Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH:12]=O)[N:5]2[N:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH2:12][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]2[N:4]=1
Reactant: Nc1ccccc1
Reactant: CSc1ncc2ccc(C=O)n2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1ncc2ccc(CNc3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (0.200 g, 1.04 mmol) and Aniline (0.104 mL, 1.14 mmol) were dissolved in a solution of Acetic acid (0.100 mL, 1.76 mmol) and Methylene chloride (10 mL, 200 mmol) and the reaction was allowed to stir at room temperature for 1 hour. Sodium triacetoxyborohydride (0.439 g, 2.07 mmol) was then added and the reaction was allowed to continue stirring at room temperature until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 0.280 g of (2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine. 1H NMR (400 MHz, DMSO, d6) δ 8.92 (s, 1H), 7.06 (m, 2H), 6.90 (d, 1H, J=4.61 Hz), 6.83 (d, 1H, J=4.61 Hz), 6.65 (m, 2H), 6.54 (t, 1H, J=7.28 Hz), 6.13 (t, 1H, J=6.16 Hz), 4.61 (d, 2H, J=6.16 hz), 2.56 (s, 3H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([O:27][CH3:28])[C:21]=1B(O)O>C(Cl)(Cl)Cl.ClCCl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([O:27][CH3:28])[C:21]=1[Pb+3:17]
Reactant: [Pb+4]
Reactant: COc1cc(C)cc(OC)c1B(O)O
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1[Pb+3]
Temperature: 40 °C
Reaction time: 1.25 h
Yield: 90 %

Procedure:
45.4 g of lead tetraacetate and 3.2 g of mercuric acetate are suspended in 150 ml of anhydrous chloroform and the mixture is heated to 40° C. under an argon atmosphere. A solution of 20 g of 2,6-dimethoxy-4-methylphenylboronic acid (prepared above) in 100 ml of chloroform is added dropwise to the reaction mixture at 40° C. The reaction mixture is left for 75 minutes at 40° C. and is then left to return to room temperature while stirring well. The reaction mixture is stirred at room temperature for 18 hours and is then diluted with 800 ml of dichloromethane. The solution is filtered over a bed of celite and the solvent is then evaporated to dryness in order to obtain yellow crystals of 2,6-dimethoxy-4-methylphenyllead triacetate, M.p.=172° C., Yield: 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8].C[CH2:26][N:27]([CH:31]([CH3:33])C)[CH:28](C)C.BrC/C=[CH:37]/[C:38](Cl)=[O:39].[Cl-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH:20][C:38](=[O:39])[CH:37]=[CH:33][CH2:31][N:27]([CH3:26])[CH3:28])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: O=C(Cl)/C=C/CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(C)C
Yield: 61.1 %

Procedure:
To a mixture of 1.08 g (3.1 mmol) of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-amino-quinoline-3-carbonitrile and 1.7 ml (9.7 mmol) of Hunig's base in 30 ml of dry THF at 0° C., with stirring, was added a THF solution containing 1.99 g (9.3 mmol) of 4-bromo crotonyl chloride dropwise. The mixture was stirred for additional 0.5 hour at 0° C. under nitrogen. 50 ml of saturated sodium chloride solution was introduced to the reaction mixture, then it was extracted with ethyl acetate. The ethyl acetate solution was separated and dried over sodium sulfate and then it was added to 31 ml of dimethyl amine solution (2.0 M in THF) at 0° C. dropwise. After addition, the solution was stirred for another hour at room temperature. The mixture was poured into diluted sodium bicarbonate solution. The organic layer was separated and the residue was chromatographed to give 0.86 grams of white solid: mass spectrum (electrospray, m/e):
Reaction SMILES: [Br:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[Br:1][C:2]([F:7])([F:6])[C:3]([O:5][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C(O)C(F)(F)Br
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: O=C(OCc1ccccc1)C(F)(F)Br

Procedure:
This compound was prepared according to Example 2a from bromodifluoroacetic acid (9.82 g; 68.7 mmol), benzyl alcohol (7.0 g; 65 mmol), and p-toluenesulphonic acid monohydrate (50 mg) in cyclohexane (120 mL). The crude product obtained after evaporation was used as is without any further workup in 3b.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]([NH2:16])=[O:15].Br[C:18]1[N:23]=[C:22]([C:24]([OH:28])([CH3:27])[CH2:25][OH:26])[CH:21]=[CH:20][CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C.C(OCC)(=O)C.CO>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:6][C:2]([NH:1][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:24]([OH:28])([CH3:27])[CH2:25][OH:26])[N:23]=3)=[C:3]([C:14]([NH2:16])=[O:15])[N:4]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1nc(-c2ccc(Cl)cc2)sc1N
Reactant: CC(O)(CO)c1cccc(Br)n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCC(C)(C)O
Product: CC(O)(CO)c1cccc(Nc2sc(-c3ccc(Cl)cc3)nc2C(N)=O)n1

