Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: CO
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (5.0 g, 17.7 mmol) and dimethylpiperidin-4-ylamine (2.7 g, 21.2 mmol) in DCE (100 mL) was stirred at room temperature for 4 hours then triacetoxyborohydride (5.6 g, 26.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (2×70 g). The cartridge was washed with MeOH/DCM (1/1: v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1: v/v). The solvents were removed and the residue was precipitated from IMS to give [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]dimethylamine as a white solid (4.45 g, 64%). LCMS (Method B): RT 0.37 min and 1.85 min; [M+H]+ 396
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[F:13])#[N:2].[NH2:27][NH2:28].O>CO>[F:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]([O:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1)=[N:4][C:3]([C:1]([NH:27][NH2:28])=[NH:2])=[CH:12]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(F)c23)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3cccc(F)c23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-8-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (600 mg, 1.61 mmol) in MeOH (15 mL) was added NH2NH2—H2O (10 mL) and the resulting mixture was heated to reflux for 2 hours. The solvent was removed in vacuo to afford the title compound as a white solid, which was used without further purification (500 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([O:23][C:24]([F:27])([F:26])[F:25])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:19])([F:18])[F:17])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2)[CH3:2].[OH:28]S(O)(=O)=O>CC(C)=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([O:23][C:24]([F:25])([F:27])[F:26])[CH:9]=[C:10]2[C:15]=1[O:14][CH:13]([C:16]([F:17])([F:18])[F:19])[C:12]([C:20]([OH:22])=[O:21])=[CH:11]2)[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOC#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 198.8 %

Procedure:
To a solution of the crude product from Step 1 (2.13 g) in a mixture of acetone (80 mL) and H2O (10 mL) was added H2SO4 (0.250 g, 2.55 mmole) and the resulting mixture was stirred at room temperature for 2.5 hrs. Brine (200 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2.10 g of the crude product as a yellow oil: ESLRMS m/z 414.0 (M+H, C16H12F6O6, Calc'd 415.0).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7](=[O:13])[CH:8]=[C:9]([C:11]#[N:12])[O:10][C:5]=2[CH:4]=1.[Na].[OH:17][C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=1)[O:21][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.O>CS(C)=O>[C:11]([C:9]1[O:10][C:5]2[CH:4]=[C:3]([CH2:2][O:17][C:18]3[CH:35]=[CH:34][CH:33]=[C:20]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)[CH:19]=3)[CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[CH:8]=1)#[N:12]
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1cc(=O)c2ccc(CBr)cc2o1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(=O)c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.5 g of 7-bromomethyl-2-cyano-4-oxo-4H-1-benzopyran and 1.5 g of the sodium salt of 2-(3-hydroxyphenoxy)methylquinoline are combined in 10 ml of dimethylsulfoxide and stirred at room temperature for 5 hours. The mixture is poured into water and extracted with methylene chloride. The organic solution is dried and evaporated. The residue is recrystallized from ethyl acetate/dimethylformamide to give 0.72 g of 2-cyano-7-(3-(quinolin-2- ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran.
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]1[O:12][CH:11]2[CH:8]([C:9](=[O:27])[N:10]2[C:13](=[C:24]([CH3:26])[CH3:25])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:7]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:5])=[N-].CCOCC.C(Cl)[Cl:44]>>[Cl:44][CH2:3][C:4]([CH:6]1[O:12][CH:11]2[CH:8]([C:9](=[O:27])[N:10]2[C:13](=[C:24]([CH3:26])[CH3:25])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[N:7]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:5]
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)C=[N+]=[N-])N2C(=O)OCc1ccccc1
Reactant: ClCCl
Solvent: CCOCC
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2C1OC(C(=O)CCl)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 435 mg of benzyl α-(3ξ-diazoacetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 4 ml of methylene chloride is added 1 ml of ether containing 16% hydrogen chloride, and the mixture stirred at room temperature for 30 minutes and then concentrated under reduced pressure to yield 433 mg of benzyl α-(3ξ-chloroacetyl-2-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crystals.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[NH:24][CH3:25].C(OCC)(=O)C>O1CCCC1>[CH3:25][N:24]1[C:15]2[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:22]=[CH:23][C:14]=2[NH:13][C:1]1=[O:2]
Reactant: CNc1cc(C(=O)OC)ccc1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Add carbonyl diimidazole (567 mg, 3.50 mmol) to a solution of methyl 4-amino-3-(methylamino)benzoate (586 mg. 3.19 mmol) in tetrahydrofuran (20 mL) at room temperature. Stir the yellow solution at room temperature for 16 hours. Add carbonyl diimidazole (500 mg, 0.96). Stir at room temperature for 4 hours. Add ethyl acetate (75 mL). Wash with 10% citric acid (5 mL), 1N sodium hydroxide (5 mL), and brine (5 mL). Dry the organics over magnesium sulfate, filter, concentrate, and dry under high vacuum to yield a crude yellow solid (690 mg, 100%). Triturate this crude solid with ethyl acetate (10 mL). Filter the precipitate and dry under high vacuum to yield methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (422 mg, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 3.46 (s, 3H), 3.92 (s, 3H), 7.12 (d, J=8.21 Hz, 1H), 7.68 (s, 1H), 7.84 (dd, J=8.31, 1.47 Hz, 1H), 9.87-10.03 (m, 1H).
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>C1COCC1>[CH3:16][C:17]1([CH3:24])[CH2:22][CH2:21][C:20](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:19][CH2:18]1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: CC1(C)CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(=C2SCCCS2)CC1
Temperature: -78 °C

