Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.CCN(C(C)C)C(C)C.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C(Cl)Cl.O>[O:23]=[C:14]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]34[CH2:6][CH:5]3[CH2:4][N:3]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:2]4)=[CH:12][CH:11]=2)[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15]1
Reactant: Brc1ccccn1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(c3ccccn3)C4)cc2)C(=O)O1
Temperature: 90 °C
Yield: 69.5 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (0.4 g, 1.1 mmol) in DCM (5 mL) were added DIPEA (0.5 mL, 3.4 mmol) and 2-bromopyridine (0.9 mL, 5.7 mmol) at r.t. The reaction mixture was stirred at 90° C. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 0.2:9.8 MeOH:CHCl3) to provide the title compound (0.3 g, 67%) as white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][CH2:22][CH:23]([CH3:33])[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH2:16]1)=O)(C)(C)C.[C:34]1(CC=O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)(=O)C>[CH2:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][CH2:22][CH:23]([CH3:33])[C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:25])[CH2:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(CCC1CCCN(C(=O)OC(C)(C)C)C1)C(=O)Nc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(CCC1CCCN(Cc2ccccc2)C1)C(=O)Nc1ccccc1

Procedure:
Trifluoroacetic acid (0.38 mL, 4.99 mmol) in CH2Cl2 (0.38 mL) was added dropwise to a 0° C. stirring solution of 101 (0.115 g, 0.318 mmol) in CH2Cl2 (0.40 mL). When the reaction was judged complete by TLC, the solvent and excess trifluoroacetic acid were removed in vacuo. The crude residue was dissolved in DMF (1.54 mL, 0.18M), then phenylacetaldehyde (0.10 mL, 0.832 mmol), acetic acid (0.078 mL), and Na(OAc)3BH (0.118 g, 0.555 mmol) were added sequentially. When the reaction was judged complete by TLC, saturated aqueous K2CO3 was added. The organic layer was removed, and 5% aqueous HCl was added. The organic layer was discarded, and the aqueous layer was basified with saturated aqueous NH4OH. The organic layer was removed, dried with Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (99:1::CH2Cl2:2N NH3 in EtOH) provided (1-benzylpiperidine-3-ylethyl)-N-phenylpropionamide (103). 1H NMR (CDCl3): 7.46-7.24 (8H, m), 7.15 (2H, broad d, J=7.8 Hz), 3.72 (2H, J=7.8 Hz), 3.52 (1H, J=13.2 Hz), 3.45 (1H, d, J=13.2 Hz), 2.79 (2H, broad d, J=8.2 Hz), 2.03 (2H, q, J=7.3 Hz), 1.91 (1H, td, J=11.0, 3.3 Hz), 1.84-1.30 (7H, m), 1.05 (3H, t, J=7.4 Hz), 0.98-0.84 (1H, m) ppm. 13C NMR (CDCl3): 173.65, 142.93, 138.4, 129.83, 129.35, 128.52, 128.31, 127.95, 127.07 63.68, 60.21, 54.22, 47.34, 34.14, 32.51, 30.84, 28.04, 25.34, 9.78 ppm. LRMS: 350.95.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:9]2[C:4](=[C:5]([NH2:23])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:23][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=[C:10]3[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Cc1nc(Oc2cccc(C(F)(F)F)c2)c2cccc(N)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Oc2cccc(C(F)(F)F)c2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 13.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 2-methyl-4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-49, 150 mg, 0.47 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 200 mg, 0.71 mmol), oxalyl chloride (135 mg, 1.07 mmol), DMF (1 drop) and DIPEA (182 mg, 1.41 mmol) in CH2Cl2 (6 mL) to afford 38 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.99 (d, 1H), 8.12 (m, 2H), 7.84-7.74 (m, 4H), 7.41 (m, 2H), 4.32 (d, 2H), 2.50 (s, 3H), 1.14 (s, 9H); MS (m/z): 589.20 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@H:23]([CH2:44][C:45]4[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[C:48]([NH2:55])=[C:47]([Cl:56])[CH:46]=4)[C:24]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][N:35]([CH2:38][C:39]([O:41]CC)=[O:40])[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[O:25])=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:57]=1.[Li+].[OH-]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C@H:23]([CH2:44][C:45]4[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[C:48]([NH2:55])=[C:47]([Cl:56])[CH:46]=4)[C:24]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][N:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[O:25])=[O:21])[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:57]=1
Reactant: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5cc(OC)ccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)N3CCC(N4CCN(CC(=O)O)CC4)CC3)CC1)C(=O)N2

