Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(CO)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCC1CCCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CCCCCC4)c(C)c3C)c2cc1OC
Yield: 104.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cycloheptylmethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 100%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH2:42]([NH:46][CH3:47])[CH:43]([CH3:45])[CH3:44]>C(Cl)Cl.CN(C=O)C>[CH2:29]([N:27]([CH3:28])[C:25]1[C:24]([C:33]([F:35])([F:36])[F:34])=[CH:23][C:18]2[NH:19][C:20](=[O:22])[CH2:21][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:46]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH3:47])[CH:8]=4)[CH:10]=3)=[N:16][C:17]=2[CH:26]=1)[CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: CNCC(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CN(C)Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 366) (248 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with isobutyl-methyl-amine in DMF according to the general procedure of Example 288. Obtained as an off-white solid (176 mg, 45%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][N:24]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(Cl)Cl>[C:29]([C:28]1[C:23]([NH2:15])=[N:24][CH:25]=[C:26]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH:40]([CH3:41])[CH3:42])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[N:27]=1)#[CH:30]
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
TFA (34.45 g, 23.28 mL, 302.1 mmol) was added to a stirred solution of tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate (5 g, 9.968 mmol) in DCM (200 mL) and the reaction mixture stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo and the residue re-dissolved in DCM and stirred with saturated aqueous NaHCO3 for 30 minutes. The layers were separated and the organic layer washed with saturated aqueous NaHCO3 (×3). The combined aqueous layers were extracted with DCM (×3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from DCM and precipitate isolated by filtration and dried under vacuum to give the title product as a beige solid (2.8 g, 93% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, 6H), 3.44 (t, 1H), 4.76 (s, 1H), 7.01 (s, 2H), 7.89 (d, 2H), 8.20 (d, 2H) and 8.75 (s, 1H) ppm; MS (ES+) 302.12.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:13][OH:14]>>[CH2:5]([O:4][C:2](=[O:3])[NH:13][OH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NO
Agent: Cl
Product: O=C(NO)OCc1ccccc1

Procedure:
170.5 parts of benzyl chloroformate are reacted with 69.5 parts of ground hydroxylamine hydrochloride in a similar manner to Example 8 to give 149 parts of benzyl-N-hydroxycarbamate as a waxy solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[F:29][C:27]1[CH:28]=[C:23]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:9]=3)[C:14]([OH:15])=[C:5]([C:3]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])[N:6]=2)[CH:24]=[N:25][CH:26]=1
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1nc(-c2cncc(F)c2)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A mixture of 1-(5-fluoro-pyridin-3-yl)-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.13 mmol), 5-aminovaleric acid (751 mg, 6.41 mmol) and NaOMe (10 mL, 5.13 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling the mixture to r.t., the solvent was evaporated. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (5-50% EtOAc/hexanes+2% AcOH) to give 33 mg of the title compound as an off-white solid. MS: (+) m/z 476.12 (M+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([N:32]1[CH2:40][CH2:39][CH:35]([C:36]([OH:38])=O)[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN1CCOCC1.[NH2:48][C:49]1[N:50]=[CH:51][C:52](/[C:64](=[N:66]/[NH2:67])/[NH2:65])=[N:53][C:54]=1[C:55]1[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=1>CC(N(C)C)=O>[NH2:65]/[C:64](/[C:52]1[CH:51]=[N:50][C:49]([NH2:48])=[C:54]([C:55]2[O:56][C:57]([C:60]([CH3:63])([CH3:62])[CH3:61])=[N:58][N:59]=2)[N:53]=1)=[N:66]\[NH:67][C:36]([CH:35]1[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:40][CH2:39]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)c1nnc(-c2nc(/C(N)=N/N)cnc2N)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2cnc(N)c(-c3nnc(C(C)(C)C)o3)n2)CC1
