Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(F)c1
Product: O=C(Cc1cccc(F)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-fluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.41 (td, J=8.0, 6.2 Hz, 1H), 7.21-7.26 (m, 2H), 7.10-7.14 (m, 1H), 3.81-3.83 (m, 4H), 3.71 (s, 2H), 3.08-3.11 (m, 4H); MS (ESI−) M/Z 381 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:38]([C:35]5[CH:36]=[CH:37][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[O:30][N:29]=[C:28]([CH3:31])[CH:27]=7)=[CH:25][C:20]=6[CH3:19])=[CH:33][CH:34]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: Cc1cc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)on1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: Cc1cc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)on1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 2'-methyl-4'-(3-methylisoxazol-5-yl)biphenyl-4-carboxylic acid (D79) using a procedure similar to that of Example 1 (58%) m.p. 224-5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC)Cn1c2ccc(Br)cc2c2cc(Br)ccc21

Procedure:
To a solution of 3,6-dibromocarbazole (3.0 g, 8.95 mmol) in 25 mL of dried DMF was added potassium carbonate (2.47 g, 17.9 mmol). The mixture was stirred and degassed for 1 h, after which 1-bromo-2-ethylhexane (2.70 g, 13.4 mmol) was added dropwise, followed by refluxing for 2 days. The reaction mixture was poured into 100 mL of distilled water and extracted with chloroform. The combined organic layer was dried with anhydrous magnesium sulfate. After removal of the solvent and unreacted 2-ethylhexyl bromide under reduced pressure, the residue was purified by column chromatography on silica gel using hexane and ethyl acetate as the eluent to afford 3,6-dibromo-9-(2-ethylhexyl)-carbazole as a waxy solid. Yield: 3.02 g (77.2%), M.P.: 62.4-63.6° C.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:7][C:4]2[CH:3]=[CH:2][C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3ccccc3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 72.3 %

Procedure:
To a solution of biphenyl-4-amine (338 mg, 2 mmol) in 10 mL of dry pyridine followed by 529 mg of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 21 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between EtOAc and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. After drying over Na2SO4, solvent was removed in vacuo. The crude product (0.79 g) was obtained as a glass which slowly crystallized. Addition of hexane caused complete solidification. The solid was taken up in EtOAc (11 mL), diluted with hexane (11 mL) and seeded to give 534 mg of white needles. The product had mp 171-173° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)=[O:2].CO>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+].O>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12
Reactant: CC1(C)CCc2c(C(=O)O)sc(C=O)c2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CCc2c(C(=O)O)sc(CO)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
To a solution of crude 3-formyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.38 g, 10 mmol) in methanol (20 mL) NaBH4 (756 mg, 20 mmol) is added in portions. The mixture is stirred at rt for 15 min, diluted with 10% aq. citric acid and brine and extracted with TBME. The organic extract is dried over Na2SO4 and the solvent is removed under reduced pressure to give 3-hydroxymethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (2.30 g) as a beige foam; LC-MS: tR=0.83 min, [M+1]=241.22; 1H NMR (CDCl3): δ 4.69 (s, 2H), 3.00 (t, J=7.0 Hz, 2H), 2.32 (s, 2H), 1.50 8 t, J=7.0 Hz, 2H), 0.94 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)[OH:9])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc2ccncc2[nH]1
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1cc2ccncc2[nH]1
Yield: 67 %

