Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19]I)([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CNC=[O:24].O>CCOCC>[C:1]([O:11][C:12]([C:15]([CH2:18][CH2:19][OH:24])([F:17])[F:16])([F:14])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Reactant: CNC=O
Solvent: O
Solvent: CCOCC
Product: OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A mixture of C3F7OCF2CF2CH2CH2I (300 g, 0.68 mol) and N-methyl-formamide (300 mL), was heated to 150° C. for 26 h. Then the reaction was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (77 mL) and p-toluene sulfonic acid (2.59 g) were added to the crude ester, and the reaction was stirred at 70° C. for 15 minutes. Then ethyl formate and ethyl alcohol were distilled out to give a crude product. The crude product was dissolved in ether, washed with aqueous sodium sulfite, water, and brine in turn, then dried over magnesium sulfate. The product was then distilled to give 199 g of C3F7OCF2CF2CH2CH2OH in 85% yield. The boiling point was 71˜73° C. at 40 mm Hg (5333 Pa).
Reaction SMILES: F[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH3:16])[C:5]([C:14]#[N:15])=[C:6]2[C:10]=1[O:9][C:8]([N:11]([CH3:13])[CH3:12])=[N:7]2.C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>CS(C)=O.ClCCl>[CH3:12][N:11]([CH3:13])[C:8]1[O:9][C:10]2[C:6](=[C:5]([C:14]#[N:15])[C:4]([CH3:16])=[C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:2]=2[N:34]2[CH2:35][CH2:36][C@H:32]([N:31]([CH3:37])[CH3:30])[CH2:33]2)[N:7]=1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)C)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
7-Fluoro-2-(dimethylamino)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-132) (0.18 g, 0.61 mmol) was suspended in dimethyl sulfoxide (5 ml), then triethylamine (0.17 ml, 1.23 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.16 ml, 1.26 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), then diisopropyl ether was added, and the insoluble matter was collected by filtration to obtain a pale beige solid (78.5 mg, 33%).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][N:27]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:42])[CH2:35][CH2:34]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[N:30]([CH3:31])[N:29]=[N:28][N:27]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnnn2C)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 171.7 %

Procedure:
To a solution of 3-butyl-4-[4-cyclohexyloxy-3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.379 mmol, 214 mg) in DCM (2 mL) was added formaldehyde solution in water (37%, 1.14 mmol, 0.085 mL) and 2 drops of acetic acid. Sodium triacetoxyborohydride (1.52 mmol, 339 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1 h and partitioned between ethyl acetate (20 mL) and saturated aq. sodium bicarbonate solution (20 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel using 2 M ammonia in MeOH/DCM 1:19 to 1:14, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The yellow solid was dried overnight under high vacuum to provide the title compound (188.2 mg). LCMS: m/z 507 [M+1] 1H NMR (400 MHz, CD3OD) δ 7.85 and 7.93 (1H, s), 7.79-7.85 (1H, m), 7.69 (1H, dd), 7.49-7.53 (1H, m), 5.38-5.56 (1H, m), 4.64-4.69 (1H, m), 4.05 and 4.06 (3H, s), 3.13-3.69 (6H, m), 2.94 (3H, s), 1.97-2.54 (12H, m), 1.30-1.63 (6H, m), 0.84 (3H, dt).
Reaction SMILES: I[C:2]1[S:14][C:5]2[N:6]([CH3:13])[S:7](=[O:12])(=[O:11])[CH2:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[CH2:15]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[C:16]#[CH:17].CO>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:13][N:6]1[C:5]2[S:14][C:2]([C:17]#[C:16][CH2:15][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)=[CH:3][C:4]=2[C:9](=[O:10])[CH2:8][S:7]1(=[O:12])=[O:11]
Reactant: C#CCOC1CCCCO1
Reactant: CN1c2sc(I)cc2C(=O)CS1(=O)=O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1c2sc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a stirring mixture of 6-iodo-1-methyl-1H-thieno[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide (Preparation 34, 1.0 g), triethylamine (1.5 mL) CuI (13.8 mg), and tetrahydro-2-(2-propynyloxy)-2H-pyran (0.49 g) in toluene (50 mL) at ambient temperature is added tetrakis triphenylphosphine palladium (40 mg). The resulting mixture is stirred overnight at ambient temperature. MeOH (50 mL) is added, the mixture is stirred 20 min and the solvent is removed in vacuo. The residue is partitioned between 10% HCl/H2O/EtOAc (100 ml each), and the organic layer is separated. The solvent is removed in vacuo and the residue purified by flash column chromatography (4/1, hexanes/EtOAc) to afford 0.68 g (66%) of the title compound as a white solid. Physical characteristics: 1H NMR (CDCl3) δ1.52-1.86, 3.39, 3.55, 3.84, 4.21, 4.45, 4.81, 7.38; MS (ESI−) m/z 354 (M−H)−. Anal. Found: C, 50.70; H, 4.89; N, 3.95.
Reaction SMILES: C[Zn]C.[CH3:4]CCCCCC.Br[C:12]1[CH:13]=[C:14]([C:35]([F:38])([F:37])[F:36])[C:15]2[N:16]([N:19]=[C:20]([CH2:22][CH2:23][C:24]3[N:25]([CH3:34])[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:28]=3)[N:21]=2)[C:17]=1[CH3:18]>O1CCOCC1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Ni](Cl)Cl>[CH3:18][C:17]1[N:16]2[N:19]=[C:20]([CH2:22][CH2:23][C:24]3[N:25]([CH3:34])[N:26]=[C:27]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:28]=3)[N:21]=[C:15]2[C:14]([C:35]([F:38])([F:36])[F:37])=[CH:13][C:12]=1[CH3:4]
Reactant: CCCCCCC
Reactant: Cc1c(Br)cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)nn3C)nn12
Agent: Cl[Ni]Cl
Agent: C[Zn]C
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)nn3C)nn2c1C
Temperature: 100 °C
Yield: 62.1 %

