Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[N:20]([CH3:28])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[N:20]([CH3:28])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN=C=O
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Reaction time: 144 h
Yield: 24.3 %

Procedure:
Ethyl isocyanate (0.13 mL, 1.68 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.27 g, 0.84 mmole) and triethylamine (0.29 mL, 2.1 mmole) in DMF (30 mL) at RT. The reaction was stirred for 6 days, then was concentrated in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. Flash chromatography on silica gel (ethyl acetate) gave the tide compound (80 mg, 24%) as a light yellow solid: MS (ES) m/e 392 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(C(F)(F)F)c3)ccc2n1-c1ccc(OC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 24 from 2-ethoxycarbonylmethyl-1-(4-methoxyphenyl)-5-hydroxyindole-3-carboxylic acid ethyl ester (153 mg, 0.40 mmol, see (b) Example 4) and 3-trifluoromethylphenylboronic acid (114 mg, 0.60 mmol). Yield 166 mg (77%).
Reaction SMILES: [C:1]([C@H:4]([O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1)[CH3:5])([OH:3])=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][CH2:48][NH:49][C:50](=[O:52])[CH3:51]>>[C:50]([NH:49][CH2:48][CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:40][C:1]([C@H:4]([O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:8]1)[CH3:5])=[O:3])(=[O:52])[CH3:51]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O[C@H](C)C(=O)O)cc1
Reactant: CC(=O)NCCc1ccccc1N
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O[C@H](C)C(=O)Nc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Example 3a, 0.165 g of tert-butyl 3-(1(R)-carboxyethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1 carboxylate and 0.066 g of N-[2-(2-aminophenyl)ethyl]acetamide (Example 34c) are reacted. The title compound is obtained as a yellow oil. Rf=0.22 (95:5 dichloromethane-methanol); Rt=5.34.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:8]([CH2:18][NH:19][C:20]2[C:21](=[O:39])[N:22]([CH2:28][C:29]([O:31]CC3C=CC=CC=3)=[O:30])[C:23]([CH3:27])=[C:24](Cl)[N:25]=2)[CH2:7]1>[Pd].CO>[CH3:5][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:8]([CH2:18][NH:19][C:20]2[C:21](=[O:39])[N:22]([CH2:28][C:29]([OH:31])=[O:30])[C:23]([CH3:27])=[CH:24][N:25]=2)[CH2:7]1
Reactant: Cc1c(Cl)nc(NC[C@H]2C[C@H](C)CCN2C(=O)C(F)(F)F)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cnc(NC[C@H]2C[C@H](C)CCN2C(=O)C(F)(F)F)c(=O)n1CC(=O)O
Temperature: 25 °C
Yield: 88.3 %

Procedure:
10% Palladium on charcoal (200 mg), followed by ammonium formate (1.1 g, 17.4 mmol) were added to a solution of benzyl 2-[3-({[(2R,4R)-4-methyl-1-(2,2,2-trifluoroacetyl)piperidinyl]methyl}amino)-5-chloro-6-methyl-2-oxo-1(2H)-pyrazinyl]acetate (preparation 90) (900 mg, 1.74 mmol) in methanol (20 ml) and the reaction was stirred at room temperature ovemight. Additional 10% palladium on charcoal (50 mg) was added and the reaction stirred for a further 24 hrs. The mixture was filtered through Whatman® fibre and the filtrate concentrated under reduced pressure. The residue was suspended in a methanol:dichloromethane (10:90) solution, the resulting precipitate filtered off, and the filtrate evaporated under reduced pressure to provide the title compound as a white solid, (600 mg, 92%). LRMS: m/z=391 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.Br[C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: COc1cccc(OC)c1B(O)O
Product: CCOC(=O)/C=C(\C)c1ccc(-c2c(OC)cccc2OC)cc1
Yield: 71 %

