixture was heated for 40 hours to 120° C., while continuously separating off the water of reaction. Thereafter the reaction mixture was concentrated in vacuo and the oil which remained was distilled (boiling range 130°-160° C./0.04 mm Hg). The distillate was stirred with ethanol, whereupon crystals separated out. These were filtered off and dried. 35 g (12% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (E isomer) of melting point 110° C. were thus obtained.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33](O)=[O:34])=[CH:23][N:22]=1>>[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:23][N:22]=1
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1ncc(C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c(-c2ccccc2)n1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-4-phenyl-pyrimidine-5-carboxylic acid. LC-MS (basic): tR=1.19 min; [M+H]+=473.2.
Reaction SMILES: O.[NH2:2]N.C[N:5](/[CH:7]=[N:8]/[C:9]([C:11]1[C:19]2[N:18]=[C:17]([CH3:20])[N:16]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:14]=[C:13]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:12]=1)=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:20][C:17]1[N:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:14]=[C:13]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:12]=[C:11]([C:9]3[N:8]=[CH:7][NH:5][N:2]=3)[C:19]=2[N:18]=1
Reactant: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Hydrazine hydrate (3 mL) was added to a solution of N-[(1E)-(dimethylamino)methylidene]-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide (130 mg, 0.29 mmol) in acetic acid (10 mL) and stirred at 130° C. for 30 min. The reaction mixture was cooled to rt and poured into saturated Na2CO3 solution (20 mL). A filtration was performed, and the filter cake was purified by silica gel chromatography eluted with EtOAc to give the product (88 mg, 72%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.50 (s, 3H), 3.09 (s, 4H), 3.71 (s, 4H), 6.06 (s, 2H), 6.37 (d, 1H, J=7.8 Hz), 7.20 (s, 1H), 7.34 (t, 1H, J=7.8 Hz), 7.54 (s, 1H), 7.61-7.72 (m, 2H), 7.86 (d, 1H, J=8.4 Hz), 8.02 (d, 1H, J=7.8 Hz), 8.09 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 13.85 (s, 1H); LC-MS: m/e=425 [M+1]+
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].C(ON1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2C1=O)(=[O:11])C.[O:24]=O>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:17]([OH:24])(=[O:18])[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:15]=1.[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:11])[CH3:2]
Reactant: CC(=O)ON1C(=O)c2ccccc2C1=O
Reactant: CCc1ccccc1
Reactant: O=O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccccc1
Product: O=C(O)c1ccccc1

Procedure:
A mixture of 1.062 g (10 mmol) of ethylbenzene, 0.205 g (1 mmol) of N-acetoxyphthalimide, 0.025 g (0.1 mmol) of cobalt(II) acetate tetrahydrate, 0.025 g (0.1 mmol) of manganese(II) acetate tetrahydrate and 15 ml of acetic acid was stirred at 100° C. in an atmosphere of oxygen gas (1 atm=0.1 MPa) for 8 hours and thereby yielded benzoic acid and acetophenone in yields of 86% and 5% (analyzed by gas chromatography), respectively, with a conversion from ethylbenzene of 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[CH2:29][CH2:28][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][NH:18][C:17]3=[O:27])[CH2:15][CH2:14]1)[CH2:7]2.[CH2:30](Br)[CH3:31]>>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[CH2:29][CH2:28][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:18]([CH2:30][CH3:31])[C:17]3=[O:27])[CH2:15][CH2:14]1)[CH2:7]2
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCc3c(Cl)ccc(Cl)c3C1)CC2
Reactant: CCBr
Product: CCN1CN(c2ccccc2)C2(CCN(C3CCc4c(Cl)ccc(Cl)c4C3)CC2)C1=O
Product: Cl

