Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[C:9]([C:16]#[N:17])[CH:8]=2)[CH:2]=1.[N:18]1C=CC=C(C2N3C(CCCC3)=CC=2C#N)[CH:19]=1.S(Cl)(N=C=O)(=O)=O>>[C:19]([C:8]1[C:9]([C:16]#[N:17])=[C:10]2[N:15]([C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:14][CH2:13][CH2:12][CH2:11]2)#[N:18]
Reactant: N#Cc1cc(-c2cccnc2)n2c1CCCC2
Reactant: N#Cc1cc2n(c1-c1cccnc1)CCCC2
Agent: O=C=NS(=O)(=O)Cl
Product: N#Cc1c(C#N)c(-c2cccnc2)n2c1CCCC2

Procedure:
2-Cyano-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile is prepared according to the same method described in Example 15, from 19.3 g of a mixture of approximately 35 mol % of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 65 mol % of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-2-carbonitrile and from 36.6 g of sulphonyl isocyanate chloride. 2.8 g of 2-cyano-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of a white solid melting at 178° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 66.6 %

Procedure:
3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester (33 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylic acid (41 mg), 3-amino-propionic acid methyl ester (35 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 495. 1H NMR (DMSO-d6, 400 MHz): δ 8.53 (t, 1H), 8.12 (br, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.42 (m, 2H), 7.48 (d, 1H), 7.38 (d, 1H), 3.65 (s, 3H), 3.62 (s, 3H), 3.04 (m, 2H), and 2.62 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[C:5]1[C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])(O)[CH2:14][CH2:13][CH2:12][N:6]12.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)=[C:5]1[CH:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13][CH2:12][N:6]12
Reactant: COC(=O)CC1(O)CCCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)CC1CCCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Yield: 45.6 %

Procedure:
To a solution of the alcohol of Step 5 (70 mg, 0.1 mmol) in CH2Cl2 (2 mL) at r.t. was added 0.25 mL of trifluoroacetic acid and 0.1 mL of triethylsilane. The reaction mixture was stirred at r.t. for 4 hours Water was added, the phases were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The residue was swished in EtOAc to provide 22 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:47])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]1=[O:46])[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([C@@:4]1([CH3:47])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][OH:26])[C:5]1=[O:46])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1004 g (1.47 mol) of (3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 185, Step E) in THF (3.0 L) was added 2.50 L (2.50 mol) of a 1 M solution of TBAF in THF over a 10 min period. The orange solution was stirred at room temperature for 4 h. The reaction was quenched with 1 N HCl (3 L) and extracted with EtOAc (3×). The combined organic layers were washed with a 3:1 mixture of water and saturated aqueous sodium chloride (4×) and then saturated aqueous sodium chloride (1×). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 10 to 50% EtOAc/hexanes, where the EtOAc contains 2% MeCN, gradient elution) provided the title compound as a white foam.
Reaction SMILES: [CH2:1]1[CH2:16][O:15][C:3]2([CH2:12][CH2:11][CH2:10][C:9]3[C:4]2([CH3:14])[CH2:5][CH2:6][C:7](=[O:13])[CH:8]=3)[O:2]1.C[O-].[Na+].[CH:20](OC)=[O:21]>C1COCC1>[CH2:16]1[CH2:1][O:2][C:3]2([CH2:12][CH2:11][CH2:10][C:9]3[C:4]2([CH3:14])[CH2:5][C:6](=[CH:20][OH:21])[C:7](=[O:13])[CH:8]=3)[O:15]1
Reactant: COC=O
Reactant: CC12CCC(=O)C=C1CCCC21OCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC12CC(=CO)C(=O)C=C1CCCC21OCCO1
Reaction time: 0.5 h
Yield: 26103 %