Procedure:
Prepared analogously to Example 15.1 from 20 mg (0.02 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxycarbonyl methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 2 mg (0.08 mmol) LiOH.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH:15][C:16](=O)OC)[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: COC(=O)NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNCC1Cc2c(Cl)cc3c(c2O1)CCC3
Yield: 29.8 %

Procedure:
Treatment of (±)-methyl (4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (0.60 g, 2.12 mmol) with lithium aluminum hydride (95 wt. %, 0.35 g, 8.75 mmol) generally according to the procedure described for Example 24 provided 0.15 g (30%) of (±)-1-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)-N-methylmethanamine as a white solid. mp 58-60° C.; Anal. calcd. for C13H16ClNO: C, 65.68; H, 6.78; N, 5.89. Found: C, 65.31; H, 6.79; N, 5.52.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:13](OCC)(OCC)(OCC)[CH3:14]>C(O)C.CN(C)C(=O)C>[CH3:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]3[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]3)=[CH:10][C:11]=2[N:12]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1cc2ccccc2cc1N
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: Cc1nc2cc3ccccc3cc2[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 4.74 g of 2,3-diaminonaphthalene in 150 ml of ethanol and 30 ml of N,N-dimethylacetamide was added 4.86 g of triethyl orthoacetate, and the mixture heated at 60° C. for 2 hours. An additional 5.5 ml of triethyl orthoacetate was added and stirring continued at 60° C. overnight. The solvent was removed and the residue treated with chloroform. The solids were filtered and the filtrate concentrated to a small volume, treated with ether and filtered. The solids were combined to give 4.07 g of the product as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].C([O-])([O-])=O.[Na+].[Na+].[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.O1CCOCC1>[CH2:17]([O:16][C:14]([NH:3][C:2]([CH3:4])([C:5]([OH:7])=[O:6])[CH3:1])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-methylalanine (50 g, 0.49 mmol) and Na2CO3 (156 g, 1.47 mol) in water (1 L) was added a solution of CbzCl (91 g, 0.54 mmol) in dioxane (500 mL) at 0° C. over 15 minutes. The resulting solution was stirred at room temperature for 18 hours. The reaction was extracted with Et2O (2×500 mL), and the aqueous layer collected, acidified to pH=1 with cHCl and extracted with EtOAc (2×500 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford a white solid as the title compound that was used directly in the next step (111 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](O)[CH2:10][C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][C:10]#[CH:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: C#CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCCOc1ccc(F)cc1

Procedure:
To a solution of 4-fluorophenol (5.00 g, 44.6 mmol), 3-butyn-1-ol (3.38 ml, 44.6 mmol) and triphenylphosphine (17.5 g, 66.9 mmol) in tetrahydrofuran (100 ml) was added diethyl azodicarboxylate (11.7 g, 66.9 mmol) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 18 hours. After stirring,the reaction mixture was evaporated in vacuo, and to the residue were added hexane (200 ml) and ethyl acetate (20 ml). The precipitate separated out was filtered off, and the filtrate was evaporated in vacuo. The residue obtained was purified by flash chromatography on a silica gel column using hexane as the eluent to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1.[Cl:49][C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][C:58]=1[Cl:59])[C:53](Cl)=[O:54]>O.CCOCC.CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1>[Cl:49][C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][C:58]=1[Cl:59])[C:53]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:54]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cc1cc(O)c(C(C)C)cc1C1(c2cc(C(C)C)c(O)cc2C)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
A solution of L-proline (30 g, 0.26 mol), thymolphthalein (5 mg), and Na2CO3 (100 g) in water (500 mL) was treated at room temperature with concentrated aqueous NaOH solution until the solution was blue to the thymolphthalein indicator. The stirred solution was cooled to about 10° C. and treated portionwise with a solution of 3,4-dichlorobenzoyl chloride (58.65 g, 0.28 mol) in ether (100 mL) with periodic addition of concentrated aqueous NaOH solution as necessary to maintain the blue color. The reaction mixture was stirred for an additional 10 min after the addition was completed and then extracted with ether (2×150 mL). The aqueous phase was acidified to pH 1 with concentrated HC1 and extracted with ethyl acetate (4×250 mL). The combined ethyl acetate solution was washed with brine (150 mL), dried (Na2SO4), and concentrated in vacuo. The solid residue was crystallized from hot ethyl acetate-petroleum ether (2:1, 300 mL) to give 60.5 g (81%) of N-(3,4-dichlorobenzoyl)proline as fine white prisms. Recrystallization from the same solvents afforded the analytical sample of N-(3,4-dichlorobenzoyl)proline.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:49])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[N:47][OH:48])=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:49])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[N:47][OH:48])([OH:7])=[O:5]
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=NO)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)O)C(=NO)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)O)C3=O)cc1)O2

