Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[CH2:9][CH2:8][C:7]1=[O:18].[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1>>[CH3:19][C@@H:20]1[NH:21][CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:7](=[O:18])[CH2:8][CH2:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)[CH2:25]1
Reactant: C[C@H]1CNCCN1
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Product: C[C@H]1CN(CCCCN2C(=O)CCC(=O)c3ccccc32)CCN1
Yield: 22.5 %

Procedure:
Analogously to the method for Example 12b, reaction of 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.56 mmol, 0.15 g) with (S)-(+)-2-methylpiperazine (0.54 mmol, 0.05 g) afforded 40.0 mg of the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]([CH2:7]Br)([CH2:5]Br)[CH2:3]Br.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].[C:19](=[O:22])([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN(C)C=O>[CH:14]([C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[O:10][CH2:1][C:2]([CH2:7][O:10][C:11]1[CH:12]=[CH:13][CH:16]=[C:17]([CH:19]=[O:22])[CH:18]=1)([CH2:5][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH:14]=[O:15])[CH:12]=1)[CH2:3][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH:14]=[O:15])[CH:12]=1)=[O:15]
Reactant: BrCC(CBr)(CBr)CBr
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCC(COc2cccc(C=O)c2)(COc2cccc(C=O)c2)COc2cccc(C=O)c2)c1
Yield: 85.6 %

Procedure:
5 g of pentaerythrityl tetrabromide, 9.5 g of 3-hydroxybenzaldehyde, 11 g of potassium carbonate, and a catalytic amount of sodium iodide were mixed. Thereto was added dimethylformamide, to conduct reaction at 130° C. for 6 hours. After cooled, water was added thereto, and the thus-precipitated crystal was collected by filtration. Dimethylformamide was added to this crystal, and the resultant solution was filtrated. Then, methanol was added to the filtrate, and the precipitated crystal was collected by filtration (yield amount 6.1 g, and yield 85.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([CH3:34])[CH2:29][CH2:28][CH:27]([CH:30]([CH3:32])[CH3:31])[CH:26](O)[CH2:25]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:30]([CH:27]1[CH2:28][CH2:29][CH:24]([CH3:34])[CH2:25][CH:26]1[O:22][C:21]([CH:9]1[CH2:10][C:11](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23])([CH3:32])[CH3:31]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2cccc(F)c2)CC1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1CCC(C(C)C)C(OC(=O)C2CC(=Cc3cccc(F)c3)CN2C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 31.3 %

Procedure:
To a solution of 4-(3-Fluoro-benzylidene)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.68 g, 8.35 mmol), 1R,2S,5R(−) menthol (1.31 g, 8.35 mmol) was added followed by dimethylaminopyridine (1.02 g, 8.35 mmol). The mixture was cooled to 0° C. and dicyclohexylcarbodiimide (1.89 g, 9.19 mmol) in dichloromethane (10 ml) was added in one portion. The mixture was warmed to room temperature stirred for 18 h. The mixture was filtered and the filtrate was washed with 1N hydrochloric acid (30 ml), sat. sodium hydrogen carbonate (30 ml) and water (30 ml). The organics were dried over magnesium sulphate and the solvent was removed by evaporation under reduced pressure. Purification by flashmaster column chromatography eluting with heptane:ethyl acetate (12:1) yielded the title compound (1.20 g, 31%) as a colourless oil.
Reaction SMILES: [C:1]([CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)([OH:3])=[O:2].CCN(CC)CC.CN([P+](O[N:34]1[N:42]=[N:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[N:41]1([O:2][C:1]([CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[O:3])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[N:42]1
Reactant: COC(=O)c1ccc(C=CC(=O)O)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=CC(=O)On2nnc3ccccc32)cc1
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a stirred solution at room temperature of VII (264 mg, 1.28 mmol) in anhydrous DMF (10 ml) under nitrogen were added Et3N (196 μl, 1.41 mmol) and BOP reagent (680 mg, 1.1.54 mmol), respectively. After few min, a precipitate appeared. After 3 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat NH4Cl, H2O and brine, concentrated a little bit, and hexane was added. The suspension was filtered off and rinsed with hexane. The solid was triturated in water, filtered off, rinsed with water, and dried to afford the title compound VIII (346 mg, 1.07 mmol, 84% yield) as a pale yellow solid (not stable on silica gel !). 1H NMR (300 MHz, CDCl3) δ(ppm): 8.56 (d, J=8.3 Hz, 1H), 8.21–8.02 (m, 3H), 7.90–7.72 (m, 4H), 7.62 (t, J=7.4 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:12])[CH:3]=1.Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:10]=[C:6]2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Cc1cc(Cl)n2nc(N)nc2c1
Agent: Cl
Product: Cc1cc(Cl)n2nc(NC(=O)c3cccnc3)nc2c1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine (282 mg; 1.54 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (330 mg; 1.85 mmol; 1.20 eq.) as a off-white powder (244 mg, 55%). HPLC, Rt: 1.51 min. (purity 90.4%). LC/MS, M+(ESI): 288.1, M−(ESI): 286.2.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:38]>CO>[ClH:20].[ClH:38].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][NH2:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Yield: 187.2 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.3 g.), conc.hydrochloric acid (1.2 g.) and methanol (20 ml.) were treated in similar manner to that of Example 11(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 1.1 g.).
Reaction SMILES: Cl.[C:2]1([NH:8][C:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1([C:26]#[N:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(OCC)(=O)C>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(O)(C)C>[C:2]1([NH:8][C:9]([CH2:11][CH2:12][CH2:13][C:14]2[CH:20]=[CH:19][C:17]([NH:18][C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[NH:27])=[CH:16][CH:15]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(CCCC(=O)Nc2ccccc2)cc1
Reactant: N#CN1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: N=C(Nc1ccc(CCCC(=O)Nc2ccccc2)cc1)N1CCCC1

