Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:41]1([NH:47][C:48]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccccc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and phenylisocyanate (30 μl) instead of ethylisocyanate, in the same manner as Example 1-D-03, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid phenylamide was obtained, and then the PMB groups were removed according to Deprotection method 1′, to obtain the desired compound (D-28) as a yellow solid (4.2 mg, 25%).
Reaction SMILES: [S:1]1[CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4](=[O:17])[NH:3][C:2]1=[O:18].[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][NH2:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][NH:32][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]2[S:1][C:2](=[O:18])[NH:3][C:4]2=[O:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1oc(-c2ccccc2)nc1CN
Reactant: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Cl)cc2)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CNS(=O)(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4-[(Thiazolidine-2,4-dion-5-yl)methyl]benzenesulfonyl chloride (1.62 g, 5.31 mmol) in 25 mL of CH2Cl2 was cooled to 0° C. N-[(5-Methyl-2-phenyl-4-oxazolyl)methyl]amine (1.0 g, 5.31 mmol) in 10 mL of CH2Cl2 was added dropwise, followed by diisopropylethylamine(1.1 mL, 6.37 mmol) and the mixture stirred at 0° C. for 20 minutes,then at room temperature for 18 hours. The reaction mixture was diluted with 20 mL CH2Cl2, washed 3×25 mL 1N HCl, 1×25 mL 5% NaHCO3 and 2×25 mL brine, dried (MgSO4) and stripped to1.9 g of solids. The latter was flash chromatographed on silica gel using 3:40 ethyl acetate:hexane as eluant to yield 0.34 g of purified, present title product, mp 120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.CC(C1C=CC(Cl)=CC=1)=O.ClC1C=CC([C@H](O)C)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Cl)cc1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: C[C@@H](O)c1ccc(Cl)cc1
Product: C[C@H](O)c1ccc(Cl)cc1
Reaction time: 192 h
Yield: 42 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized green pea protein for the substrate (±)-1-(4-chlorophenyl)ethanol (200 mg) requires 8 days by going through bioconversion to 4-chloroacetophenone accompanying sterically selective oxidation of (R)-1-(4-chlorophenyl)ethanol to obtain 84 mg of (S)-1-(4-chlorophenyl)ethanol at a yield of 42%. Optical purity was obtained at 87% e.e.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:35])([F:34])[O:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[N+:15]([C:13]1[N:12]=[C:9]2[N:8]([CH:14]=1)[CH2:7][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([O:25][C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:34])[F:35])=[CH:33][CH:32]=3)[CH2:27][CH2:28]1)[CH2:11][O:10]2)([O-:17])=[O:16]
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 56 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(trifluoromethoxy)phenoxy)piperidine (275 mg, 1.0 mmol) as crude materials, title compound as 140 mg yellow powder was generated and yield was 56%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:12]([C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[O:11]
Reactant: COC(=O)c1sc(CO)cc1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1sc(C=O)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
DMSO (0.643 ml, 9.06 mmol) in 4 mL of DCM at −70° C. was added dropwise to a solution of oxalyl chloride (0.529 ml, 6.04 mmol) in 10 mL of DCM at −78° C. and stirred for 10 min. Then 169 (0.75 g, 3.02 mmol) in 4 mL of DCM and TEA in 4 ml, DCM were added dropwise, stirred for an additional 10 min and warmed up slowly to 0° C. The reaction mixture was poured into an ice-cooled solution of NaHCO3 (ss) and extract the product with DCM, washed with brine, dried over sodium sulfate, filtered, concentrated under vacuum to yield compound 172 (706 mg, 95%) as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=[O:15])C(O)=O)([O-:3])=[O:2].N1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]=[O:15])([O-:3])=[O:2]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCN1
Solvent: C1COCCO1
Product: O=CCc1ccccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 325.2 %

Procedure:
To a solution of 2-Nitrophenylpyruvic acid (1.3 g, 6.22 mmol) in dry dioxane 12 mL was added morpholine (1.5 ml, 17.23 mmol) and a catalytical quantity of p-TSA. Then the resulting mixture was firstly sonicated and then heated in microwave conditions at 120° C. for 30 min. Dioxane was evaporated at reduced pressure and the crude vigourously stirred in 1/1 EtOAc/H2O (10 mL) overnight. The organic layer was separated and the aqueous phase washed with EtOAc (×2). The combined organic layer was dried over Na2SO4 anhydrous and solvent was removed at reduced pressure. Finally, the crude product was purified by flash chromatography on silica (ETP to 1:1 ETP/EtOAc) to obtain the titled compound (3.34 g, yield 64%).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]([F:43])([F:42])[O:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>CN(C=O)C>[F:32][C:33]([F:42])([F:43])[O:34][C:35]1[CH:40]=[CH:39][C:38]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]2=[O:24])=[CH:37][CH:36]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OC(F)(F)F)cc1
Temperature: 120 °C
Yield: 32.8 %