Procedure:
To a solution of 2-trimethylsily-1,3-dithiane (42.3 g, 0.22 mol) in THF (400 mL) at 0° C. under an argon atmosphere was added a solution of n-butyl lithium (2.5 M in hexanes, 88 mL, 0.22 mol) and the mixture was cooled to −78° C. A solution of 4,4-dimethyl cyclohexanone (13.9 g, 0.11 mol) in THF (50 mL) was added over 10 min. After 2 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (200 mL). The aqueous phase was extracted with EtOAc (200 mL×2) and the combined organic layers were dried (MgSO4) and were evaporated. The reaction by-products were removed by vacuum distillation to yield the desired product as a white wax (21 g, 85%). MH+229
Reaction SMILES: [CH2:1]([N:5]([CH2:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].[CH2:36]=O>C1COCC1>[CH2:1]([N:5]([CH2:13][C:14](=[O:35])[CH:15]=[CH2:36])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCN(CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Reactant: C=O
Solvent: C1CCOC1
Product: C=CCCN(CC(=O)C=C)C(=O)OC(C)(C)C
Temperature: 18 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
To a mixture of tert-butyl N-but-3-enyl-N-[2-oxo-3-(triphenyl-phosphanylidene) propyl]carbamate (5.80 g, 11.90 mmol, 1.00 Eq) in THF (30 mL), was added HCHO (96.58 g, 1.19 mol, 100.00 Eq) in one portion at 18° C. The mixture was stirred at 18° C. for 15 hr. TLC showed the reaction was completed. The mixture was extracted with PE (100 mL*3). The combined organic phase was washed with saturated brine (200 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=50/1, 40/1) to afford tert-butyl N-but-3-enyl-N-(2-oxobut-3-enyl)carbamate (1.40 g, 5.85 mmol, 49.16% yield) as yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:26]([NH:28][CH3:29])[CH3:27]>CN(C=O)C>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([N:28]([CH2:26][CH3:27])[CH3:29])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: CCNC
Solvent: CN(C)C=O
Product: CCN(C)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (Intermediate 6: step c, 0.100 g, 0.231 mmol), N-ethylmethylamine (1.5 mL) and DMF (0.5 mL) were heated in a sealed tube at 80° C. for 8 hours, cooled to room temperature, evaporated in vacuo, diluted with acetonitrile and filtered. The filtrate was evaporated in vacuo and chromatographed (EtOAc/Heptane) to provide the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].C(N(CC)C(C)C)(C)C.[F:16][C:17]([F:38])([F:37])[C:18]([N:20]([CH:28]1[CH2:30][CH:29]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:19]>C(#N)C>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:20]([CH:28]2[CH2:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18](=[O:19])[C:17]([F:16])([F:37])[F:38])[CH2:27][CH2:26]1)#[N:6]
Reactant: N#CCCCBr
Reactant: O=C(N(CC1CCNCC1)C1CC1c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCCN1CCC(CN(C(=O)C(F)(F)F)C2CC2c2ccccc2)CC1

Procedure:
Added 4-bromobutanenitrile (100 mg, 0.674 mmol) to a solution of N,N-diisopropylethylamine (0.353 mL, 2.022 mmol), 2,2,2-trifluoro-N-(2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (220 mg, 0.674 mmol) in acetonitrile (25 mL) and heated to reflux for 16 hours. Concentrated on rotovap and the residue was purified via Biotage (0% to 100% EtOAc:Hex; then 0% to 20% MeOH:DCM to get off more product: 10 g-HP—silica gel column).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15](N3C=NC=N3)[C:16]=2[N:17]=1.CC(O)C>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:4][CH:2]([CH3:3])[CH3:1])[C:16]=2[N:17]=1
Reactant: CC(C)(C)[O-]
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Potassium tert-butoxide (4.0 mL; 1M in THF) was added to a suspension of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (1.0 g) and 2-propanol (0.313 mL) in DCM (50 mL). After stirring at room temperature for 30 minutes, the mixture was diluted with DCM (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-(2-propoxy)-pyrido[3,2-d]pyrimidin-2-ylamine as a yellow solid (0.65 g, yield: 67%) which was characterized by its mass spectrum as follows: MS (m/z) 239.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][C:4]#[N:5].[CH3:7][N:8]([CH:10](OC)OC)[CH3:9]>>[CH3:9][N:8](/[CH:10]=[C:3](/[C:2](=[O:1])[CH3:6])\[C:4]#[N:5])[CH3:7]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC#N
Product: CC(=O)/C(C#N)=C/N(C)C