Procedure:
The title compound, m.p.>250° C. and MS: m/e=458.3, 460.3 (M+H+) was prepared in accordance with general method of example 4 from 8-(5,8-dichloro-1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and ethyl bromide.
Reaction SMILES: [CH:1]([C:4]1[C:5](Cl)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([Cl:14])=[C:9]([Cl:15])[CH:8]=2)([CH3:3])[CH3:2].[CH3:17][C:18]1[N:19]=[C:20]([SH:23])[S:21][CH:22]=1.C(=O)([O-])[O-:25].[K+].[K+].C1C=C(Cl)C=C(C(OO)=O)C=1>CN(C=O)C>[Cl:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[Cl:14])[N:13]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([S:23]([C:20]1[S:21][CH:22]=[C:18]([CH3:17])[N:19]=1)=[O:25])=[N:6]2
Reactant: O=C([O-])[O-]
Reactant: Cc1csc(S)n1
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(S(=O)c2nc3cc(Cl)c(Cl)cc3nc2C(C)C)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-isopropyl-2,6,7-trichloroquinoxaline (100 mg, 0.364 mmol) in DMF (3 ml) was added 4-methylthiazole-2-thiol (45 mg, 0.38 mmol) followed by potassium carbonate (106 mg, 0.728 mmol). After stirring at room temperature for 5 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate one more time. The combined organic layers were concentrated to dryness. This residue was dissolved in dichloromethane (3 ml). To this solution was added mCPBA (157 mg, 0.73 mmol, 79% pure). The reaction mixture was stirred overnight at room temperature. The reaction was quenched by addition of a saturated solution of sodium bicarbonate. After separating the layers, the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and concentrated under reduced pressure yielding a white solid. This solid was further purified by column chromatography affording two components as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:48]=[CH:47][C:10]([CH2:11][N:12]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:13]2[N:18]=[C:17]([C:19]3[C:20]([NH:28][C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:21][CH:22]=[C:23]([C:25]([CH3:27])=[CH2:26])[CH:24]=3)[N:16]=[C:15]([CH3:37])[N:14]=2)=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:1]([C:25]([C:23]1[CH:24]=[C:19]([C:17]2[N:16]=[C:15]([CH3:37])[N:14]=[C:13]([N:12]([CH2:11][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:48][CH:47]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:18]=2)[C:20]([NH:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[N:21][CH:22]=1)([CH3:27])[CH3:26])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(C)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N=[N+]=[N-])cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A slurry of sodium azide (0.075 g, 1.160 mmol) and N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(prop-1-en-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.171 g, 0.290 mmol) in CHCl3 (1 mL) at −15° C. was treated with a solution of trifluoroacetic acid (0.223 mL, 2.90 mmol) in CHCl3 (1 mL) added via syringe over 10 min. The cooling reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction was sealed and heated at 60° C. After 2 h, the reaction was poured onto ice and basified with 10 N NaOH. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-(2-azidopropan-2-yl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.184 g, 0.291 mmol, 100% yield). m/z (ESI, +ve ion) 633 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.67 (br. s., 1H); 8.90 (d, J=2.7 Hz, 1H); 8.38 (d, J=2.5 Hz, 1H); 8.26 (d, J=2.5 Hz, 1H); 7.91 (dd, J=8.8, 2.7 Hz, 1H); 7.18-7.26 (m, 4H); 6.81-6.94 (m, 4H); 6.73 (d, J=8.8 Hz, 1H); 4.90 (s, 2H); 4.81 (s, 2H); 3.94 (s, 3H); 3.82 (s, 3H); 3.78 (s, 3H); 2.59 (s, 3H); 1.64 (s, 6H).
Reaction SMILES: O=[C:2]([CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:2]([CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:18][CH:17]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)C(=O)CCCCCCC(=O)O
Product: CC(C)C(CCCCCCC(=O)O)NCc1ccc(F)cc1

Procedure:
Using the procedure exemplified in example I step D and starting from 8-oxo 9-methyl decanoic acid and para-fluorobenzylamine, dl 8-(para fluorobenzylamino) 9-methyl decanoic acid is obtained.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:31]#[N:32])[CH:28]=5)[C:23]4=[O:33])=[CH:20][N:19]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(Cl)Cl.CO>[NH2:32][CH2:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:33])[N:22]([C:21]1[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=4)[N:14]=3)[N:19]([C:34]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:20]=1)[CH2:30]2
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cc(C#N)ccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cc(CN)ccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]-1-oxo-isoindoline-5-carbonitrile (111 mg, 0.1586 mmol) dissolved in a mixture of DCM (10 mL) and MeOH (5 mL) under N2. CoCl2 (41.18 mg, 0.3172 mmol) added and resulting green solution cooled in an ice bath. NaBH4 (60 mg, 1.586 mmol) added in one portion and the ice bath removed. After 2 h reaction re-cooled in an ice bath and water (˜5 mL) added. Mixture diluted with DCM (˜20 mL) and stirred vigorously for 20 mins. Layers separated and aqueous extracted with DCM. Aqueous phase basified by addition of sat NaHCO3 solution and extracted with DCM (×2). Combined organics dried and concentrated to give the title compound as a yellow solid 88% pure by UV (112 mg, 82%); MS (ES+) 704.0.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:56](O)=[O:57])[C@H:52]([CH2:54][CH3:55])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:56](=[O:57])[C@H:51]([C@H:52]([CH2:54][CH3:55])[CH3:53])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:34])([CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 292 mg of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane (Example 2d) and 165 μl (1.5 mmol) of NMM in 4.8 ml of DMF are added to 113 mg of N-methoxycarbonyl-(L)-iso-leucine and 149 mg (0.50 mmol) of TPTU in 2.5 ml of DMF, and the mixture is stirred at room temperature for 14 hours and worked up analogously to Example 3, yielding the title compound: m.p: 139-141° C.; TLC: Rf =0.7 (methylene chloride/methanol 10:1); HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =711.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[NH3:10]>O>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:10].[NH4+:1].[NH3:1]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: N
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Product: [NH4+]