Procedure:
A mixture of 370 mg of t-butyl α-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared as described in Example 55) and 4 ml of a 4N dioxane solution of hydrogen chloride was treated in the same manner described in Example 61, to give the title compound as a pale yellow powder, softening at 90°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:15](N(CC)CC)[CH3:16]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8](=[O:12])[C:9]([O:11][CH2:15][CH3:16])=[O:10])=[CH:13][CH:14]=1
Reactant: O=C(O)C(=O)C=Cc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C=Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
To the p-chlorobenzalpyruvic acid from step A in wet ethyl acetate was added triethylamine (11.1 g, 0.11 moL) at a rate less than 0.5 mL/min followed by azeotropic removal of water. Ethyl chloroformate (11.9 g, 0.11 moL) was then added at room temperature over a one hour period and the batch aged one hour to effect complete reaction. Workup followed, as in Example 1, to afford ethyl p-chlorobenzalpyruvate in 99% yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC(C([NH:18][C:19]2[CH:20]=[N:21][C:22]([OH:25])=[CH:23][CH:24]=2)=O)=CC=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:19]2[CH:20]=[N:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1ccc(O)nc1)c1ccc(F)cc1

Procedure:
Starting from 4-fluorobenzoyl chloride (1.59 g, 10.0 mmol) and using the procedure as described for the preparation of 4-Chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide yielded the title compound, which was used without further purification.
Reaction SMILES: Cl[S:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5].[CH3:8][C:9]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH:12]([C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)[CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:4]([C:3]([S:2][N:19]1[CH2:18][CH2:17][N:16]=[C:15]1[CH:12]([O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:9]=1[CH3:8])[CH2:13][CH3:14])([CH3:7])[CH3:6])#[N:5]
Reactant: CC(C)(C#N)SCl
Reactant: CCC(Oc1cccc(C)c1C)C1=NCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(Oc1cccc(C)c1C)C1=NCCN1SC(C)(C)C#N

Procedure:
With continuous stirring and cooling, 4.1 g of α-(chlorothio)-isobutyronitrile are added dropwise at 0° to 10° C. to a solution of 6.97 g of 2-[1-(2,3-dimethylphenoxy)-propyl]-2-imidazoline of the formula ##STR4## and 4 g of triethylamine in 80 ml of toluene. The reaction mixture is stirred for 1 hour at room temperature, then the toluene phase is washed repeatedly with water and dried. The toluene is then evaporated off, affording 1-(2-cyano-prop-2-ylthio)-2-[1-(2,3-dimethylphenoxy)-propyl]-2-imidazoline of the formula ##STR5## in the form of a yellow viscous oil with a melting point of 58°-60° C. The following compounds of the formula I can be obtained by procedures analogous to the one described in this Example: ##STR6##
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[CH3:11])[CH:18]=1)[CH3:13]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)cc2C)c1