Procedure:
A suspension containing 5-amino-2-(4-chlorophenyl)-1,3-thiazole-4-carboxamide (Example 1, Step 1) (200 mg, 0.788 mmol), 2-(6-bromopyridin-2-yl)propane-1,2-diol (179 mg, 0.773 mmol), 2-dicylohexylphosphino-2′,4′,6′-triisopropyl-1,1-biphenyl (92 mg, 0.193 mmol), dibenyzlideneacetone bis(triphenylphosphine) (35.4 mg, 0.039 mmol) and potassium carbonate (117 mg, 0.850 mmol) in tert-amyl alcohol (3.0 mL) was sealed in a 5 mL microwave reaction vessel and was purged of oxygen by doing 5 vacuum/argon flush cycles. After heating the reaction at 100° C. for 16 hours, the mixture was cooled, diluted with ethyl acetate (100 mL) and methanol (5 mL), washed with saturated aqueous sodium bicarbonate (30 mL), and filtered both layers through filter paper. The layers were separated, and the organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The resulting solid was diluted with acetonitrile (40 mL) and methanol (10 mL), and this solution was extracted with hexanes (2×50 mL) and then concentrated. The crude product was purified by reverse phase HPLC (40-90% acetonitrile/water with 0.05% trifluoroacetic acid), and then the appropriate fractions were diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (15 mL) and water (2×15 mL), dried over sodium sulfate, filtered and concentrated to yield the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26])[CH3:2].N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+]>C(O)(=O)C.O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]=[N+:31]=[N-:32])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26])[CH3:2]
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N=[N+]=[N-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole (466 mg) in acetic acid (8 mL) a solution of sodium nitrite (1.1 eq) in water (4 mL) is added dropwise. After stirring at 0° C. for 1 h, a solution of sodium azide (1.3 eq) in water (5 mL) is added dropwise. Stirring is continued for 0.5 h at 0° C., and then at room temperature for 0.5 h. The reaction mixture is concentrated to ⅓ volume, water (10 mL) is added and then mixture is then extracted with ethyl acetate (3×). The combined organic layers are washed with aqueous sodium bicarbonate (2×), then washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 641 mg of crude 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][N:9]2[C:13]([CH:14]=1)=[C:12]([C:15]#[N:16])[CH:11]=[CH:10]2)=[O:5])C.[OH-].[Li+].Cl>O1CCCC1.C(O)C.O>[C:15]([C:12]1[CH:11]=[CH:10][N:9]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[CH:8]2)#[N:16]
Reactant: CCOC(=O)c1ccn2ccc(C#N)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccn2ccc(C(=O)O)cc12
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a mixed solution of 1-cyanoindolizine-7-carboxylic acid ethyl ester (0.42 g) in tetrahydrofuran (4.2 mL), ethanol (2.1 mL) and water (2.1 mL) was added lithium hydroxide (0.25 g) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was acidified with 2 mol/L hydrochloric acid, and a precipitated solid was collected by filtration. This solid was washed with water and n-hexane to give 1-cyanoindolizine-7-carboxylic acid (0.29 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[NH:33][CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1nc(OCc2ccc(Oc3cccc(C(F)(F)F)c3)c(Cl)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E65 using sodium hydride (13.87 mg, 0.347 mmol), (3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol in THF (8 mL) and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (62.8 mg, 0.231 mmol).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[S:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:29]([N:31](CC)CC)C.CN.Cl>C(Cl)Cl.CN(C=O)C>[CH3:29][NH:31][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[S:12][CH:13]=[C:9]([C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(-c2cc(C(=O)N3CCCCC3)cs2)cc1
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cc(C(=O)N3CCCCC3)cs2)cc1
Reaction time: 1 h
Yield: 17 %