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (74.3 g, 195.44 mmol) was added to a solution of N-Boc-isonipecotic acid (41.1 g, 179.15 mmol) and 4-methylmorpholine (35.9 mL, 325.74 mmol) in DMA (800 mL). The mixture was stirred for 10 minutes then (Z)-5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (45 g, 162.87 mmol) was added to the solution in one portion (exotherm observed from 22° C. to 27° C.). After a few minutes the product crystallised from the reaction mixture. The reaction mixture was removed from the vessel and filtered through a sinter. Additional DMA was added to wash product from the sides of the vessel (150 mL) and this was poured onto the filter cake. Isopropanol (600 mL) was added to the vessel and the remainder of the product in the vessel was suspended in this solvent using vigorous agitation. The isopropanol suspension was used to wash the filter cake once the DMA had been removed by suction. The filter cake was sucked dry then washed with MTBE and sucked dry once again. The filter cake was dried in vacuo to afford (Z)-tert-butyl 4-(2-(amino(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)methylene)hydrazinecarbonyl)piperidine-1-carboxylate (76 g, 95%) as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.40 (9H, s), 1.46 (9H, s), 1.63-1.9 (2H, m), 2.33-2.6 (2H, m, obscured by DMSO signal), 2.63-3.03 (2H, m), 3.18-3.48 (4H, obscured by water signal), 3.88-4.11 (2H, m), 6.43 (2H, s), 7.76 (2H, br), 8.84 (0.5H, s), 8.87 (0.5H, s), 9.85 (1H, s); Mass Spectrum [M+H]+=488
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH3:19][C:17]1[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=[C:13]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:18]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(-n2cncn2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a solution of 1,2,4-triazole (4.0 g, 58 mmol) in dry DMF (20 mL) was added potassium carbonate (12.0 g, 87 mmol) and 2-chloro-4-methyl-5-nitropyridine (10 g, 58 mmol) and the mixture stirred at ambient temperature under nitrogen for 24 hours. Ethyl acetate (500 mL) and water (250 mL) were added to the mixture and the resulting precipitate was collected by filtration to give the title compound (5.08 g, 43%) as a pale brown solid. The filtrate was separated and the organic phase was washed with water (250 mL) and brine (250 mL), dried (MgSO4) and evaporated. The residue was triturated with ethyl acetate and the precipitate collected by filtration to give the title compound as a brown solid (4.11 g, 35%, overall yield 78%). mp 198-200° C. 1H NMR (360 MHz, CDCl3) δ 2.72 (3H, s), 7.86 (1H, s), 8.07 (1H, s) 9.03 (1H, s) and 9.15 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH3:29])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]O.[OH-].[Na+]>CCOC(C)=O.Cl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH3:29])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:36])=[O:18])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CO
Reactant: Cc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)sc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)c(C(F)(F)F)c2)c2sc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[4-Fluoro-3-(trifluoromethyl)-benzyl]-N-(3-methylbenzo[b]thiophen-2-yl)-4-carboxy-benzenesulfonamide (not shown). A 3-L 4-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, condenser and thermocouple was charged with MeOH (1.9 L) and compound 141 (190 g, 0.35 mol) followed by 3M NaOH (412 mL, 1.2 mol) and the reaction mixture was refluxed for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 L) and 1N HCl (2 L), the layers separated and the aqueous phase extracted with EtOAc (2 L). The organic extracts were combined, washed with brine (1.5 L), dried over Na2SO4, filtered and evaporated under reduced pressure. The yellow solid was placed in vacuum oven for 18 h at 50° C. to afford 158 g of the titled compound (not shown) as a yellow solid. 1H-NMR (DMSO-d6): δ 13.63 (s, 1H), 8.19 (d, 2H), 8.01 (d, 2H), 7.86-7.83 (m, 1H), 7.71-7.63 (m, 3H), 7.49-7.37 (M, 3H), 4.89 (br s, 1H), 1.95 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[C:25]5[C:24](=O)[NH:23][CH:22]=[N:21][C:20]=5[S:19][CH:18]=4)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:24]1[C:25]2[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8]4)=[CH:13][CH:12]=3)=[CH:18][S:19][C:20]=2[N:21]=[CH:22][N:23]=1
Reactant: O=c1[nH]cnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(2-phenylquinolin-7-yl)-3H-thieno[2,3-d]pyrimidin-4-one (30 mg, max. 0.084 mmol, 77% purity) and POCl3 (1.0 ml) was stirred at 110° C. for 1 h under N2. The excess POCl3 was removed in vacuo, and the residue was basified by cold NH3 (2M in isopropanol). The precipitate that was formed was filtered off. The filtrate [crude 7-(4-chlorothieno[2,3-d]pyrimidin-5-yl)-2-phenylquinoline] was used without further purification for the next step. MS (ES+): 374.2/376.2 (M/M+2). HPLC: tR=6.8 min (MicromassZQ, polar—15 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](B1OC(C)(C)C(C)(C)O1)=[CH:8]2.Cl[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:23]1[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=1)=[CH:8]2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1cccc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Product: COc1cccc2cc(-c3cnnc(Cn4ccnc4C)c3)ccc12