Procedure:
4-Bromo-2-methylbenzoic acid (120 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20]>C1COCC1>[C:3]([NH:5][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(N)=O
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
A −78° C. solution of 2,2,2-trimethylacetamide (1 g, 9.89 mmol) in THF (20 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1.0N in THF, 11.86 mL, 11.86 mmol), stirred for 30 min, treated drop-wise with a solution of isopropenyl chloroformate (1.43 g, 11.86 mmol) in THF (5 mL), warmed to RT and stirred for 1 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with satd. NH4Cl, then brine, dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl pivaloylcarbamate (1.94 g, 106%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.O.CN(C)[CH:21]=[O:22]>>[CH:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:4]2[C:5]3[NH:9][C:21]([NH:8][C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Nc1nc(N)c(N)c(OCc2ccccc2)n1
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2[nH]c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4,5-Triamino-6-benzyloxypyrimidine (Pfleiderer et al., Chem. Ber., 94, 12-18 (1961)) (1.85 g, 8 mmol) and 1,11-carbonyldiimidazole (1.30 g, 8 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) under argon. The solution was stirred at room temperature overnight and was mixed with water (200 mL) to precipitate a white solid. The solid was collected by filtration, and dissolved in 250 mL of aqueous 2 N NaOH solution. Undissolved material was removed by filtration, and the filtrate was neutralized with glacial acetic acid to precipitate a white solid. The solid was collected by filtration, was washed with water, and was recrystallized from 50% aqueous ethanol to afford analytically pure 1c: yield, 1.63 g (79%); mp 256-257° C. dec.; UV (pH 1) 1max 243 nm (e=0.717×104), 306 (1.499×104); (pH 6.9) 243 (0.915×104), 290 (1.108×104); (pH 13) 249 (sh) (0.443×104), 293 (1.368×104); 1H NMR d 5.41 (s, 2 H, ArCH2), 6.13 (s, 2 H, NH2, exchange with D2O), 7.33-7.51 (m, 5 H, ArH), 10.46 (s, 1 H, exchanges with D2O), 11.04 (s, 1 H, exchanges with D2O); MS (EI) Calcd. m/z for C12H11N5O2 : 257.0912. Found: 257.0914. Anal. (C12H11N5O2. 1/2 H2O) C, N, H.
Reaction SMILES: [CH3:1][P:2](=[O:9])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].C([Li])CCC.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28](OCC)=[O:29])[CH2:24][CH2:23]2)[CH:17]=1.C(O)(=O)C>C1COCC1>[CH2:4]([O:3][P:2]([CH2:1][C:28]([CH:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][N:19]=2)[CH2:23][CH2:24]1)=[O:29])([O:6][CH2:7][CH3:8])=[O:9])[CH3:5]
Reactant: CCOP(C)(=O)OCC
Reactant: CCOC(=O)C1CCN(c2cc(C)ccn2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOP(=O)(CC(=O)C1CCN(c2cc(C)ccn2)CC1)OCC
Reaction time: 0.33 h

Procedure:
Diethyl methylphosphonate (1.27 g, 8.36 mmol) was dissolved in anhydrous THF (7 ml), the solution was purged with argon and cooled to −78° C. n-Butyllithium (2M in hexane, 2.67 ml, 5.34 mmol) was added at such a rate that the temperature remained below −65° C. After addition was complete, stirring was continued for 20 minutes, then a solution of ethyl 1-(4-methyl-2-pyridyl)piperidine-4-carboxylate (626 mg, 2.52 mmol) in anhydrous THF (1 ml) was added dropwise so that the temperature remained below −70° C. Stirring was continued overnight while the temperature was allowed to reach room temperature. The mixture was neutralized with glacial acetic acid, concentrated under reduced pressure, water was added and the mixture was extracted with DCM (3×). The combined organic phases were dried (sodium sulfate), and concentrated under reduced pressure to give a brown oil that was used directly in the next step MS (multi-mode) m/z=355.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:26]=[C:27]([C:31]1[N:39]2[C:34]([CH2:35][CH2:36][CH2:37][CH2:38]2)=[CH:33][C:32]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:28](=[O:29])[C:27](=[O:26])[C:31]3[N:39]4[C:34]([CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:33][C:32]=3[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)CN1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CN1CCN(c2ccc(NC(=O)C(=O)c3c(-c4ccccc4)cc4n3CCCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
To an ice-cold solution of 4-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 93, 300 mg, 1.21 mmol) and triethylamine (0.33 mL, 2.4 mmol) in dry DCM (12 mL) was added a solution of oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 407 mg, 1.41 mmol) in DCM (5 mL). The mixture was warmed to room temperature and stirred for 30 min then diluted with DCM, washed successively with water, sodium bicarbonate solution and brine, then dried over sodium sulfate. Concentration gave a residue which was purified by preparative TLC using ethyl acetate and hexane (3:7) as eluent to afford N-{4-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (220 mg, 36%) as a yellow powder.