Procedure:
3-Oxo-butyronitrile (113 g, 1.36 mol) and DMF-DMA (215 g, 1.81 mol) were heated to 80° C. for two hours. The solvents were then removed under vacuum to yield a solid. The solid was partitioned between ethyl acetate (1.5 L) and saturated sodium bicarbonate solution (1 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (1.5 L). The organic layers were combined and the solvent removed under vacuum to yield the title compound as a solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43][C:44]3[N:48](COCC[Si](C)(C)C)[N:47]=[N:46][CH:45]=3)=[CH:39][CH:38]=2)O1>>[NH:48]1[C:44]([S:43][C:40]2[CH:41]=[CH:42][C:37]([C:2]3[N:7]4[CH:8]=[C:9]([CH2:11][CH2:12][C:13]5[CH:22]=[CH:21][C:20]6[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:38][CH:39]=2)=[CH:45][N:46]=[N:47]1
Reactant: CC1(C)OB(c2ccc(Sc3cnnn3COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Product: c1ccc2nc(CCc3cn4c(-c5ccc(Sc6cnn[nH]6)cc5)cnc(N5CCOCC5)c4n3)ccc2c1

Procedure:
The title compound 36 was prepared from compound 3a and compound 63c using the methods described in Example 1, Step G. Subsequently, the SEM group was removed using the methods described in Example 37, Step C. 1H-NMR (400 MHz CDCl3) δ (ppm): 3.22-3.32 (m, 2H), 3.35-3.43 (m, 2H), 3.83 (br. s., 4H), 4.14 (br. s., 4H), 7.17-7.30 (m, 3H), 7.31-7.39 (m, 4H), 7.48-7.59 (m, 1H), 7.73 (br. s., 1H), 7.76-7.88 (m, 2H), 8.01 (d, J=8.6 Hz, 1H), 8.10 (d, J=8.6 Hz, 1H). Mass Spectrum LCMS, ESI (pos.) Calcd. for C29H26N8OS: 535.0 [M+H]. found 535.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30].CCN(CC)CC>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: O=C=Nc1ccccc1F
Reactant: COc1cc(CC(=O)OCc2ccccc2)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OCc2ccccc2)ccc1NC(=O)Nc1ccccc1F
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a stirred solution of benzyl 4-amino-3-methoxyphenylacetate (1.36 g, 5 mmol) in THF (20 mL) was added 2-fluorophenyl isocyanate (561 ul, 5 mmol) and a catalytic amount of Et3N. The resulting mixture was stirred for 3 hr. The mixture was quenched by the addition of H2O (10 mL) and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 as eluent to give 2.06 g (q.y.) benzyl 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetate as a green oil. 1H-NMR (CDCl)3 δ3.63 (2H, s), 3.82 (3H, s), 5.14 (2H, s), 6.79-7.37 (12H, m), 8.01 (1H, d, J=7.8 Hz), 8.09-8.14 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Br)[CH:11]=[CH2:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)C>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: C=CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
3-Hydroxybenzaldehyde (1.00 g, 8.19 mmol) and allyl bromide (0.780 mL, 9.01 mmol) in N,N-dimethylacetamide (35 mL) was treated with Cs2CO3 (4.01 g, 12.3 mmol) and allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with diethyl ether (150 mL), washed with 1N HCl, saturated NaHCO3, brine, dried (MgSO4), filtered and the filtrate concentrated. The residue was purified by flash chromatography (silica gel, using 7% ethyl acetate/hexanes as eluent) to provide the title compound as a clear oil (1.19 g, 89%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Li].[Cl-:20].[Cl-].[Cl-].[Cl-].[Zr+4:24]>C(OCC)C>[Cl-:20].[Cl-:20].[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Zr+2:24][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH2:12][C:4]1[C:5]3[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][C:10]=3[N:2]([CH3:1])[C:3]=12
Reactant: [Zr+4]
Reactant: [Li]c1cccc2c1Cc1c-2n(C)c2ccc(C)cc12
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccc2c(c1)c1c(n2C)-c2cccc([Zr+2]c3cccc4c3Cc3c-4n(C)c4ccc(C)cc34)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under the nitrogen protection, 0.24 gram (0.001 mole) of 5,8-dimethyl-5,10-dihydroindeno[1,2-b]indolyllithium is dissolved in 20 mL of diethylether. The solution is slowly added to zirconium tetrachloride (0.12 gram, 0.0005 mole) slurry in 20 mL of diethylether. The mixture is stirred at 25° C. for two hours, filtered, washed with diethylether and dried under vacuum, yielding 0.23 gram of Catalyst III.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[CH2:30][CH2:31][CH2:32][CH3:33].ClCCl>N1C=CC=CC=1>[NH2:29][C:20]1[C:19]2[N:18]=[C:17]([CH2:30][CH2:31][CH2:32][CH3:33])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Benzenesulfonyl chloride (0.45 ml in 10 ml dichloromethane, 3.5 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol), dichloromethane (140 ml), and pyridine (0.8 ml). The reaction was maintained at room temperature for four hours and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol, Rf 0.28) followed by recrystallization from dichloromethane\diethyl ether to provide 1.14 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzenesulfonamide as a white powder, m.p. 75.5-79.0° C. 1H NMR (500 MHz, DMSO-d6) δ7.99 (d, J=7.7 Hz, 1H), 7.76 (d, J=7.2, 2H), 7.63-7.53 (m, 5H), 7.42 (m, 1H), 7.25 (m, 1H), 6.43 (broad s, 2H), 4.45 (t, J=7.6 Hz, 2H), 2.87 (t, J=7.7 Hz, 2H), 2.78 (m, 2H), 1.79 (m, 4H), 1.55-1.40 (m, 4H), 0.95 (t, J=7.4 Hz, 3H); MS (EI) m/e 451.2036 (451.2042 calcd for C24H29N5O2S); Anal calcd for C24H29N5O2S: C, 63.83; H, 6.47; N, 15.51. Found: C, 63.89; H, 6.42; N, 15.30.
Reaction SMILES: [CH2:1]([CH:9]1[C:13](=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:12](=O)[CH2:11][CH:10]1O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[Cl-].[Na+].[O:28]1CCCC1>>[CH2:1]([CH:9]1[C:13](=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:12][C:11](=[O:28])[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1C(=CCCCCCC(=O)O)C(=O)CC1O
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCC1CC(=O)CC1=CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 70 %