Procedure:
To a solution of 3-(1,3-dioxoisoindolin-2-yl)propyl 4-methylbenzenesulfonate (3 g, 8.35 mmol) in DMF (25 mL, 3 mL/mmol) was added potassium carbonate (1.8 g, 12.5 mmol) and 4-trifluoromethoxyphenol (1.5 g, 8.35 mmol) and the reaction was heated at 120° C. for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×60 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-(3-(4-(trifluoromethoxy)phenoxy) propyl) isoindoline-1,3-dione (1 g, 33%) as a solid. Observed mass (M+1): 366.0.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[C:10]3[N:11]([C:19]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[N:21]=3)[C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:10]2[N:11]([C:19]([CH2:26][C:27]([CH3:28])([OH:29])[CH3:30])=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[N:21]=2)[C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3n3c(CC(C)(C)O)c(CC(C)C)nc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1nc2c(N)nc3ccccc3n2c1CC(C)(C)O
Yield: 77.1 %

Procedure:
The solution of 1-(4-(bis(4-methoxybenzyl)amino)-2-isobutylimidazo[1,2-a]quinoxalin-1-yl)-2-methylpropan-2-ol (15 mg, 0.027 mmol) in 1 mL of trifluoroacetic acid was stirred at 70° C. for 6 hours. The solvent was removed under reduced pressure. And then 10 mL of saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with 70 mL of ethyl acetate. The organic layer was separated and then washed with water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by preparative TLC sheet (ethyl acetate and hexanes) to give the titled compound (6.5 mg, 77%). MS: MH+=313. 1H NMR (300 MHz, CDCl3): δ 8.41 (dd, 1H), 7.64 (dd, 1H), 7.25-7.41 (m, 2H), 5.63 (brs, 2H), 3.51 (s, 2H), 2.64 (d, 2H), 2.21 (m, 1H), 1.37 (s, 6H), 0.95 (d, 6H).
Reaction SMILES: O=[C:2]([C:14]1[S:18][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].O.NN>C(O)COCCOCCO>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:14]2[S:18][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CCCCc1ccc(C(=O)CCCCCc2ccccc2)s1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: O=C(O)CCCCc1ccc(CCCCCCc2ccccc2)s1

Procedure:
This compound is prepared analogously to Example 1b from: 22.8 g of methyl 5-[5-(1-oxo-6-phenylhexyl)-thien-2-yl]-valerate, 11.1 g of potassium hydroxide, 250 ml of triethylene glycol and 7.0 g of hydrazine hydrate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][C:9](=[O:13])O[C:11]=1[CH3:12])=[O:5])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(NC1C=CC=CC=1)(=O)C.C(NC1C=CC(C(=O)C)=CC=1)(=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[CH:8][C:9](=[O:13])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1c(C)cc(=O)oc1C
Agent: CC(=O)Nc1ccc(C(C)=O)cc1
Agent: CC(=O)Nc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cc(=O)n(-c2ccccc2)c1C
Reaction time: 5 h
Yield: 32.6 %

Procedure:
A mixture of 4,6-dimethyl-2-oxo-2H-pyran-5-carboxylic acid ethyl ester (=ethyl isodehydroacetate, 1.967 g, 10.02 mmol), aniline (1.865 g, 20.03 mmol) and acetic acid (0.5 mL, 9 mmol) was shaken at 90 C for 5 hours, then at 55° C. for 3 days. The excess of volatiles were removed in vacuo (0.1 mbar, 70 C, 30 min). It was transferred on to a SiO2 column (50 g) with 1,2-dichloroethane/heptane 1:3 purified by flash chromatography with gradient 20% to 100% of ethyl acetate in heptane. The pure fractions gave 906 mg of the title compound as pale yellow oil, yield 33% (non-pure additional fractions gave 886 mg of the title compound contaminated with acetanilide and 4′-acetamidoacetophenone). LC-MS (m/z) 272.4 (MH+); tR=1.07. 1H NMR (600 MHz, DMSO-d6): 1.28 (t, J=7.1 Hz, 3H, Me of Et), 1.9 (s, 3H, 2-Me), 2.16 (d, J=0.9 Hz, 3H, 4-Me), 4.28 (q, J=7.1 Hz, 2H, CH2 of Et), 6.3 (s, 1H, 5-H), 7.27 (dm, J=7.7 Hz, J<1.5 Hz, 2H, two ortho-H of Ph), 7.47 (tt, J=7.4 Hz, J=1.2 Hz, 1H, para-H of Ph), 7.53 (tm, J=7.5 Hz, J<1.7 Hz, 2H, two meta-H of Ph).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1>ClCCl>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([Cl:32])([Cl:33])[Cl:34])=[O:28])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(CCCCCCCCCO)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCC(=O)OCC(Cl)(Cl)Cl
Yield: 69.8 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (1.00 g; 4.3 mmol), the product from 12a (1.37 g; 4.3 mmol), N,N′-dicyclohexylcarbodiimide (DCC, 1.03 g; 5.0 mmol), and pyridine (2.0 mL) in dichloromethane (40 mL) using Procedure E. The crude product was purified on a 100×50 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2), collecting 16×50 mL fractions. From evaporation of fractions 4-9 gave 1.6 g (71%) product was obtained (yellowish oil).
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].C([C@H]1N([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)C2C(=CC(F)=CC=2)NC1=O)C>CCOCC>[CH2:1]([C@@H:3]1[N:12]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2]
Reactant: CC[C@@H]1Nc2cc(F)ccc2NC1=O
Reactant: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: CC[C@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Yield: 82 %