Procedure:
(4-Chlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (108 mg, 67%) was prepared as a yellow solid following the procedure described for Example 100 using (4-chlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (Example 101) and tetrahydrofuran as a solvent: mp 274-277° C. dec.; 1H NMR (300 MHz, CD3OD) δ7.21 (1H, s), 7.60-7.63 (2H, m), 7.73-7.76 (1H, m), 7.99-8.03 (2H, m), 8.16 (1H, d, J=5.6 Hz), 8.88 (1H, s); ESI MS m/z 257 [C14H9ClN2O+H]+; HPLC (Method A) >99% (AUC), tR=16.3 min.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([O:24]CC)=O)[N:21]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH3:39]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[S:27][C:18]=4[N:19]=[C:20]([C:22]([NH2:39])=[O:24])[N:21]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2cc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A suspension of ethyl 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate (40 mg, 0.07 mmol) in 7N NH3 in MeOH (1 ml) was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 40:1) to yield the title compound as a white solid (25 mg, 66%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]3[CH:49]=[CH:48][C:47]([C@@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=3)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)[CH3:30]>CN(C=O)C>[C:1]([CH2:3][C:4]([NH:52][C@H:50]([C:47]1[CH:46]=[CH:45][C:44]([CH:41]2[CH2:40][CH2:39][N:38]([C:35]3[CH:34]=[CH:33][C:32]([O:31][CH2:29][CH3:30])=[CH:37][CH:36]=3)[CH2:43][CH2:42]2)=[CH:49][CH:48]=1)[CH3:51])=[O:6])#[N:2]
Reactant: CCOc1ccc(N2CCC(c3ccc([C@H](C)N)cc3)CC2)cc1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CCC(c3ccc([C@H](C)NC(=O)CC#N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 7.0 mg (0.08 mmol) cyanoacetic acid in 1 mL DMF 35 μL (0.20 mmol) DIPEA and 29 mg (0.08 mmol) TBTU are added and the mixture is stirred for 10 min at rt. Subsequently 29 mg (0.09 mmol) (S)-1-{4-[1-(4-ethoxy-phenyl)-piperidin-4-yl]-phenyl}-ethylamine (XIII.1) in 1 mL DMF are added and stirring is continued over night. The mixture is filtered through basic aluminum oxide, followed by washing with DMF/MeOH (9:1) and concentration in vacuo. The residue is purified using reversed phase column chromatography (water/MeOH, 0.1% TFA) and the corresponding fractions are concentrated to yield the desired product.
Reaction SMILES: C([C:3]([C:9]([F:12])([F:11])[F:10])=[C:4]([CH3:8])[C:5]([OH:7])=[O:6])C>S(=O)(=O)(O)O>[F:10][C:9]([F:12])([F:11])[CH:3]=[C:4]([CH3:8])[C:5]([OH:7])=[O:6]
Reactant: CCC(=C(C)C(=O)O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(=CC(F)(F)F)C(=O)O
Yield: 62.5 %

Procedure:
Heat a solution of ethyl 4,4,4-trifluoro-2-methylbut-2-enoic acid (0.544 g, 2.99 mmol) in 5M sulfuric acid (5 mL) at 120° C. for 2.5 days. Saturate the solution with sodium chloride and extract with diethyl ether (1×40 mL). Dry the organic phase with magnesium sulfate and concentrate under reduced pressure to provide 0.288 g (62.6%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([S:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[N:6][C:5]=2[S:4][C:3]=1C(O)=O.C([N:33](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(O)(C)(C)C>[NH2:33][C:3]1[S:4][C:5]2[N:6]=[C:7]([S:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)[NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[CH3:1]
Reactant: CCN(CC)CC
Reactant: Cc1c(C(=O)O)sc2nc(SCCCN3CCN(c4ccccn4)CC3)[nH]c(=O)c12
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Cc1c(N)sc2nc(SCCCN3CCN(c4ccccn4)CC3)[nH]c(=O)c12
Reaction time: 9 h
Yield: 18 %

Procedure:
In 20 ml of tert-butanol, 470 Milligrams of 5-methyl-4-oxo-2-[3-(4-pyridin-2-ylpiperazin-1-yl)propylthio]-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid as synthesized in Example 2-17 was dissolved to which 107 mg of triethylamine and 305 mg of DPPA were added by the order stated, followed by 9 hours' heating under reflux. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (chloroform:methanol=50:1). The purified product was added to 6 ml of 4N-hydrochloric acid-dioxane solution, stirred for an overnight and from which the solvent was distilled off under reduced pressure. To the residue chloroform was added, followed by washing with saturated aqueous sodium hydrogencarbonate solution, drying over anhydrous magnesium sulfate and removal of the solvent by distillation under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=25:1) to provide 78 mg (18%) of 6-amino-5-methyl-2-[3-(4-pyridin-2-ylpiperazin-1-yl)propylthio]-3H-thieno[2,3-d]pyrimidin-4-one.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].O>FC(F)(F)C(O)=O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)C(=Cc1ccc(C(F)(F)F)cc1)C(C)=O
Temperature: 20 °C