Procedure:
1 M dimethylzinc in heptane (70 μL, 70 μmol, Eq: 1.00) was added to 6-bromo-5-methyl-2-[2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-8-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 65.5 μmol, Eq: 1.00) and 1,3-bis(diphenylphosphino)propane-nickel(II) chloride (13 mg, 24.0 μmol, Eq: 0.366) in dioxane (1 ml). The mixture was heated to 100° C. for 1 h in a microwave oven. Purification by preparative HPLC gave the desired product (16 mg, 61.7%) as a white solid. MS: m/z=394.4 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH2:30]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:30][CH3:29])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 27) (4.70 g, 11.9 mmol) in ethanol (80 ml) was treated with methylamine (33% w/v in ethanol, 12.0 ml, 96.0 mmol) and the solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: ethyl acetate (9:1) gradually changing to dichloromethane:ethyl acetate (8:2) to afford the title compound as a pale yellow oil which crystallised on standing (4.23 g).
Reaction SMILES: Cl[CH:2]1[NH+:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([O:23][CH3:24])=[C:4]([O:25][CH3:26])[C:3]1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3.[Cl-].[CH2:28]([Mg]Cl)[CH:29]=[CH2:30].O1C[CH2:36][CH2:35][CH2:34]1>C(OCC)C>[CH2:28]([C:2]1([CH2:36][CH:35]=[CH2:34])[N:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([O:23][CH3:24])=[C:4]([O:25][CH3:26])[C:3]1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3)[CH:29]=[CH2:30]
Reactant: C=CC[Mg]Cl
Reactant: COc1ccc2c(c1OC)C(Cl)[NH+]1CCc3cc4c(cc3C1=C2)OCO4
Reactant: C1CCOC1
Agent: [Cl-]
Solvent: CCOCC
Product: C=CCC1(CC=C)c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a suspension of 8-chloro-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; chloride (0.2 g, 0.5 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of allylmagnesium chloride in tetrahydrofuran (1.3 M, 2.16 mL, 4 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8,8-diallyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (28 mg, 13%). LC/MS m/e calcd for C26H27NO4 (M+H)+: 418.51, observed: 418.3; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.66-2.78 (m, 4 H) 2.94 (dd, J=15.41, 6.06 Hz, 2 H) 3.26 (t, J=5.43 Hz, 2 H) 3.77 (d, J=10.36 Hz, 6 H) 4.88 (d, J=10.36 Hz, 2 H) 4.98 (d, J=17.43 Hz, 2 H) 5.35 (s, 1 H) 5.66-5.78 (m, J=16.99, 10.29, 7.07, 6.82 Hz, 2 H) 5.98 (s, 2 H) 6.51 (d, J=8.34 Hz, 1 H) 6.72 (s, 1 H) 6.80 (d, J=8.34 Hz, 1 H) 7.15 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].Cl[N:29]1C(=O)CC[C:30]1=O.[Cl-].[F:37][C:38]([F:46])([F:45])[CH2:39][NH:40][C:41]([NH2+]C)=[O:42].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:30][C:41]([NH:40][CH2:39][C:38]([F:37])([F:45])[F:46])=[O:42])=[N:5][OH:6]
Reactant: C[NH2+]C(=O)NCC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CNC(=NO)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl)NCC(F)(F)F
Temperature: 75 °C
Yield: 52 %