Procedure:
4-[4-(Piperidine-1-carbonyl)-thiophen-2-yl]-benzoic acid was taken up in DCM (5 mL) and oxalyl chloride (0.099 mL, 3 eq.) added with a drop of DMF. The mixture was then stirred for 1 hour and then evaporated and the residue taken up in DCM (5 mL). Triethylamine (0.106 mL, 2 eq.) was added followed by methylamine.HCl (28 mg, 1.1 eq). The mixture was stirred for 2 hours and then evaporated and the residue purified by column chromatography (EtOAc/iso-hexane) to give the desired product (21.9 mg, 17%). LCMS m/z 329 [M+H]+ R.T.=2.47 min (Analytical Method 3).
Reaction SMILES: [CH:1]1[N:5]=[C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[N:3]2[CH2:19][CH2:20][CH2:21][C:2]=12.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH:8]1[CH2:9][CH2:10][CH2:11][CH:6]([C:4]2[N:3]3[CH2:19][CH2:20][CH2:21][C:2]3=[CH:1][N:5]=2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ncc3n2CCC3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1nc(C2CCCNC2)n2c1CCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
t-Butyl 3-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate (65 mg, 0.1 mmol) was dissolved into a 20% trifluoroacetic acid in dichloromethane solution (2.4 mL). The reaction mixture was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure to afford 3-(piperidin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole trifluoroacetate salt as an oil (94 mg, 100%). The material was used without further purification.
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH3:9][Si:10]([CH3:29])([CH3:28])[O:11][C:12]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](=[O:15])[CH3:14].C(Br)C#C.CCOCC>C1COCC1>[CH3:29][Si:10]([CH3:28])([CH3:9])[O:11][C:12]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13](=[O:15])[CH2:14][CH2:3][C:1]#[CH:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(=O)C(O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Agent: C#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCCC(=O)C(O[Si](C)(C)C)(c1ccccc1)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide is dissolved in dry THF and the solution cooled to -78° C. A solution containing 1-(trimethylsilyloxy)-1-cyclohexyl-1-phenylpropan-2-one in dry THF is added dropwise to the stirring solution at -78° C. After the addition is complete the reaction mixture is stirred for 1 hour. Then a solution of propargyl bromide in dry THF is added dropwise to the solution at -78° C. The solution is then warmed to 0° C. and stirred for 5 hours. An ether-acetic acid solution (9:1) is slowly added and the resultant mixture warmed to room temperature. Ether is added and the solution transferred to a separatory funnel and washed with water. The ether layer is dried over sodium sulfate and evaporated to dryness to afford the product as a white crystalline solid after recrystallization.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@@H:14]([CH2:16][OH:17])[O:13][C:12]3=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:21])C.CC1(C)N([O])C(C)(C)CCC1.C([O-])([O-])=O.[Na+].[Na+]>CC(=O)OCC.O.CC#N>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@@H:14]([C:16]([OH:21])=[O:17])[O:13][C:12]3=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: O=C1O[C@H](CO)CN1c1ccc2c(c1)OCCO2
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)[C@@H]1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of (S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one (985 mg, 3.92 mmol) in 1:1 water/MeCN (20 mL) cooled to 0° C. was added diacetoxyiodobenzene (2.83 g, 2.2 eq.) and TEMPO (122 mg, 0.2 eq). The mixture was stirred at 0° C. for 30 min and at rt overnight. EA and sat. Na2CO3 were added and the phases were separated. The aq. layer was washed once more with EA and then carefully acidified with 1M HCl. The water phase was then extracted twice with EA. The combined org. layers were washed with brine and dried over MgSO4 and concentrated to afford the title intermediate as a colourless solid (847 mg, 81% yield).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Br:12])=[CH:5][N:6]=[CH:7]2.N([O-])=O.[Na+].[S:17](=[O:19])=[O:18].[ClH:20]>O.C(O)(=O)C>[Br:12][C:4]1[C:3]2[C:2]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]=[N:6][CH:5]=1
Reactant: Nc1cccc2cncc(Br)c12
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-5-isoquinolinesulphonyl chloride may be obtained in the following manner: a solution of 5-amino-4-bromoisoquinoline (4.46 g) in hydrochloric acid (d=1.19) (44 cc) is cooled to -5° C. and then treated with a solution of sodium nitrite (1.93 g) in water (10 cc). The reaction mixture is stirred for 1 hour at 0° C. The solution obtained is poured into a saturated solution of sulphur dioxide in acetic acid (48 cc) to which a solution of cuprous chloride (0.65 g) in water (5.6 cc) has been added. The reaction mixture is stirred until the gaseous evolution has ceased and is then extracted with dichloromethane (2×100 cc). The organic phases are combined, washed with water, dried over magnesium sulphate and concentrated. 4-Bromo-5-isoquinolinesulphonyl chloride (5.6 g) is obtained in the form of a yellow solid, which is used without further treatment in the subsequent syntheses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCCCOC(=O)C(C)=O
Product: CCCCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and n-butyl pyruvate (prepared by following General Procedure AO above using n-butanol in place of iso-butanol), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.7 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH3:7].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C1CCCCC1.C(OCC)(=O)C>[C:9]([C:11](=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: CCCC(=O)CCC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCCC(CCC)=C(C#N)C(=O)OCC
Yield: 80000 %

