Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)=[O:6])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:16]1[O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH:5]([C:2]3([CH3:1])[CH2:3][CH2:4]3)[OH:6])=[CH:10][C:11]=2[O:17]1
Reactant: CC1(C(=O)C=Cc2ccc3c(c2)OCO3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(C(O)CCc2ccc3c(c2)OCO3)CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)ethyl 1-methylcyclopropyl carbinol [IV; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 23.4 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-methylcyclopropyl ketone (Preparation A3) and 3.88 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 18.8 g., b.p. 120°-130° C. (0.003 mm.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:33])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: COC(=O)CCCCSc1ccc(-c2ccc(C(=N)N)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)CCCCS(=O)c1ccc(-c2ccc(C(=N)N)cc2)cc1

Procedure:
Prepared from 4-amidino-4'-(4-methoxycarbonylbutylthio)biphenyl by oxidation with m-chloro-perbenzoic acid in methylene chloride at -20° C. for 15 hours.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([F:13])[C:10]3[O:14][C:15]4[C:20]([C@@:21]5([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]5)[C:9]=3[CH:8]=2)=[CH:19][C:18]([NH2:28])=[CH:17][CH:16]=4)[CH2:2]1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:27][C:23]1[O:24][CH2:25][CH2:26][C@:21]2([C:9]3[CH:8]=[C:7]([C:3]4[CH2:2][O:1][CH2:6][CH2:5][CH:4]=4)[N:12]=[C:11]([F:13])[C:10]=3[O:14][C:15]3[C:20]2=[CH:19][C:18]([NH:28][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][N:34]=2)=[CH:17][CH:16]=3)[N:22]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(C2=CCCOC2)nc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1c2cc(C2=CCCOC2)nc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.8 %

Procedure:
To a solution of (S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.095 g, 0.248 mmol) in DMF (1 mL) were added 5-chloro-2-pyridinecarboxylic acid (0.043 g, 0.273 mmol), 0-(−7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium pf6 (0.099 g, 0.261 mmol) and Hunig's base (0.086 ml, 0.497 mmol) and the resulting mixture was stirred at rt for 15 h. The mixture was quenched with 5 drops of 2 N HCl and stirred for 1 min followed by the addition of water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-3% MeOH/DCM. The product was repurified by HPLC to afford (S)—N-(2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.0334 g, 0.064 mmol, 25.8% yield). MS m/z=522.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14]Br)[CH2:7][OH:8])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CC(C)=O>[CH2:16]([NH:23][CH2:14][CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOc1cc(CO)ccc1OCCBr
Reactant: NCc1ccccc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CO)ccc1OCCNCc1ccccc1
Yield: 74.7 %

Procedure:
A mixture of 27.5 g of 3-ethoxy-4-(2-bromoethoxy)benzyl alcohol and 53.5 g of benzylamine was heated to 130°-135° C. for 1.5 hours with stirring. After cooling the reaction mixture, 300 ml of ethyl acetate was added therein and the mixture was washed twice each time with 50 ml of water, dried with anhydrous sodium sulfate and distilled under reduced pressure to provide an orange oily product. To the product was added 50 ml of acetone to form crystals, which were recovered by filtration under suction to provide 22.5 g of N-benzyl-2-(2-ethoxy-4-hydroxymethylphenoxy)ethylamine having a melting point of 164°-167° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:18])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:17])[CH:5]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:44]1[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][O:17][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:2]([Br:1])[C:3]3=[O:18])=[CH:8][CH:7]=2)[CH2:42][CH2:43]1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A flask was charged with 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one (3.0 g, 10.0 mmol) obtained in Step 5, PPh3 (3.93 g, 1.5 eq), 4-(2-hydroxyethyl)morpholine (1.8 mL, 1.5 eq), and THF (33 mL, 0.3M). The resulting mixture was cooled to 0° C. and diisopropyl azodicarboxylate (DIAD, 2.9 mL, 1.5 eq) was added. The reaction mixture was stirred at 0° C. for 30 min and allowed to increase to ambient temperature. After being stirred for 2 h, the solution was concentrated by rotary evaporation under reduced pressure. The residue was dissolved in EtOAc, washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc/hexanes=4:1) to afford the desired product (3.2 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:30]=[CH:29][C:23]2[O:24][C:25]([F:28])([F:27])[O:26][C:22]=2[CH:21]=1>>[F:28][C:25]1([F:27])[O:24][C:23]2[CH:29]=[CH:30][C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])=[CH:21][C:22]=2[O:26]1
Reactant: FC1(F)Oc2ccc(CBr)cc2O1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)OC(F)(F)O2