Procedure:
To a solution of 2-Chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzaldehyde oxime (i.e. the product of Step 3, 250 mg) in DMF (5 mL) was added N-chloro succinimide (80 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of (2,2,2-trifluoro-ethylcarbamoyl)-methyl-ammoniumchloride (110 mg) and triethylamine (0.29 mL, 0.21 g) in THF (10 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (176 mg, 52%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([F:33])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH2:49][CH2:50][CH2:51][N:52]1[CH:56]=[CH:55][NH:54][C:53]1=[O:57]>C(O)CCC>[F:33][C:13]1[N:12]=[CH:11][C:10]([CH2:9][N:7]([CH3:8])[C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:15]([C:16]2[C:21]3[S:22][C:23]([C:25]4[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:49][CH2:50][CH2:51][N:52]5[CH:56]=[CH:55][NH:54][C:53]5=[O:57])[N:26]=4)=[CH:24][C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH:14]=1
Reactant: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12)C(=O)OC(C)(C)C
Reactant: NCCn1cc[nH]c1=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4cc[nH]c4=O)ncc3F)sc12)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 45.4 %

Procedure:
Combine {4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-6-fluoro-pyridin-3-ylmethyl}-methyl-carbamic acid tert-butyl ester (0.52 g, 1.04 mmol) and triethylamine (0.87 mL, 6.24 mmol) in n-butanol (10.0 mL). Add 1-(2-amino-ethyl)-1,3-dihydro-imidazol-2-one; compound with trifluoro-acetic acid (0.75 g, 3.12 mmol). Heat the reaction mixture at 120° C. for 54 hours for completion, then cool to room temperature. Remove solvent on a rotovap to obtain the crude product. Purify the crude by column chromatography (0.5% to 6% 2 M NH3 in methanol solution in dichloromethane) to afford the desired product (0.28 g). MS (ES) m/z 594 [M+1]+.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][C:7](=[NH:14])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13].[NH2:15][C:16](=[NH:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].[C:24]([O:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34])(=[O:28])[C:25]([CH3:27])=[CH2:26]>C(O)C>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[C:24]([O:29][CH2:30][CH2:31][NH:32][C:33]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]([NH2:6])=[NH2+:14])=[O:34])(=[O:28])[C:25]([CH3:27])=[CH2:26].[C:24]([O:29][CH2:30][CH2:31][NH:32][C:33]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]([NH2:15])=[NH2+:23])=[O:34])(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: N=C(N)NCCCCN
Reactant: O=S(=O)(O)O
Reactant: C=C(C)C(=O)OCCN=C=O
Solvent: CCO
Product: C=C(C)C(=O)OCCNC(=O)NCCCCNC(N)=[NH2+]
Product: O=S(=O)([O-])[O-]
Reaction time: 0.5 h

Procedure:
A solution of agmatine hemisulfate (2.00 g, 11.2 mmol) dissolved in 20 mL of ethanol was treated with 2-isocyanatoethyl methacrylate (1.50 mL, 10.6 mmol) over the course of a few minutes. The solution was allowed to stir for 30 min after which time the reaction mixture was concentrated at ambient temperature. The resulting syrup was concentrated twice with toluene to give the title compound as a white foam. 1H NMR (500 MHz, D2O) δ 6.13 (s, 1H), 5.73 (s, 1H), 4.23 (t, J=4.8 Hz, 2H), 3.44 (t, J=4.8 Hz, 2H), 3.18 (t, J=7.0 Hz, 2H), 3.11 (t, J=6.7 Hz, 2H), 1.92 (s, 3H), 1.65-1.49 (m, 4H).
Reaction SMILES: CC1CC[C@@H](C(C)=C)CC=1.C([O-])([O-])=[O:12].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[C:29]1(=O)[O:34][C:32](=O)[C:31]2=CC=CC=C12.[C:40]1([CH3:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH3:46][C:40]12[O:12][CH:45]1[CH2:44][CH:43]([C:32]1([CH3:31])[O:34][CH2:29]1)[CH2:42][CH2:41]2
Reactant: O=C([O-])[O-]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccccc1
Agent: C=C(C)[C@H]1CC=C(C)CC1
Agent: OO
Agent: [Na+]
Product: CC1(C2CCC3(C)OC3C2)CO1
Temperature: 60 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
Limonene (1.36 g, 10 mmol) was dissolved in toluene (25 ml), and a composition containing sodium percarbonate (10.5 g, 66.7 mmol) and phthalic anhydride (14.8 g, 100 mmol) was added thereto. The mixture was stirred at 60° C. After 12 hours, the reaction solution was washed with water to thereby completely remove phthalic acid, sodium phthalate, and disodium phthalate, which were generated as by-products, and the remaining H2O2. Toluene was distilled off from the organic phase by distillation, and as a result, 1.66 g (99% yields) of limonene diepoxide with a GC purity of 100% was obtained.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH3:5])[CH3:3].C(Cl)(Cl)=C.S(=O)(=O)(O)O.C[OH:17].C[CH2:19][O:20][CH2:21][CH3:22]>>[CH3:1][C:2]([CH3:3])([CH2:4][CH3:5])[CH2:22][C:21]([O:20][CH3:19])=[O:17]
Reactant: CO
Reactant: CCC(C)(C)O
Reactant: CCOCC
Agent: O=S(=O)(O)O
Solvent: C=C(Cl)Cl
Product: CCC(C)(C)CC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-Methyl-2-butanol (480 mL, 4.4 mol) and vinylidene chloride (508 mL, 5.2 mol) were added to sulfuric acid (2 L) at 10° C. Methanol (1750 mL) was added slowly allowing exotherm to attain 40° C. and subsequently 60° C. for 15 minutes. The reaction mixture was cooled and poured into a stirred mixture of ether and ice water. The ethereal layer was washed with 1 N aqueous sodium hydroxide and brine, dried (magnesium sulfate), filtered, and concentrated in vacuo to afford methyl 3,3-dimethylpentanoate which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:38][CH:37]1[CH2:49]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:49][CH:37]2[CH2:38][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][CH2:41][N:36]2[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(CC4CN(Cc5ccccc5)CCN4Cc4ccccc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with 1,4-dibenzyl-2-chloromethyl-piperazine described in Journal of Medicinal Chemistry 1999, 42(9), 1587-1603) gave the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[C:9]1([NH:15][C:16](=[O:30])[NH:17][N:18]=[C:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.C(O)C>[N:2](=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[C:19]1=[N:18][NH:17][C:16]([NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:30])[OH:3]
Reactant: NO
Reactant: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(NN=c1c(=O)c2ccccc2c1=NO)Nc1ccccc1