Procedure:
An ammonium aspartate solution is prepared in a reactor with a capacity of 2 liters by suspending 133.1 g (1 mol) of aspartic acid in 500 g of water with stirring and adding 68 g (1 mol) of 25% strength aqueous ammonia solution. The resulting clear solution corresponds to the composition of an ammonium aspartate solution as produced by enzymatic addition of ammonia onto fumaric acid after removal (stripping) of excess ammonia. 98 g of concentrated sulfuric acid are added to the solution over the course of 30 minutes, during which the aspartic acid precipitates. The complete suspension is evaporated to dryness under water pump vacuum while stirring at 130° C., and the thick melt remaining as residue is polycondensed for 4 hours under water pump vacuum at 180° C. to form a foam. The solidified foam is broken up at intervals to produce powder particles 0.1-5 mm in size. After cooling, the polycondensate is taken up in 2 liters of water. The residue is filtered off and washed with water and dried at 70° C. The yield of polyaspartimide is 96.6 g (99.6% of theory). The K value of the sodium polyaspartate is 35.9.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[F:14][C:15]([F:24])([F:25])[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:21][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:13])=[O:8])=[CH:22][CH:23]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 6.5 g (0.03 mole) of 2,6-dichloro-benzoylisocyanate in 20 ml of toluene was added to 5.4 g (0.03 mole) of 4-trifluoromethoxy-aniline dissolved in 80 ml of toluene at 60° C. The batch was stirred for two hours at 80° C, a part of the solvent was distilled off in vacuo and the product which had precipitated was filtered off. After drying, 10 g (84.5% of theory) of analytically pure N-(4-trifluoromethoxyphenyl)-N'-(2,6-dichlorobenzoyl)-urea of melting point 202° C were obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([CH2:18][NH2:19])[CH2:17][CH2:16]1.O>C(O)C>[CH:15]1([CH2:18][NH:19][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:17][CH2:16]1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CC1
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Following general procedure 2B: To a solution of N-(4-fluoro-3-nitrophenyl)acetamide (15.4 g, 77.7 mmol) in 80% aqueous ethanol (150 mL) was added cyclopropanemethylamine (10 mL) at room temperature. The reaction mixture was heated to reflux overnight. After cooling to room temperature, H2O (300 mL) was added and the desired product precipitated out as an orange solid (18 g, 92%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[N:23]([CH3:31])[C:22]2=[O:32]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:28][CH2:29]1)[N:23]([CH3:31])[C:22]2=[O:32]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: CN1C(=O)c2cccc(Cl)c2C12CCNCC2
Product: CN1C(=O)c2cccc(Cl)c2C12CCN(C(=O)CCc1ccccc1C(F)(F)F)CC2

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 7-chloro-2-methylspiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1 tR=1.77, min, m/z=453, 451
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][OH:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][O:33][C:41](=[O:43])[CH3:42])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)cc1OCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CC(=O)NC(COC(C)=O)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of ethyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.227 g, 0.5 mmol) and absolute triethylamine (0.126 ml, 0.9 mmol) in absolute chloroform (3 ml), a solution of acetyl chloride (0.063 ml, 0.9 mmol) in absolute chloroform (1 ml) is added dropwise. After 4 days' stirring at ambient temperature the mixture is diluted with chloroform, washed with dilute aqueous sodium bicarbonate solution, the chloroform solution is dried and filtered and evaporated down in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone=4/1).