Procedure:
169 mg (0.5 mmole) of 4-octyl-5-(6-carboxyhexylidene)-3-hydroxycyclopentanone was dissolved in 3 ml of tetrahydrofuran, and ml of 0.5N hydrochloric acid was added. The mixture was stirred at room temperature for 4 days. A saturated aqueous solution of sodium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The dried product was filtered, concentrated, and purified by preparative silica gel-thin-layer chromatography to give 12 mg (0.35 mmole; yield 70%) of 4-octyl-5-(6-carboxyhexylidene)-2-cyclopentanone. The resulting compound had the following spectral data.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.CS(O[CH2:17][CH:18]1[CH2:20][CH2:19]1)(=O)=O.C(N(CCCC)CCCC)CCC>C(OCC)C>[CH:18]1([CH2:17][N:4]2[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:6][C:2]([CH3:1])=[N:3]2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: CS(=O)(=O)OCC1CC1
Solvent: CCOCC
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)c1cc(C)nn1CC1CC1
Yield: 47.7 %

Procedure:
A mixture comprising 3.8 g of ethyl 3-methyl-1H-pyrazole-5-carboxylate, 3.8 g of cyclopropylmethyl methanesulfonate and 4.6 g of tri-n-butylamine was allowed to react at 110 ° C. for three hours without using any solvent. Then the reaction mixture was allowed to cool and diethyl ether was added thereto. The obtained mixture was successively washed with 1 N hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (eluent: hexane:ethyl acetate=14 : 1). Thus 0.62 g of the aimed ethyl 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylate (compound No. 1001) (yield: 12.1 %) and 2.45 g of ethyl 1-cyclopropylmethyl-3-methyl-1H-pyrazole-5-carboxylate (yield: 54.3 %) were obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:12]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH:22]2[O:24][CH2:23]2)=[CH:18][CH:17]=1)(=[O:14])[CH3:13].O>CS(C)=O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH:2]1[NH:1][CH2:23][CH:22]([OH:24])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Reactant: NC1CCc2ccccc2C1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CNC2CCc3ccccc3C2)cc1
Temperature: 80 °C
Yield: 35.7 %

Procedure:
A mixture of 2-aminotetralin (2.5 g) and 1-(4-acetamidophenoxy)-2,3-epoxypropane (3.52 g) in dimethylsulfoxide (40 ml) is heated at 80° C. for 5 hours. The reaction mixture is allowed to cool toat room temperature and water (180 ml) is then added thereto. The precipitate which forms is recovered by filtration and crystallized from absolute ethanol (120 ml) yielding 2.15 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-acetamidophenoxy)-propanamine; m.p. 133°-136° C.