Procedure:
4-Trifluoromethylbenzaldehyde (8,7 g) was condenced with 2,4-pentanedione (5,01 g in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over right at 20° C. The solvent was evaporated and the residue was destilled in vacuo, bp 110° C./1,5 mbar. The crude product was crystallized from a mixture of ether-petroleum ether (1:1), mp 46°-48° C., yield 3,8 g (30 %).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[F:14][C:15]([F:27])([F:28])[O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[O:25])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.3 %

Procedure:
To a mixed solution of t-butyl (S)pyrrolidin-3-ylcarbamate (93 g), 4-trifluoromethoxyphenylacetic acid (112 g), and THF (550 mL) were added EDC.HCl (114 g) and HOBt-1H2O (114 g), and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, then diluted with chloroform, and washed with saturated aqueous sodium hydrogencarbonate, water, and brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting solids were washed with chloroform to obtain t-butyl ((S)-1-(2-(4-trifluoromethoxyphenyl)ethanoyl)pyrrolidin-3-yl)carbamate (144 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH3:30][O:31]CCO>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:28][O:31][CH3:30])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: COCCO
Reactant: CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: COCCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A solution of the compound (0.050 g, 0.12 mmol) of Example 108, 2-methoxyethanol (0.20 mL, 2.6 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 3.5 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0029 g, y. 5%).
Reaction SMILES: [C:1]1([S:7][C:8](=[C:16]([C:19]#[N:20])[C:17]#[N:18])SC2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[NH2:20][C:19]1[N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=[C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]=1[C:17]#[N:18]
Reactant: N#CC(C#N)=C(Sc1ccccc1)Sc1ccccc1
Reactant: NNc1ccccc1
Solvent: CO
Product: N#Cc1c(Sc2ccccc2)nn(-c2ccccc2)c1N
Yield: 94 %

Procedure:
A mixture comprised of 14.7 g (50 mmol) of bis (phenylthio)methylenepropanedinitrile [see Chem. Ber., 99, 2900 (1966)], 6.5 g (60 mmol) of phenylhydrazine and 80 ml of methanol was heated under reflux for 7 hours. The solvent was removed by distillation, and 100 ml of ethanol was added to the residue to crystallize the residue. The crystals formed were taken out by filtration under suction to obtain 13.7 g (47mmols) of the intended product as colorless, needle-like crystals having a melting point of 172° to 173° C. The yield was 94%.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.O>ClCCl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)C(N)C(=O)OC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OC
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Part A: To a stirred solution of dimethyl aminomalonate hydrochloride (25 gram, 0.136 mol) in dichloromethane (200 mL) triethylamine (41.4 mL, 2.2 molar equivalent) is added at 0° C. 4-Chlorobenzoyl chloride (23.8 gram, 0.136 mol) is slowly added and the resulting solution is allowed to stand at room temperature overnight. Water is added and the organic layer is separated. The water layer is extracted twice with dichloromethane. The collected organic layers are washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallised from methanol (400 mL) to give dimethyl 2-(4-chlorobenzoylamino)malonate (30.5 gram, 79% yield). Melting point: 146-148° C. 1H-NMR (200 MHz, CDCl3): δ 3.86 (s, 6H), 5.38 (d, J=6 Hz, 1H), 7.15 (br d, J˜6 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].I[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>C(NC(C)C)(C)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH3:2]
Reactant: Ic1cccs1
Reactant: C#CC(OCC)OCC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(C#Cc1cccs1)OCC
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of propargylaldehyde diethyl acetal (405 mg) in diisopropylamine (8 ml) were added 2-iodothiophene (1.2 g) and copper(II) acetate monohydrate (66.4 mg). The suspension was flushed with a stream of N2. Pd(PPh3)4 (75 mg) was added, the reaction mixture was flushed with nitrogen again. The suspension was stirred for 1 h at 55° C. A precipitate was formed and it was necessary to dilute the reaction mixture with diisopropylamine (6 ml) to keep it stirring. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/0→17/3 (v/v)] as eluent.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:5]1([N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][N:13]([C:1](=[O:3])[CH3:2])[CH2:12][C:11]=3[CH:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:7]1
Reactant: c1ccc(-c2cc3c(n2C2CC2)CCCNC3)cc1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2c(cc(-c3ccccc3)n2C2CC2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.9 g. of acetyl chloride in 25 ml. of chloroform is added to a cooled solution of 11.0 g. of 1-cyclopropyl-2-phenyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine and 5.0 g. of triethylamine in 50 ml. of dry chloroform. The mixture is stirred at ambient temperature for 20 hours, washed with water, dried, and concentrated to provide 1-cyclopropyl-2-phenyl-5-acetyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine as an oil. The oil is treated according to the manipulative procedure described above in Example 2, to give crystals, m.p. 85°C. dec., of 1-cyclopropyl-2-phenyl-5-ethyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine oxalate.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([CH2:13][OH:14])[CH2:8][O:7]2)([O-:3])=[O:2].[I:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.[H-].[Na+]>>[I:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:14][CH2:13][CH:9]2[CH2:8][O:7][C:6]3=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]3[CH2:10]2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OCC(CO)C2
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cn2c(n1)OCC(COCc1ccc(I)cc1)C2
Yield: 42 %