Procedure:
To a stirred suspension of the product of step (a) (1.7 g; 0.0052 moles) in 30 ml of chlorobenzene was added a catalytic amount of 4-dimethylaminopyridine. To this was added 1-pyrrolidinecarbonitrile (1.2 ml; 0.016 moles) and the reaction then heated to reflux for 6 hours. The reaction was then cooled and the solvent decanted. To the residue was added 100 ml of 2N sodium hydroxide. The aqueous phase was then extracted 3×75 ml of chloroform and the organic extract was dried over magnesium sulphate. Evaporation of the solvent gave a white solid which was the dissolved in hot isopropanol 5 ml, and 100 ml ethyl acetate. Upon cooling a white solid crystallized and was collected by filtration. The above compound was dried at 70° C. for 72 hours to give N-(4(3-((phenylamino)carbonyl)propyl)phenyl)-1-pyrrolidinecarboximidamide, M.P.164°-165° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1.[K].[Cl-:11].[Cl-].[Cl-].[Cl-].[Zr+4:15].O.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[Cl-:11].[Cl-:11].[CH3:1][O:2][CH2:3][CH2:4][C:5]1([Zr+2:15][C:18]2([CH2:17][CH2:21][O:20][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:9]=[CH:8][CH:7]=[CH:6]1
Reactant: COCCC1=CC=CC1
Reactant: C1CCOC1
Reactant: [Zr+4]
Agent: [Cl-]
Agent: [K]
Solvent: O
Product: COCCC1([Zr+2]C2(CCOC)C=CC=C2)C=CC=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 4.5 g (37.7 mmol) 2-methoxyethylcyclopentadiene in 50 ml THF was added to 2.20 g (58.0 mmol) clean, dry potassium metal under nitrogen. This was stirred for two hours at room temperature and warmed to 40 20 C. for a further two hours. After cooling, the solution was filtered and the remaining potassium washed, dried and weighed. The yield of potassium 2-methoxyethylcyclopentadienylide (KCp*) was calculated to be 4.20 g (26.4 mmol). The KCp* solution was added to a slurry of 3.03 g (13.0 mmol) zirconium tetrachloride in 20 ml THF and stirred for two hours. Approximately 0.5 ml water was added to the reaction vessel and the volatiles removed under reduced pressure. The residue was extracted with diethyl ether and filtered. The volume of ether was reduced under vacuum until precipitation began. Cooling to -50° C. in a low temperature freezer yielded 3.50 g of product as colourless needles (8.58 mmol, 66.0%), shown to be spectroscopically pure by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]=2[C:14]([NH2:16])=[O:15])=[CH:21][CH:20]=1
Reactant: NC(=O)c1c(Nc2cccnc2)n[nH]c1N
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=Nc2[nH]nc(Nc3cccnc3)c2C(N)=O)cc1
Yield: 50 %