Procedure:
The title compound, MS: m/e 331.4 (M+H+), was prepared from 2-(5-methoxy-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][S:4][CH:3]=1.[Cl:16][C:17]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[C:19]([Cl:36])[N:18]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN1CCCC1=O.C(OCC)(=O)C>[Cl:16][C:17]1[C:22]([C:2]2[C:6]([C:7]3[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][S:4][CH:3]=2)=[CH:21][CH:20]=[C:19]([Cl:36])[N:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)nc1Cl
Reactant: CCNc1ncccc1-c1cscc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCNc1ncccc1-c1cscc1-c1ccc(Cl)nc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.3 %

Procedure:
A mixture of 3-bromo-4-(2-ethylaminopyridin-3-yl)thiophene [synthesis described above] (0.757 g), 2, 6-dichloro-3-tributylstannylpyridine (1.331 g), triphenylarsine (0.261 g), and trisdibenzylideneacetone dipalladium (0.092 g) in N-methylpyrrolidinone (3 mL) was heated at 100° C. for 48 hours. Tetrabutylammonium fluoride (1M in tetrahydrofuran, 3 mL) was added . After 2 hours, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 3-(2,6-dichloropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.059 g) which was used directly in the next step. To a solution of 3-(2,6-dichloropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.059 g) in tetrahydrofuran (2 mL) was added sodium hexamethyldisilazide (1 molar in tetrahydrofuran, 1 mL). After 20 minutes, the reaction was quenched with methanol, diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 6-chloro-8-ethyl-thienyl[3',4':6,5]dipyrido[2,3-b:3',2'-f]azepine (0.024 g) mp 139-141° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:10]=[C:15]([NH:14][CH:11]([CH3:13])[CH3:12])[NH:9][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(Cl)cc(Cl)c1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)cc(Cl)cc2[nH]1
Yield: 59.9 %

Procedure:
3,5-Dichloro-1,2-phenylenediamine (1.30 g, 7.32 mmol), isopropyl isothiocyanate (0.81 g, 8.00 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (4.19 g, 9.89 mmol) and pyridine (25 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 1.07 g (60%) of a white solid; 1H NMR (DMSO-d6) δ: 10.9 (s, 1H, NH), 7.07 (d, J=1.5 Hz, 1H, ArH), 6.98 (d, J=1.6 Hz, 1H, ArH), 6.92 (d, J=7.9 Hz, 1H, NH), 3.89 (m, 1H, CH), 1.17 (d, J=6.6 Hz, 6H, overlapping CH3).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=2)=[C:9]([CH3:23])[C:8]=1[CH3:24])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]([F:39])[CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([CH3:24])=[C:9]([CH3:23])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]([F:39])[CH:27]=3)[CH:16]=2)=[C:11]([CH3:14])[C:12]=1[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Reactant: CCOCCOc1c(C)c(C)c(-c2cccc(C=O)c2)c(C)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOCCOc1c(C)c(C)c(-c2cccc(CNc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 4′-(2-ethoxyethoxy)-2′,3′,5′,6′-tetramethylbiphenyl-3-carbaldehyde (0.300 g, 0.99 mmol) and ethyl 3-(4-amino-2-fluorophenyl)propanoate (0.194 g, 0.99 mmol) in 1,2-dichloroethane (7.0 mL) was added acetic acid (0.158 mL, 2.76 mmol), and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (0.585 g, 2.76 mmol) was added, and the mixture was further stirred for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (0.400 g, yield 84%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:28])[C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:16]([O:24][CH3:25])=[CH:15][C:14]=2[O:26][CH3:27])=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:27][O:26][C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:18][C:13]=1[C:12]#[C:11][C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(OC)c(-c2cccs2)cc1C#CC(=O)c1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-benzoic acid methyl ester (50 mg, 0.12 mmol) from Ex-1 was dissolved in THF (2 mL) and methanol (2 mL). Sodium hydroxide solution (1 N, 1 mL) was added and the resulting solution was stirred at room termperature under nitrogen for 1 h. The reaction was then diluted with water (10 mL) and washed with ethyl acetate (10 mL). The aqueous phase was acidified with conc. HCl and extracted with ethyl acetate (2×10 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford 20 mg (42%) of the desired 4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-benzoic acid as a yellow solid, m.p. 220° C. with decomposition. 1H-NMR (300 MHz, d6-DMSO) δ 8.30 (d, 2H, J=8.0 Hz), 8.14 (d, 2H, J=8.0 Hz), 8.01 (s, 1H), 7.58 (m, 1H), 7.50 (m, 1H), 7.08 (m, 1H), 6.88 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H); EIMS m/z 392 (M+).