Procedure:
(E)-Ethyl 3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enoate (1.02 g, 73% yield) was prepared from 2,6-dimethoxyphenylboronic acid (1.20 g, 6.60 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedure analogous to that described in example 52 a.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:36]=[CH:35][C:7]2[O:8][C:9]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:10][O:11][C:6]=2[CH:5]=1.[CH3:37]I>CN(C)C=O>[CH3:37][O:3][C:4]1[CH:36]=[CH:35][C:7]2[O:8][C:9]([C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH2:18][CH2:19]3)=[O:13])=[CH:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Add 0.98 mmol of 60% sodium hydride suspended in oil to a solution of 0.82 mmol of 6-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin in 10 cm3 of N,N-dimethylformamide under a nitrogen atmosphere. Stir for 15 minutes at room temperature, then add dropwise 0.98 mmol of methyl iodide. Stir for 2 hours at room temperature and then concentrate to dryness under reduced pressure and purify the resulting crude product by chromatography on a silica column (eluant: petroleum ether/ethyl acetate, 50:50). 6-Methoxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 83%. Melting point: 65° C. ##STR75##
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:8]([CH:11]1[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:20][S:17]([N:14]1[CH2:13][CH2:12][CH:11]([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:21])=[O:3])(=[O:9])=[O:10])[CH2:16][CH2:15]1)(=[O:18])=[O:19]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
To a suspension of 2.91 g (8.53 mmol) of 2-(1-methanesulfonyl-piperidine-4-sulfonyl)-2-methyl-propionic acid ethyl ester in THF/water (1/1, 60 mL) are added 2.56 g (34.13 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 3 d and then concentrated under reduced pressure. The residue is partitioned between brine (20 mL) and DCM (20 mL). The aqueous layer is further acidified with 2M aqueous HCl solution to pH 1 and extracted with DCM. The combined organic extracts are concentrated under reduced pressure to afford 1.68 g of 2-(1-methanesulfonyl-piperidine-4-sulfonyl)-2-methyl-propionic acid. Yield 63%, ES-MS: 314 [M+H]; 1H NMR (500 MHz, MeOD) δ ppm 1.66 (6H, s), 1.86-1.97 (2H, m), 2.24 (2H, dd, J=13.64, 2.54 Hz), 2.87 (3H, s), 2.92 (2H, td, J=12.00, 2.59 Hz), 3.81 (2H, dt, J=12.45, 3.13 Hz), 3.94 (1 H, tt, J=11.41, 3.79 Hz)
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+:2]=[N-:3].C.[CH:44]#[C:45][CH3:46].C(N(CC)CC)C>O1CCOCC1.[Cu]>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[C:21]1[N:20]=[C:19]([C:18]([NH:17][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:11]=2[N:7]2[CH2:8][C@H:9]([CH3:10])[C@H:4]([N:1]3[CH:44]=[C:45]([CH3:46])[N:3]=[N:2]3)[C@H:5]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6]2)=[O:34])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C#CC
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: [Cu]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cn([C@H]2[C@@H](C)CN(c3ccncc3NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)C[C@H]2NC(=O)OC(C)(C)C)nn1
Temperature: 60 °C
Yield: 95 %

Procedure:
In a high pressure vial was added tert-butyl (3R,4S,5S)-4-azido-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.), copper in charcoal (0.2 equiv.), prop-1-yne (10.0 equiv.) and triethylamine (1.5 equiv.), in dioxane (0.15 M) to give a black suspension. The pressure tube was sealed and the mixture was stirred with heating to 60° C. for 48 hrs. The reaction was cooled to RT, filtered through celite, concentrated to yield tert-butyl (3R,4S,5S)-1-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-5-methyl-4-(4-methyl-1H-1,2,3-triazol-1-yl)piperidin-3-ylcarbamate in 95% yield. LC/MS (m/z)=623.2 (MH+), Rt=0.87 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24]1>>[CH2:30]([O:29][C:27]([CH:26]1[CH2:32][CH2:33][N:23]([CH2:22][CH2:21][C:17]2[N:16]=[C:15]3[CH2:14][O:13][C:12](=[C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=5)[NH:7][C:6]4=[O:11])[C:20]3=[CH:19][CH:18]=2)[CH2:24][CH2:25]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1CCNCC1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Product: CCOC(=O)C1CCN(CCc2ccc3c(n2)COC3=C2C(=O)Nc3ccc(F)cc32)CC1
Yield: 26.1 %

Procedure:
Following the method described in Example 19, 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (50 mg, 0.17 mmol) and ethyl isonipecotate (300 mg, 1.96 mmol) are reacted to provide the title compound (20 mg, 26%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:5]1
Reactant: Clc1ccc2ccccc2n1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(c2ccc3ccccc3n2)C[C@H](C)N1