Procedure:
5-amino-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide (1.0 g) was suspended in 10 mL of ethanol and 4-methoxybenzaldehyde (559 mg, 1.0 eq.) and piperidine (0.10 eq, 47 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-methoxybenzylidene)amino)-3-(pyridin-3-ylamino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-methoxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (800 mg, 50% yield).
Reaction SMILES: Br[C:2]1[C:6](Br)=[CH:5][S:4][CH:3]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].O1[CH2:18][CH2:17]CC1.C(NC(C)C)(C)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][Si:9]([C:12]#[C:13][C:2]1[C:6]([C:17]#[C:18][Si:9]([CH3:11])([CH3:10])[CH3:8])=[CH:5][S:4][CH:3]=1)([CH3:11])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: C1CCOC1
Reactant: Brc1cscc1Br
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cscc1C#C[Si](C)(C)C
Temperature: 70 °C

Procedure:
2.5 ml (22.6 mmol) of 3,4-dibromothiophene, commercially available from Aldrich under the Product No. 24, 715-4, and 8 ml (56.5 mmol) of trimethylsilylacetylene were mixed with a solvent of tetrahydrofuran/diisopropylamine (1:1), and 0.15 g (0.23 mmol) of palladium dichlorodiphosphine, 21 mg (0.11 mmol) of copper iodide and 0.1 g (0.36 mmol) of triphenylphosphine were then sequentially added thereto. The reaction solution was heated at 70° C. for 8 hours, and washed with an aqueous solution of ammonium chloride. The resulting organic layer was dried over magnesium sulfate, dried under reduced pressure, and purified using silica gel column chromatography, thus obtaining 1.5 g of 3,4-bis(trimethylsilylethynyl)thiophene (IIa).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:43])[CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[OH:43][CH:35]([CH2:36][N:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1)[CH2:34][CH2:33][CH2:32][NH:31][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: NCCCC(O)CN1CCCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 1. MS (APCI, m/z): 530 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[C:13]1([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:43][P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([F:43])[CH:18]=3)=[CH:24][N:23]=2)=[O:11])=[CH:4][C:3]=1[CH3:12]
Reactant: F[P-](F)(F)(F)(F)F
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Reactant: Nc1ccc(-c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cccc(F)c3)cn2)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 74-4 (222 mg, 1.2 mmol), 5-phenylpyridin-2-amine (336 mg, 1.8 mmol) and HATU (684 mg, 1.8 mmol) in DMF (5 mL) was added DIEA (600 μL, 3.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in dichloromethane to give 2-(6-chloro-5-methylpyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 74-5 as dark yellow solid. MS m/z 356.1 (M+1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Br:20]C1C=C2C(=CC=1)NC=C2>>[O:4]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([Br:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C1=C(c2c[nH]c3ccccc23)CCC2(C1)OCCO2
Product: Brc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Yield: 78 %

Procedure:
This compound was prepared in the manner described above for intermediate 1a by replacing indole with 5-bromoindole (7.84 g, 40 mmol)) to afford 10.5 g (78%) of the title compound as a white solid; MS EI m/e 333 (M30).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.C(O)=O.C([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.Cl>O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=CN1CCCCC1
Reactant: Cc1ccsc1C=O
Agent: Cl
Solvent: O
Solvent: O=CO
Product: Cc1ccsc1CN1CCCCC1

Procedure:
A mixture of 3-methyl-2-thiophenecarboxaldehyde (20 g), formic acid (6 ml) and N-formyl piperidine (44.4 ml) was heated under reflux for 12 h. Water (50 ml) and 2M hydrochloric acid (30 ml) were added; and the aqueous solution was washed with ether. The solution was basified to pH 10 with 2M sodium hydroxide (30 ml) and extracted with ether. The organic extract ws evaporated to give a brown oil which was distilled to afford the title compound as a colourless oil (11.8 g) b.p. 70°/0.4 mm.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].Cl.[O:9]([CH2:16][CH2:17][CH2:18][NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.O>C(Cl)Cl>[O:7]=[C:2]([NH:19][CH2:18][CH2:17][CH2:16][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: NCCCOc1ccccc1
Reactant: COC(=O)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=O)NCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloro(oxo)acetate (1.77 mL) was added to a stirred solution of (3-phenoxypropyl)amine hydrochloride (3000 mg) and pyridine (2.98 mL) in DCM (100 mL) at 0° C. After the addition was complete the solution was allowed to warm to ambient temperature and stirred for 16 hours. Water (50 mL) was added and the mixture was extracted with DCM (2×75 mL). The organic extracts were combined, washed with brine (50 mL), dried and concentrated in vacuo to give an oil. This was purified by flash chromatography on a 90 g Biotage™ silica column using a gradient of 10-60% EtOAc in hexane as the eluent to give methyl oxo[(3-phenoxypropyl)amino]acetate (3212 mg) as a solid; 1H NMR δ (CDCl3) 7.60 (1H, bs), 7.28 (2H+CHCl3, m), 6.94 (3H, m), 4.07 (2H, t), 3.90 (3H, s), 3.58 (2H, quartet), 2.08 (2H, m), +0.1 mole of EtOAc; MS m/e MH+ 238.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[OH:18][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([C:19]#[N:20])=[N:7][CH:6]=2)[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1
Reactant: OC1(c2ccc(F)nc2)CCC2(CC1)OCCO2
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Yield: 36.1 %