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 5-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 406.17 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22](Br)[CH:23]=[CH2:24]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:24][CH:23]=[CH2:22])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromophenylacetic acid (12.0 g) of Formula XIII-A in 450 ml of anhydrous THF is cooled to 0° C. via an ice bath. The solution is treated with lithium bis(trimethylsilyl)amide (LiHMDS, 1.0M in THF, 112 ml) which initially results in a light yellow slurry which becomes an orange homogeneous solution. The solution is stirred at 0° C. for 2 hrs followed by warming to room temperature. The solution is recooled to 0° C. and is treated dropwise with allyl bromide (5.0 ml). The mixture is left to stir overnight with gradual warming to room temperature. After 18 hrs the mixture is cooled to 0° C. and quenched with 250 ml of 10% aqueous HCl. The mixture is poured into a separatory funnel and extracted with EtOAc (2×300 ml). The combined organic extracts are dried over anhydrous Na2SO4, filtered and concentrated to give a viscous oil. This material is distilled (0.5 mm Hg, collected 158°-161° C.) to give 10.1 g of the title product.
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][NH:5]/[C:4]/1=[N:13]\[C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40]([N:10]2[CH2:9][CH2:8][C:7]3([NH:3]/[C:4](=[N:13]/[C:14]([C:16]4[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=4)=[O:15])/[NH:5][CH2:6]3)[CH2:12][CH2:11]2)=[O:41])=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)Cc4ccc(OCc5ccccc5)cc4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (300 mg, 0.83 mmol), 4-benzyloxyphenylacetic acid (200 mg, 0.83 mmol), N-methyl morpholine (0.40 ml, 3.64 mmol) and HATU (315 mg, 0.83 mmol) in anhydrous DMF (20 ml) is stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo and subjected to column chromatography (basic alumina, 0-3% MeOH in DCM) to obtain pale yellow solid. The product is dissolved in DCM and MeOH and re-precipitated by adding diethyl ether. The supernatant solvent mixture is decanted and the product is washed again with diethyl ether and dried under vacuum to afford the title compound as a pale yellow solid; [M+H]+ 549.
Reaction SMILES: NCCC1C=CC(O)=C(O)C=1.O[C:13]1C=C2[C:16]([NH:17][CH:18]=[C:19]2[CH2:20][CH2:21]N)=[CH:15][CH:14]=1.OC1C=C(CC(O)=O)C=CC=1O.OC1C=C(C=CC=1O)CN>CO>[CH2:16]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14][CH3:13]
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: NCCc1ccc(O)c(O)c1
Agent: NCc1ccc(O)c(O)c1
Agent: O=C(O)Cc1ccc(O)c(O)c1
Solvent: CO
Product: CCCCNCCCC

Procedure:
Dopamine (DA, Fluka Corporation); 5-hydroxyl tryptamine (5-HT, Sigma Corporation); 3,4-dihydroxyl phenylacetic acid (DOPAC, Sigma Corporation); 3,4-dihydroxyl benzylamine (DHBA, Sigma Corporation); di-n-butylamine (Shanghai Chemical Works), D-8 ion pair reagent (Tianjin Chemical Co., Ltd.), methanol (Guaranteed Reagent, Beijing Chemical Works), other reagents are domestically produced and analytically pure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[C@@H:9]([NH:17]P(OCC)(OCC)=O)[C@H:8]([O:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:7]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.[OH-].[Na+].[NH4+].[OH-]>CCOC(C)=O.O.CCO>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[C@@H:9]([NH2:17])[C@H:8]([O:26][CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NP(=O)(OCC)OCC)[C@H](OS(C)(=O)=O)C1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a solution of 120 mg of 18 and 500 μl EtOH in a 5 mL round-bottom flask equipped with a magnetic stirrer, a reflux condenser and an inert gas supply was added 120 μl sulphuric acid (96%). The reaction mixture was refluxed for 16 h, cooled to RT and diluted with 1.0 mL of EtOAc then cooled to 0-5° C. The cooled solution was treated with 100 μl of a 28% aqueous NaOH solution and with 257 μl of a 25% aqueous NH4OH. The well stirred mixture was diluted with 1.5 mL of water, extracted and the organic phase was separated, dried (Na2SO4), filtered and evaporated at 20° C./120-10 mbar and dried for 1 h at 20° C./<10 mbar to afford 56 mg of 20 as colorless oil.
Reaction SMILES: [O-]CC.[Na+].Cl[CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([O:36][CH3:37])=[CH:34][N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:10].C(Cl)Cl.CO>C(O)C>[N:11]1([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:35]([O:36][CH3:37])=[CH:34][N:33]=[CH:32][N:31]=3)[CH2:26][CH2:25]2)[CH2:6][CH2:7][CH2:8][C:9]1=[O:10]
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(NC(=O)CCCCl)cc23)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N4CCCC4=O)cc23)CC1
Temperature: 78 °C
Yield: 36.2 %