Procedure:
0.01 mol of hydroxylamine hydrochloride and 0.01 mol sodium acetate in solution in 20 ml water were added to a solution of 0.01 mol of 2-(4-phenyl semicarbazono)-indan-1,3-dione in 150 ml ethanol. The reaction mixture was refluxed for 1 hour, then the ethanol was eliminated at reduced pressure. The resulting crystals were dried on suction pump, washed in water, dried and recrystallised from isopropanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH2:30]([NH:32][CH2:33][CH2:34][OH:35])[CH3:31]>CN(C)C(=O)C>[CH2:30]([N:32]([CH2:33][CH2:34][OH:35])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)[CH3:31]
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCNCCO
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCCOC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 509 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:14][S:15](C)=O.C[Si](C)(C)SC.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([S:15][CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Reactant: CS(C)=O
Agent: CS[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: CSc1cc(I)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-iodo-3,5-dinitrobenzene (15 g, 51 mmole) in 150 mL of DMSO trimethyl(methylthio)silane (10 mL, 70.6 mmol) was added slowly. The resulting reaction mixture turned purple at this point. Cesium carbonate 99.9% (23.13 g, 71.4 mmol) was then added. After stirring at room temperature for 18 h, the reaction mixture was diluted with 150 mL of ether, washed with 400 mL of saturated sodium bicarbonate solution and 150 mL of brine. The combined organic phase were then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1-iodo-3-methylsulfanyl-5-nitro-benzene as a yellow solid. The crude material was used in the next step without further purification. HR-EI(+) m/e calcd for C7H6NO2SI (M+) 294.9164, found 294.9164.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].C(N(CC)CC)C>CN(C=O)C.CO.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[C:25][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2
Reactant: C#CCN(C)C
Reactant: O=C1Nc2ccccc2C1=C1OCc2cc(Br)ccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 65 °C
Yield: 68.2 %

Procedure:
To a mixture of 3-(5-bromo-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (467 mg, 1.42 mmol), 1-dimethylamino-2-propyne (473 mg, 5.69 mmol), copper(I) iodide (48 mg, 0.25 mmol), triethylamine (287 mg, 2.84 mmol) in DMF (5 ml), was added tetrakis(triphenylphosphine)palladium (100 mg, 0.086 mmol). The mixture was heated at 65° C. under argon for 16 hours, and then cooled to room temperature. The mixture was diluted with MeOH (100 ml). The insoluble material was removed by filtration, and the filtrate solution was concentrated and then diluted with EtOAc (200 ml). The resulting mixture was washed with brine (3×100 ml), dried over anhydrous Na2SO4, and concentrated to give a dark-brown residue. Purification of the residue by silica gel column chromatography, eluted with a gradient of MeOH in CHCl3, afforded 3-[5-(3-dimethylamino-prop-1-ynyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a brown solid (320 mg, 68%).