Reaction SMILES: Cl.Cl.[C:3]1([CH:13]([NH:16][CH3:17])[CH2:14][NH2:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.O.C(=O)(O)[O-].[Na+].[CH3:24][O:25][C:26]([NH:28][C:29](=NC(OC)=O)SC)=[O:27]>C(Cl)(Cl)Cl.C(O)(C)C>[CH3:17][N:16]1[CH:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[CH2:14][N:15]=[C:29]1[NH:28][C:26]([O:25][CH3:24])=[O:27]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CNC(CN)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)O
Product: COC(=O)NC1=NCC(c2cccc3ccccc23)N1C
Yield: 92.7 %

Procedure:
Six grams of 1-(1-naphthyl)-1-methylamino-2-aminoethane, dihydrochloride, prepared in Part A, are stirred into 25 ml of water. Thereafter 35 ml of saturated sodium bicarbonate are added and stirred for several minutes. Then 160 ml of isopropanol followed by 4.16 g of 1,3-bis(methoxycarbonyl)-S-methylisothiourea dissolved in 120 ml of chloroform are added to the mixture. The resulting mixture is stirred under nitrogen for 7 days. The organic solvents are removed in a rotary evaporator and 10% aqueous HCl is added until the pH of the mixture is just acidic. The resulting mixture is extracted with ether and the aqueous mixture is neutralized with saturated sodium bicarbonate, filtered, and pumped dry to give 5.3 g of crude 1-methyl-4,5-dihydro-2-(methoxycarbonylamino)-5-(1-naphthyl)-imidazole, m.p. 187°-190° C. One gram of the crude material is recrystallized from ethanol to give 0.77 g of more pure material, m.p. 194°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([N:15]1[C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>C1COCC1.CSC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:12]([CH3:13])[CH2:11][C:10]([N:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:4][CH:3]=1
Reactant: C/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
To a stirred solution of copper(II)bromide dimethylsulfide complex (6.85 g, 33.3 mmol) in anhydrous THF (60 mL) and dimethylsulfide (30 mL) was added 4-fluorophenylmagnesium bromide (30.0 mL, 1.0 M in THF, 30.0 mmol) at −40° C. The resultant mixture was stirred at −40° C. for 30 min, then warmed to −10° C. The product from Step A (1.18 g, 5.10 mmol) in THF (30 mL) was added to the above reaction mixture over 1 h at −10° C. The resultant mixture was stirred at −10° C. for 2 h, then slowly warmed to room temperature and stirred at room temperature for 12 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 80:20 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: CCOc1ccc(O)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(O)c(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 4-(ethyloxy)phenol (Commercial eg Aldrich) (1.0 g) in chloroform (5 ml) cooled to 0° C. was added bromine (1.26 g) dropwise over 20 min. The resulting mixture was stirred at 25 C. for 2 h, before washing sequentially with aqueous sodium bicarbonate, and brine. The organics were dried over sodium sulphate, filtered and concentrated in vacuo to yield the title compound, 1.8 g