Procedure:
Alkylation of oxazine alcohol 180 (see Example 2MMM) with 4-iodobenzyl bromide and NaH (1.4 equiv.) as in Example 2UU above for 3 h, followed by chromatography of the product on silica gel, eluting with 0-1% EtOAc/CH2Cl2 (foreruns) and then with 3% EtOAc/CH2Cl2, gave 6-{[(4-iodobenzyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (183) (42%) as a white solid: mp (CH2Cl2/hexane) 161-163° C.; 1H NMR (CDCl3) δ 7.70 (dt, J=8.3, 2.0 Hz, 2H), 7.40 (s, 1H), 7.03 (br d, J=8.3 Hz, 2H), 4.50 (ddd, J=11.4, 3.3, 0.8 Hz, 1H), 4.46 (s, 2H), 4.34 (dd, J=11.4, 7.8 Hz, 1H), 4.13 (ddd, J=12.3, 5.6, 0.8 Hz, 1H), 4.00 (dd, J=12.3, 7.6 Hz, 1H), 3.59 (dd, J=9.6, 5.8 Hz, 1H), 3.53 (dd, J=9.6, 6.5 Hz, 1H), 2.65 (m, 1H); HRFABMS calcd for C14H15IN3O4 m/z [M+H]+ 416.0107. found 416.0108.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: Cc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 135A and 2-(3,5-difluorophenyl)acetic acid were treated as in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 8.39-8.42 (m, 1H), 7.89-8.03 (m, 2H), 7.73-7.76 (m, 1H), 7.47-7.50 (m, 2H), 7.37-7.40 (m, 2H), 7.09-7.22 (m, 3H), 3.77 (s, 2H), 2.42 (s, 3H); MS (APCI+) M/Z 406 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12]([O:14][C:15](=[O:29])[CH:16]([CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17](=O)[CH3:18])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([C:16]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:6]([C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[C:17]=1[CH3:18])=[O:29])[CH3:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C(F)(F)F)c2)c1C

Procedure:
m-Trifluoromethylaniline (5 mmol, 0.8 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The crude material was resuspended in chloroform and washed with water, then with brine. The organic layer was dried over NaSO4. The solids were separated and the solvents removed under vacuum. The resulting oil was purified over silica gel to yield the named product, 1H-NMR (CDCl3, ppm): 1.37 t (3H), 2.42 s (3H), 4.32 q (2H), 6.80 s (1H), 7.0-7.6 bm (9H).