Procedure:
A solution of 201 (20 g, 0.090 mmol) in THF (200 mL) was cooled to −5° C. in an ice/methanol bath. NaOMe (19.45 g, 0.360 mol) was added and the mixture stirred for 30 minutes. After slow addition of a cooled solution of methyl formate (55.5 mL, 0.900 mol) in 60 mL THF, the mixture was stirred at room temperature for 24 hours. The mixture was poured into ice-water-HCl (˜50 mL conc. HCl in 500 mL H2O), stirred for 5 minutes and then transferred to a separatory funnel. The aqueous layer was extracted with ether (3×100 mL) and the pooled organic extracts were washed with brine, dried (MgSO4), and concentrated. The yellow residue was flash chromatographed (0-50% EtOAc-hexanes) to yield 203 (5.88 g, 26%) as a yellow oil. 1H NMR (CDCl3) δ 1.22 (s, 3H), 1.6-1.9 (m, 4H), 2.02 (d, J=14 Hz, 1H), 2.2-2.5 (2H), 2.91 (d, J=14 Hz, 1H), 3.9-4.1 (m, 4H), 5.86 (d, J=2.0 Hz, 1H), 7.37 (s, 1H); 13C NMR (CDCl3) 188.72, 166.86, 165.35, 165.12, 124.59, 124.25, 111.92, 106.39, 65.33, 65.17, 65.04, 64.89, 46.00, 29.87, 21.33, 20.74, 20.59.
Reaction SMILES: C[N:2]([C:24](OCC1C=CC=CC=1)=O)[N:3]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)C(OCC1C=CC=CC=1)=O.C(Cl)Cl.[OH:37][CH:38]([C:41]([Cl:44])([Cl:43])[Cl:42])[CH2:39][NH2:40].[BrH:45]>C(O)(=O)C.O>[BrH:45].[OH:37][CH:38]([C:41]([Cl:44])([Cl:43])[Cl:42])[CH2:39][NH:40][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:3][NH:2][CH3:24])=[CH:23][CH:22]=1
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: NCC(O)C(Cl)(Cl)Cl
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CNNCc1ccc(C(=O)NCC(O)C(Cl)(Cl)Cl)cc1
Reaction time: 0.5 h

Procedure:
15.8 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)methyl]-benzoyl chloride were dissolved in 50 ml. of methylene chloride. This solution was added, while stirring, dropwise to a suspension of 12.6 g. of 2-hydroxy-3,3,3-trichloro-propylamine in 150 ml. of methylene chloride. Stirring was continued for 2 hours at room temperature and 30 minutes at 40°, whereupon 50 ml. of water were added thereto. The product was worked up according to Example 3 and treated with hydrogen bromide in glacial acetic acid. The crystalline crude material was recrystallized from ethanol/acetonitrile/ether, yielding 4-[(2-methylhydrazino)-methyl]-benzoic acid [2-hydroxy-3,3,3-trichloropropyl]amide hydrobromide melting at 187°-189° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([C:19]1[C:24]([Cl:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[Cl:29])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7](=[O:8])[C:16]2[CH:17]=[CH:18][C:13]([CH2:12][C:19]3[C:20]([Cl:29])=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][C:24]=3[Cl:25])=[CH:14][CH:15]=2)=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cc2ccccc2)c(Cl)c1
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Product: O=C(c1ccc(Cc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1)c1cnc(Cl)c(Cl)c1
Yield: 28.5 %

Procedure:
The title compound was prepared as pale yellow crystals at yield of 28.5%, in a similar manner as in Reference Example 1, by the reaction of 5,6-dichloronicotinoylchloride and 4-benzyl-3,5-dichloronitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1C2C(=NC=CC=2)N(OC(N(C)C)=[N+](C)C)N=1.[NH2:66][CH2:67][C@@H:68]([OH:70])[CH3:69]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:24]=[C:23]([F:25])[C:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:66][CH2:67][C@@H:68]([OH:70])[CH3:69])=[O:20])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Reactant: C[C@H](O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)CNC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Reaction time: 18 h
Yield: 16 %

Procedure:
To a solution of 5-(2-chloro-4-fluoro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 110, 100 mg, 0.22 mmol) in DMF (3 mL) was added DIPEA (0.23 mL, 1.32 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (92 mg, 0.26 mmol). The reaction was stirred at room temperature for 10 minutes before the addition of (S)-1-aminopropan-2-ol (20 mg, 0.22 mmol) and the reaction was continued stirring for 18 hours. The reaction was diluted with EtOAc (50 mL) and extracted with water (3×5 mL) and brine (25 mL). The organic layer was collected, dried over anhydrous Na2SO4 before concentration in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-80% MeCN in water to afford the title compound (18 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl>C(O)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Agent: Cl
Solvent: CCO
Product: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 96.1 %