Procedure:
To a mixture of 1-[3-[5-amino-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (2.3g, 6.3 mmol), and sodium carbonate (0.67 g, 6.3 mmol) in 25 mL of acetone, cooled to 0° C., was added dropwise 4-chlorobutyryl chloride (0.89 g, 6.3 mmol). Additional acetone (10 mL) was added and the suspension was stirred for 19 h at 23° C. The insoluble material was separated by filtration and the acetone was removed in vacuo. The crude material was dissolved in EtOAc, and the solution was washed with water, dried (brine, MgSO4), filtered, and concentrated in vacuo to give crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.98 g, 4.2 mmol, 67%) as a gum. Sodium ethoxide (0.67 mL, 2.1 mmol, 21% in ethanol) was added dropwise to a solution of crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.0 g, 2.1 mmol) in ethanol (5 mL). After the addition, the reaction mixture was heated at 78° C. for 90 min and then cooled to room temperature. The insoluble solid was separated and the filtrate was concentrated in vacuo. Silica gel column chromatography (95:5:0.5 CH2Cl2 -MeOH-30% NH4OH) afforded 1-[3-[5-[2-pyrrolidinone-1-yl]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (0.33 g, 0.76 mmol, 36%). The free base (0.25 g, 0.58 mmol) was dissolved in a minimum volume of acetonitrile. A concentrated solution of oxalic acid (0.052 g, 0.58 mmol) in CH3CN was added with stirring. The precipitate was separated by filtration, washed sparingly with CH3CN, and dried at 70° C. in vacuo overnight to give the title compound (0.17 g, 56%): mp 100°-101° C. Anal. Calcd for C24H30N6O2.1.0 C2H2O4.1.15 H2O: C, 57.26; H, 6.34; N, 15.41. Found: C, 56.90; H, 5.96; N, 15.51.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[CH2:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[NH:6]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>CC(=O)CC>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:15]3=[CH:16][C:17]4[CH2:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]1)[C:5](=[O:11])[N:6]2[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stirred solution of 4′-bromo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one (0.64 g, 1.8 mmol) in 2-butanone (25 mL) was added cesium carbonate (1.75 g, 5.3 mmol) followed by 2-(bromomethyl)-5-(trifluoromethyl)furan (0.51 g, 2.2 mmol). The mixture was refluxed for 16 h, cooled to ambient temperature, filtered and concentrated in vacuo to dryness. The residue was subjected to column chromatography (hexanes/ethyl acetate from 3:1 to 1:1) to afford 4′-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one (0.82 g, 90%) as a colorless solid: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ7.27-7.10 (m, 2H), 6.92 (td, J=6.9, 1.8 Hz, 1H), 6.77-6.70 (m, 1H), 6.44-6.33 (m, 3H), 5.15-4.96 (m, 2H), 4.91-4.76 (m, 2H), 4.53 (dt, J=8.6, 1.9 Hz, 2H), 2.98 (t, J=8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.3, 162.4, 162.2, 151.6, 143.4, 141.8 (q, J=43.0 Hz), 130.2, 127.7, 120.0, 119.7, 118.8 (q, J=267.1 Hz), 118.4, 117.0, 112.6, 109.5, 107.7, 92.9, 77.1, 72.4, 59.0, 37.0, 28.9; MS (ES+) m/z 505.8 (M+1), 507.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[C:4]([O:6]C)=O.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:13][C:8]1[CH:9]=[C:10]([Cl:12])[CH:11]=[C:2]2[C:3]=1[C:4]([OH:6])=[C:14]([C:20]([O:22][CH3:23])=[O:21])[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:1]2
Reactant: COC(=O)c1c(N)cc(Cl)cc1Cl
Reactant: COC(=O)C#CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cc(Cl)cc(Cl)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of methyl 2-amino-4,6-dichlorobenzoate (1.30 g, 5.91 mM) and dimethyl acetylenedicarboxylate (0.96 g, 6.78 mM) in t-butanol (14 mL) was refluxed for 18 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and potassium t-butoxide (0.76 g, 6.8 mM) was added to the stirred mixture whereupon a precipitate formed. After refluxing for 1.5 hr, the reaction mixture was cooled to room temperature and filtered to separate the precipitated solids. The solids were washed with t-butanol and then dissolved in water. The resulting solution was acidified with 1N H2SO4 and the resulting precipitate was collected, washed thoroughly with water and dried to give the title compound as a light green solid (1.15 g, 59%). An analytical sample was obtained by recrystallization of a portion from toluene to provide the title compound as a light tan solid, mp 109.5°-111° C. (d); MS(CI): 330 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].Br[CH2:10][CH2:11]Br.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1([C:6]#[N:7])[CH2:11][CH2:10]1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C#N)CC1
Temperature: 80 °C
Yield: 72 %