Procedure:
In a 100 mL round-bottom flask was dissolved 4-heptanone (11.4 g, 0.10 mmole) and ethyl cyanoacetate (11.30 g, 0.100 mole) in cyclohexane (25 mL). Acetic add (1.0 mL) and NH4OAc (2.0 g) were added. The solution was magnetically stirred and heated to reflux with a Dean-Stark trap in place overnight under N2. The reaction was cooled to ambient, diluted with ethyl acetate (100 mL) washed with H2O (2×50 mL) and brine (25 mL). The organic extracts were dried (Na2SO4, filtered and concentrated under vacuum to give an oil that was distilled (bp. 135°-137° C., 20 mmHg) to give Ethyl α-cyano-α-(4-heptylidene)acetate (16.65 g, 0.080 mole, 80%). IR (neat film) 2950, 2910, 2860, 2200, 1725, 1570, 1235, 1085 cm-1 ; 1H NMR (400 MHz, CDCl3 δ 4.15 (q, J=9 Hz, 2H), 2.60 (t, J=10 Hz, 2H), 2.38 (t, J=10 Hz, 2H), 1.25 (t, J=9 Hz, 2H), 1.40 (sextet, J=9 Hz, 2H), 1.25 (t, J=9 Hz, 3H), 0.88 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 181.2, 161.5, 115.5, 104.6, 61.4, 40.2, 35.2, 21.9, 21.4, 14.1, 13.8 (one carbon not observed due to overlap); MS (CI) m/e 211 (14.5), 210 (100), 209 (3.59), 182 (3.5), 164 (2.8); HRMS (CI) calcd for C12H20NO2 (M+H) m/e 210.1484, found 210.1491.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: ClCCCBr
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCCN1CCC(c2ccccc2)CC1

Procedure:
1-(3-Chloropropyl)-4-phenylpiperidine can be obtained as follows: a solution of 4-phenylpiperidine (8 g) and of 1-bromo-3-chloropropane (20 cc) in acetonitrile (80 cc) is stirred at 25° C. for 24 hours with potassium carbonate (28 g). The mixture is filtered and is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.06-0.2-mm particle size, 3-cm diameter, 25-cm height) and eluted with a mixture of cyclohexane and ethyl acetate (50--50 by volume), 60-cc fractions being collected. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1-(3-Chloropropyl)-4-phenylpiperidine (8 g) is obtained in the form of oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[I:11][C:12]1[C:16]([CH2:17][OH:18])=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:13]=1>C(Cl)Cl.CC(=O)OCC>[I:11][C:12]1[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:13]=1
Reactant: OCc1cn(C2CCCCO2)nc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1cn(C2CCCCO2)nc1I
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of oxalyl chloride (33.51 g, 22.8 mL, 263 mmol) in DCM (320 mL) at −65° C. under a dry N2 atm. was added DMSO (27.28 g, 24.8 mL, 350.3 mmol) dropwise. The reaction was stirred at −65° C. for 0.5 h then treated dropwise with a solution of (3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methanol (27 g 87.66 mmol) in DCM (75 mL. The mixture was stirred at −65° C. for 1 h then treated with TEA (53.14 g, 73.2 mL, 525 mmol) then warmed to rt and stirred for 0.5 h. DCM (300 mL) was added and the mixture washed with 1N HCl (150 mL×2). The organic layer was dried and then concentrated under vacuum. The residue was purified by SGC using Hex: EA (0%-15%) as eluent to afford 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (22 g, yield: 82%). LCMS (method C): RT=1.97 min, m/z=307.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[O:14]([CH2:21][CH2:22][CH2:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O(C(C)(C)C)[K]>O1CCOCC1>[ClH:1].[ClH:1].[N:8]1([C:7]2[C:2]([O:24][CH2:23][CH2:22][CH2:21][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: OCCCOc1ccccc1
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(C)(C)O[K]
Solvent: C1COCCO1
Product: Cl
Product: c1ccc(OCCCOc2nccnc2N2CCNCC2)cc1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
2-Chloro-3-(1-piperazinyl)pyrazine (608 mg, 3.1 mmol, from Step 1 above) and 3-phenoxypropanol (570 mg, 3.7 mmol) was dissolved in dioxane (10 mL). KO-t-Bu (870 mg, 7 7 mmol) was added and the mixture was stirred at 95° C. for 6 h. The solvent was evaporated and the residue was purified by chromatography on silica gel using CH2Cl2/MeOH (9:1 ) as eluent to give the free base of the title compound as a yellow oil The free base was converted to the dihydrochloride salt: yield 0.380 g (32%), mp 146-146.5° C. Anal. (C17H22N4O2.2HCl) C, H, N.