Procedure:
A solution of 0.5 g (1.5 mmoles) of ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 5 ml of 6.0M hydrochloric acid and 5 ml of ethanol was heated at reflux for two hours. The solvent was removed in vacuo to give 430 mg of the title compound, mp 269-271° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:24][CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]1)=[O:27]>CN(C)C=O.Cl.C(O)C.[Cu]I.N1CCC[C@H]1C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.[ClH:24]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Reactant: CN1CCc2c([nH]c3ccc(Cl)cc23)C1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)N3CCNCC3)c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.45 mmol), was dissolved in N,N-dimethylformamide. CuI (9 mg, 0.045 mmol), L-proline (11 mg, 0.091 mmol), and K3PO4 (194 mg, 0.91 mmol) was added to the reaction mixture and stirred for 10 min at room temperature, followed by drop-wise addition of tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (143 mg, 0.54 mmol) and stirred at 90° C. for 12 h. After completion of the reaction, the reaction mixture was filtered through Celite, N,N-dimethylformamide was evaporated under reduced pressure and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by Column chromatography to give Boc-protected compound (0.150 mg). The compound was dissolved in HCl in ethanol (4 mL). The ethanol was evaporated to obtain 2-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(piperazin-1-yl)ethanone as HCl salt (80 mg). 1 H NMR (CD3OD): 7.52 (s, 1H), 7.24 (d, 1H), 7.15 (dd, 1H), 5.19-5.23 (m, 2H), 4.71-4.79 (m, 2H), 4.25-4.30 (m, 2H), 3.85-4.00 (m, 4H), 3.70-3.79 (m, 2H), 3.52 (s, 3H), 3.15-3.23 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:13]([N:15](CC)CC)[CH3:14].C(Cl)(=O)C.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:13]([CH3:14])[NH:15][C:4]2=[O:6]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(=O)[nH]c(C)nc12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-3-methoxybenzoic acid (10.3 g), 4-dimethylaminopyridine (0.65 g) and triethylamine (34.3 ml) in N,N-dimethylformamide (60 ml) was added acetyl chloride (10.5 ml) at 3-15° C. for 20 minutes. Then the reaction mixture was heated at 90° C. After 3 hours, to the reaction mixture was added portionwise ammonium carbonate (17.7 g) for 10 minutes. The mixture was stirred at the same temperature for 1 hour. Cooling the mixture, water (300 ml) was added thereto. The precipitate was collected by filtration, washed with water and acetonitrile to give 8-methoxy-2-methyl-4-oxo-3,4-dihydroquinazoline (9.24 g) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([Cl:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-])=O.[NH4+]>C(O)C>[N+:10]([C:9]1[CH:8]=[CH:7][C:6]([Cl:13])=[CH:5][C:4]=1[NH2:1])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Compounds of formula I can be prepared without using the intermediate of formula II. For example, 3,4-dinitrochlorobenzene may be treated with liquid ammonium in a solvent such as ethanol to obtain 2-nitro-5-chloroaniline, which may then be treated with acetic anhydride in a solvent such as pyridine at 0°-5° C. to yield 2-nitro-5-chloroacetanilide. The 2-nitro-5-chloro acetanilide may then be converted to the corresponding 2-dialkylamino-5-chloroacetanilide by hydrogenating the nitro compound using platinum on carbon as catalyst in the presence of an aliphatic aldehyde (2:1 molar ratio to the nitro compound). The acetanilide can be hydrolyzed with a reagent such as sodium methoxide in a solvent such as methanol to give the corresponding 2-dialkylamino-5-chloroaniline. The chloroaniline can be treated with an appropriate reagent to give a 2-dialkylamino-5-substituted-aniline, e.g. the chloroaniline reacted with 1-propanethiol and sodium hydroxide in dimethylformamide/water at room temperature will yield 2-dialkylamino-5-propylthioaniline. This aniline may then be treated as the compound of formula III on page 5 to obtain a compound of formula I.
Reaction SMILES: CC(O)COC.CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(O)=O.[CH3:21][C:22]1([CH3:44])[S:26][C@@H:25]2[C@H:27]([NH:30][C:31]([C@H:33](N)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:32])[C:28](=[O:29])[N:24]2[C@H:23]1[C:41]([OH:43])=[O:42].S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].OP(O)(O)=O.[OH-].[Na+]>C(#N)C>[CH3:21][C:22]1([CH3:44])[S:26][C@@H:25]2[C@H:27]([NH:30][C:31]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:32])[C:28](=[O:29])[N:24]2[C@H:23]1[C:41]([OH:43])=[O:42]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: O=P(O)(O)O
Solvent: COCC(C)O
Solvent: CC#N
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O

Procedure:
Analisys: Concentrations of PGME, 6-APA, ampicillin and PG using HPLC. Column Waters C18: Nova-Pak, 60 Å, diameter 4 μm, 3.9×150 mm. Mobile phase: 35% acetonitrile, 2‰ SDS (sodium dodecyl sulfate), 10 mM H3PO4, 5 mM K2H2PO4, pH 4.6 and 25° C., 225 nm, flow 1 mL/min. Synthesis experiments: 25° C., pH 6.5 controlled by automatic addition of NaOH. Jacketed glass vortex flow reactor, internal cylinder of stainless steel 316. Reaction volume, 50 mL. Reactor internal diameter, 36 mm. Rotary cylinder diameter, 10 mm (radius ratio 0.28). Volume of biocatalyst, 20 mL. Enzymatic load, 10 IU/(mL of reactor).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18]>>[Cl:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Cl