Procedure:
A suspension of cyano-acetic acid ethyl ester (11.3 g, 0.1 mol), 1,2-Dibromo-ethane, Na4(n-Bu)4Br and K2CO3 in DMF (100 mL) was heated to 80° C. overnight. The mixture was poured into water (600 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether: EtOAc=10:1˜5:1) to give 1-cyano-cyclopropanecarboxylic acid ethyl ester (10 g, yield: 72%). 1H NMR (CDCl3 400 MHz): δ4.21 (q, J=7.2 Hz, 2H), 1.65-1.61 (m, 2H), 1.58-1.55 (m, 2H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[N:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17].O[C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]=[N:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([O:33][C:37]3[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[CH:39][CH:38]=3)=[O:32])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(OC(=O)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
0.6 g of N,N'-dicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 1.0 g of 4-(4-nitrophenylazo)benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichlormethane. The reaction mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The organic phases are combined, washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which are pure according to thin-layer chromatography gives 0.9 g of 4-[4-(4-nitrophenylazo)benzoyloxy]benzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:12]1[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=1Cl)[CH2:8][C:9]([CH3:11])=[CH2:10])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[Na+].CCN(CC)CC>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CS(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:7]1[C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[C:9]([CH3:11])([CH3:10])[CH2:8]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)CN(C(=O)OC(C)(C)C)c1cc(Cl)nnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2nnc(Cl)cc21
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 55.4 %

Procedure:
(3,6-Dichloro-pyridazin-4-yl)-(2-methyl-allyl)-carbamic acid tert-butyl ester (239 g), Bu4NCl (251.8 g), sodium formate (64.2 g), Et3N (354 mL) and Pd(OAc)2 (13 g) were dissolved in DMSO (6 L) and water (354 mL). The reaction mixture was heated to 100° C. and held at temperature for 10 minutes, after which time the reaction was complete and the mixture was allowed to cool to room temperature. The mixture was diluted with water (9 L) and extracted with EtOAc (4×3 L). The combined organic extracts were washed with brine (3 L). The emulsion was allowed to separate overnight and the interface back extracted with EtOAc (3 L). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated. Chromatography on silica, eluting with a solvent gradient of 10% EtOAc in heptane to 20% EtOAc in heptane, gave the title compound (118 g) [M+H]+=284.
Reaction SMILES: C([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:6](N)=[O:7])CCC.[OH-:16].[Na+].C(N)CCC.Cl>[Ni].O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:5][C:6]([OH:7])=[O:16]
Reactant: CCCCC(C(N)=O)c1ccccc1Cl
Reactant: [OH-]
Agent: [Ni]
Agent: Cl
Agent: [Na+]
Solvent: CCCCN
Solvent: O
Product: O=C(O)Cc1ccccc1Cl
Yield: 95 %

Procedure:
225.5 g (1 mol) of N-t.-butyl-(2-chlorophenyl)-acetamide (melting point: 128°-130° C.) and 281 g of 15% strength NaOH (1.05 mols) are heated at 260° C., while stirring, for 3 hours in a 0.7 l nickel autoclave. The autoclave is cooled and the reaction mixture is run into a distillation apparatus. Distillation through a 30 cm column up to a head temperature of 100° C. gives 71.5 g of t.-butylamine of 97% purity, corresponding to a yield of 95% of the theoretical yield. 200 ml of water and 100 ml of 30% strength hydrochloric acid are added to the distillation bottom product. The acid which has been precipitated is filtered off with suction and dried in vacuo. 157.8 g of o-chlorophenylacetic acid of melting point 95° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[OH-].[K+].[I:13]I.[OH-].[NH4+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:13]
Reactant: II
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Into a round-bottom flask was dissolved 5-bromo-1H-indazole (1.99 g, 0.0101 mol) in N,N-dimethylformamide (10.0 mL). To this stirred solution was added potassium hydroxide (2.03 g, 0.0362 mol) then a cold solution of iodine (2.82 g, 0.0111 mol) in N,N-dimethylformamide (12.0 mL, 0.155 mol) was added dropwise. The mixture was stirred at room temperature for 2 hours before being added dropwise to an ammonium hydroxide (150 mL, 3.8 mol) solution in water (2.0 L) to give a precipate. The precipitate was collected and dried under vacuum for 18 hours to yield 3.00 g (92%) of 5-bromo-3-iodo-1H-indazole.