Procedure:
To a solution of 1.7 g (6.6 mmol) of 8-(6-fluoropyridin-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol in 20 mL of DMF was added KCN (430 g, 6.6 mmol) and 18-crown-6 ether (1.8 g, 6.6 mmol). The reaction mixture was refluxed for 2 days. Direct chromatography on silica gel afforded the 5-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)pyridine-2-carbonitrile (620 mg, 36%): MS (m/e): 261 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14]>N1CCCCC1.CO>[C:13]([C:15](=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: COC(=O)CC#N
Reactant: COc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C(C#N)=Cc1ccc(OC)c(OC)c1

Procedure:
A mixture of 3,4-dimethoxybenzaldehyde 4.15 g, 0.025 mol), methyl cyanoacetate (2.48 g, 0.025 mol), methanol (100 mL) and piperidine (10 drops) is heated at reflux for 2 hours. The reaction mixture is then cooled and the product collected by filtration, washed with methanol and dried in air (yield--6.0 g, 97%). The following structure is supported by mass spectrometry: ##STR20## The compound has an absorption maximum at 361 nm in methylene chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:23]C(=O)N(C)C)=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:23][CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Sc1c(C(F)(F)F)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(F)(F)F)c(SCCO[Si](C)(C)C(C)(C)C)c2CC1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[d]azepine and (2-bromoethoxy)-tert-butyldimethylsilane to give the desired intermediate.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.N1[C:31]2[C:22](=[CH:23][CH:24]=[C:25]3[C:30]=2N=CC=C3)C=CC=1.C(=O)([O-])[O-:33].[Cs+].[Cs+]>[Cu]I.C1(O)CCCCC1>[CH:22]1([O:33][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH2:31][CH2:30][CH2:25][CH2:24][CH2:23]1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [Cu]I
Agent: [Cs+]
Solvent: OC1CCCCC1
Product: O=C(Nc1cc2ccc(OC3CCCCC3)cc2cn1)C1CC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
Cyclohexanol (10 mL) was added to a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.44 mmol), copper(I) iodide (83.9 mg, 0.44 mmol), 1,10-phenanthroline (79.2 mg, 0.44 mmol) and cesium carbonate (188 mg, 0.58 mmol). The resulting mixture was stirred at 140-160° C. for 2 hours under nitrogen. The reaction mixture was concentrated and purified by prep-HPLC to give the product (31.5 mg, 22.9%). LCMS (ESI): RT (min)=1.141, M+H+=310.9, method=A. 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.97 (s, 1H), 8.34 (s, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.45 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 4.40-4.50 (m, 1H), 2.01-1.98 (m, 3H), 1.80-1.70 (m, 2H), 1.60-1.21 (m, 6H), 0.82-0.78 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:22][CH2:23][CH2:24][CH:25]1[CH2:31][N:30]([CH3:32])[C:29](=[O:33])[C:28]2[CH:34]=[CH:35][CH:36]=[N:37][C:27]=2[CH2:26]1>C(O)C>[ClH:22].[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH:25]3[CH2:31][N:30]([CH3:32])[C:29](=[O:33])[C:28]4[CH:34]=[CH:35][CH:36]=[N:37][C:27]=4[CH2:26]3)[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CN1CC(CCCl)Cc2ncccc2C1=O
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Solvent: CCO
Product: CN1CC(CCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)Cc2ncccc2C1=O
Product: Cl

Procedure:
4-[Bis(4-fluorophenyl)methyl]piperidine and 8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one in ethanol are reacted by heating to reflux for about 20 hr. The solution is concentrated on a rotary evaporator and the residue is partitioned between aqueous dilute base and chloroform. The chloroform layer is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed by high pressure liquid chromatography using ethyl acetate and triethylamine over silica. After concentrating the desired fraction, the residue is converted to the hydrochloride salt in isopropyl alcohol using hydrogen chloride.