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-chloro-5-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:25]1[CH:26]=[C:27]([CH2:34][OH:35])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]>C(#N)C>[OH:35][CH2:34][C:27]1[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH2:7][CH2:8]2)[CH:26]=1
Reactant: CC(C)C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N[C@H]1CC[C@@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a suspension of N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride (200 mg, 0.906 mmol) and DIPEA (0.432 mL, 2.471 mmol) in ACN (2 mL) was added (3-fluoro-4-nitrophenyl)methanol (141 mg, 0.824 mmol). The reaction was stirred overnight at 80° C. After 16 hours, the reaction mixture was concentrated and the residue purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide N-(cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)isobutyramide as an orange foam (176 mg, 63.7% yield). MS, m/z (C17H25N3O4): calcd, 335.2. found, 336.0 [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=O.[C:28]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:30][CH3:31])=[O:29]>CO>[CH3:31][O:30][C:28]([CH:32]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:26][CH:27]=1)=[O:29]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: CO
Product: COC(=O)C=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.2 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (4.77 g) is dissolved in methanol (100 ml) and thereto is added carbomethoxymethylenetriphenylphosphorane (5.3 g) and the mixture is stirred at room temperature for 1 hour. The solvent is concentrated and the residue is purified roughly by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give a mixture (8 g) of 1-{1-[4-(2-methoxycarbonylvinyl)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril and triphenylphosphineoxide.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C@H:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:7]2>[OH-].[Na+].[Al].[Ni]>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([C@H:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1Cl
Agent: [Ni]
Agent: [Al]
Agent: [Na+]
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reaction time: 2 h

Procedure:
A solution of 1 g of (S)-2-(5-chloro-6-methoxy-2-naphthyl)-propionic acid in 20 ml of 10% aqueous sodium hydroxide solution at 90° C. is treated with 3 g of a nickel-aluminum alloy in small portions. After stirring the mixture for two hours, it is filtered, diluted with excess dilute hydrochloric acid and extracted with methylene chloride. The organic phase is evaporated to dryness and the residue recrystallized from methylene chloride/hexane to yield (S)-2-(6-methoxy-2-naphthyl)propionic acid after recrystallization.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1(C)[C:14](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd]>[CH2:9]=[C:10]([C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:14]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1ccc(N)nc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 70.9 %

Procedure:
A mixture of 2 g (11.56 mmol) of 5-bromopyridin-2-amine, 2.39 mL (13.87 mmol) of 4.4.5.5-tetramethyl-2-(prop-1-en-2-yl)-1.3.2-dioxaborolane and 3.83 g (27.74 mmol) of K2CO3 in 30 mL of DME and 10 mL of water is stirred for 5 minutes under argon, followed by addition of 1 g (2.1 mmol) of palladium bis(tri-t-butylphosphine). The reaction medium is heated for 3 hours at 80° C. After cooling to room temperature, the reaction medium is taken up in 40 mL of water and extracted with EtOAc (3×30 mL). The organic phases are washed with 0.5N HCl solution (3×30 mL). The aqueous phases are neutralized with 1N sodium hydroxide solution and then extracted with EtOAc (2×50 mL). The combined organic phases are dried over Na2SO4, filtered and concentrated under reduced pressure. 1.10 g of 5-(prop-1-en-2-yl)pyridin-2-amine are obtained in the form of a yellow solid, which is used without further purification in the following step.
Reaction SMILES: C(OC(=O)C)(=O)C.C[O:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[NH2:17])=O.C([O-])=O.[NH4+].[CH:22]([NH2:24])=O>C(O)=O>[N:17]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[C:10](=[O:9])[NH:24][CH:22]=1
Reactant: COC(=O)c1sccc1N
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]cnc2ccsc12
Temperature: 25 °C
Yield: 160.2 %

Procedure:
Acetic anhydride (185 mL, 1.96 mol) and formic acid (85 mL, 2.22 mmol) were mixed and stirred. Methyl-3-aminothiophene-2-carboxylate (50 g, 0.16 mol) was added to the reaction mixture, followed by stirring for about 3 hours at room temperature. The reaction solvent was removed under reduced pressure. Separately, ammonium formate (90 g, 1.43 mol) and formamide (150 mL, 3.76 mol) were mixed and stirred for about 30 minutes. The synthesized material in the above was added to the resulting reaction solution, followed by stirring 8 hours at 150° C. The reaction solution was cooled to room temperature and stirred for about 12 hours. The generated solid was filtered, and washed with water to obtain the title compound (39 g, 81%).