Procedure:
(3S)-3-Ethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one in ether was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (82%). MS (ESI) m/z 329 ([M+H]+); MS (ESI) m/z 327 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>O>[C:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccnc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cccnc2)cc1

Procedure:
To a solution of 23.7 g. of 3-aminopyridine in 400 ml. of pyridine is added 55 g. of 4-acetylbenzenesulfonyl chloride and the resulting solution is stirred at room temperature for 24 hours. The solution is poured into 1 l. of water and the mixture is cooled to 0°-5° C. The precipitate of 4-acetyl-N-(3-pyridyl)benzenesulfonamide is collected by filtration, washed with water and dried; m.p. 182°-183° after crystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)CC.[CH:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH3:40][C:39]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C@H:11]([N:18]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]3[CH3:29])=[O:7])=[CH:30][CH:31]=2)[C:42]([CH3:41])=[CH:37][CH:38]=1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Reactant: c1ccccc1
Solvent: CCC(=O)O
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(-n3c(C)ccc3C)cc2)c2ccccc21
Temperature: 25 °C
Yield: 80 %

Procedure:
(±)-Cis-N-{1-[4-(2,5-dimethyl-pyrrol-1-yl)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. A solution of (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (150 mg, 0.36 mmol), and propionic acid (0.5 ml) in dry benzene (20 ml) was heated at reflux under argon in a flask equipped with a Dean-Stark trap while stirring with the exclusion of light. The resulting solution was cooled to room temperature, and concentrated under vacuum. Recovered oil was purified by silica gel chromatography, eluting with hexane-ethyl acetate (3:1) to give the title compound (140 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40]O)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:64].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH2:40][Br:64])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:42][CH3:43])=[O:5])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CBr)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 3 h
Yield: 62.6 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (1 g) is dissolved in methylene chloride (20 ml), then thereto are added triphenylphosphine (855 mg) and carbon tetrabromide (1.35 g), and the mixture is stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→4:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(bromomethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (690 mg). MS (m/z): 676/678 [M+H]+
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH3:26])[C@H:19]([CH2:24][OH:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([N:18]([CH3:26])[C@@H:19]([C@@H:20]([CH3:21])[CH2:22][CH3:23])[CH:24]=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H](C)[C@@H](CO)N(C)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](C=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a stirred solution of 36 ml oxalyl chloride (0.42 mol; Fluka) in 1100 ml dichloromethane were added at −70° C. a solution of 44 ml dimethyl sulfoxide (0.62 mol) in 800 ml dichloromethane over 0.5 h. After stirring at −700 for 15 min a solution of 77.5 g N-benzyl-N-methyl-isoleucinol (0.35 mol) in 700 ml dichloromethane was added at −70° C. over ˜0.5 h and stirring was continued for 15 min. After the addition of 234 ml triethylamine (1.68 mol) at −65° C. stirring was continued for 5 min and the white suspension stirred at −50° C. for 1 h. The dry ice-bath was removed and 3000 ml deionized water was added drop wise and under stirring while the reaction mixture was warmed up to RT. The organic layer was washed twice with 2000 ml 10% brine and the organic layer was dried (Na2SO4). Removal of the solvent by rotary evaporation (40° C./≧10 mbar/0.1 mbar, 2 h) yielded 76.9 g (100.2%) yellow oily product which was used without purification in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:12][C:13]1[N:14]=[N:15][C:16]([C:7]2[CH:8]=[C:3]([CH:4]=[CH:5][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc(Cl)nn2)c1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
Nitrogen gas was bubbled through a mixture of 3-cyanophenyl boronic acid (90.0 g, 612 mmol), 3,6-dichloropyridazine (1.2 eq, 109.4 g, 735 mmol), potassium carbonate (3.0 eq, 253.5 g, 1.836 mol) in 1,4-dioxane (900 mL) and water (360 mL) for 15 minutes. After such time dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.06 eq, 26.8 g, 36.7 mmol) was added. Nitrogen bubbled through for further 10 mins then the mixture was heated to 90° C. for 3 hours. The reaction was cooled and the most of the 1,4-dioxane was removed under vacuo. The mixture taken up in dichloromethane and washed with water three times. The organic layer was concentrated and the residue was purified by column chromatography to return the title compound (60 g, 45.5% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.58˜8.59 (m, 1H), 8.44˜8.52 (m, 2H), 8.09˜8.12 (d, 1H), 8.02˜8.05 (d, 1H), 7.76˜7.81 (m, 1H); MS (m/z) 216.1 (M++1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[CH:37][N:36]=[C:35]([CH3:39])[N:34]=4)[CH:28]=3)[CH2:24][C:23](=[O:40])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1nccc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (77 mg, 0.3 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (112 mg, 0.36 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (59 mg).