Procedure:
Prepared analogously to Example 38 from cis-2,6-dimethyl-piperazine and 2-chloroquinoline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=S)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[NH:27])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Nc1ccc(Cl)c(Cl)c1)Nc1ncccc1OCc1ccccc1
Reactant: N
Product: N=C(Nc1ccc(Cl)c(Cl)c1)Nc1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-(3-benzyloxypyrid-2-yl)-N'-(3,4-dichlorophenyl)thiourea (3.59 g, 0.009 mol), yellow mercuric oxide (2.34 g, 0.011 mol) and methanolic ammonia (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 2.44 g (70%), m.p. 161°-162 ° C.
Reaction SMILES: Cl[SiH:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[CH:10]([CH3:12])[CH3:11].[NH3:13]>CCCCCC>[NH2:13][SiH:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[CH:10]([CH3:12])[CH3:11]
Reactant: N
Reactant: CC(C)N1C=CN(C(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CC(C)N1C=CN(C(C)C)[SiH]1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
In an argon atmosphere, 4.06 g (19.8 mmol) of Si(iPrNCHCHNiPr)(H)Cl was dissolved in 20 mL of hexane. The resulting solution was deaerated by Freeze-Pump-Thaw cycling and after creating an ammonia atmosphere in the reaction vessel by connecting thereto a balloon having an internal volume of 5 L and being filled with ammonia, the solution was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 80° C./8.8×102 Pa) to obtain 2-amino-1,3-diisopropyl-1,3-diaza-2-silacyclopent-4-ene (Si(iPrNCHCHNiPr)(H)NH2) as a colorless liquid (yielded amount: 2.11 g, yield: 58%).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]2[N:8]=1>CN(C)C=O>[CH2:3]([S:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]2[N:8]=1)[CH3:4]
Reactant: CCS
Reactant: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1nn2c(-c3ccccc3)nnc2c2ccccc12
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
50% Sodium hydride in mineral oil (1 g) is suspended in anhydrous dimethylformamide (50 ml) and stirred for 10 minutes. Then a solution of ethanethiol (1.5 ml) in anhydrous dimethylformamide (10 ml) is slowly added thereto and the resulting mixture is stirred at room temperature for 30 minutes. Finally 6-chloro-3-phenyl-1,2,4-triazolo[3,4-a]phthalazine (5.9 g) is added and the reaction mixture is heated at 50° C. for five hours. The solvent is evaporated off under vacuum and the obtained residue is washed a few times with water and then is crystallized from isopropanol yielding 4.7 g of the compound of the title. M.p. 190°-91° C.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>[Pd].C(Cl)Cl>[C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Oc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cccc(N)c1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To 60 mL anhydrous CH2Cl2 was added O-pivaloyl-3-nitrophenol (5.0 g, 22.4 mmol) and a catalytic amount (50 mg) of 10% Pd on C. The flask was repeatedly evacuated and flushed with N2. The reaction flask was again evacuated and H2 was introduced by balloon. After stirring under an atmosphere of H2 for 3 h, the reaction flask was flushed twice with N2. The suspension was then filtered through a bed of Celite™ and concentrated to give 4.15 g (96%) of O-pivaloyl-3-aminophenol as a viscous amber oil. Data for O-pivaloyl-3-aminophenol: Rf 0.21 (silica gel, hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 7.12 (dd, J=8.0, 8.0, 1 H), 6.52 (dd, J=7.8, 2.7, 1 H), 6.44 (ddd, J=8.0, 2.4, 1.4, 1H), 6.38 (t, J=2.2, 1 H), 3.81 (br s, 2 H), 1.34 (s, 9 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]3[C:26]=2[NH:25][CH:24]=[C:23]([I:27])[C:22]3=[O:28])[CH2:14][CH2:13]1.[CH2:30](I)[CH3:31]>O>[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([F:29])=[C:21]3[C:26]=2[N:25]([CH2:30][CH3:31])[CH:24]=[C:23]([I:27])[C:22]3=[O:28])[CH2:13][CH2:14]1
Reactant: CCI
Reactant: O=c1c(I)c[nH]c2c(OCC3CC3)ccc(F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(I)c(=O)c2c(F)ccc(OCC3CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
Potassium carbonate (450 mg, 3.26 mmol) was added to a DMF solution (5 ml) of 8-cyclopropylmethoxy-5-fluoro-3-iodo-1H-quinolin-4-one (910 mg, 2.53 mmol). The mixture was stirred for 15 minutes at room temperature. Ethyl iodide (0.31 ml, 3.87 mmol) was added thereto, and the resulting mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was then purified by silica gel column chromatography (dichloromethane:ethyl acetate=40:1→15:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 750 mg of powdery pale dark brown 8-cyclopropylmethoxy-1-ethyl-5-fluoro-3-iodo-1H-quinolin-4-one (yield: 77%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]([CH3:30])[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]=1[CH2:21][CH2:22][CH3:23])=[O:15])[CH:6]=[CH:5]2.[Br:31]Br>C(O)(=O)C>[Br:31][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH2:12][N:13]([CH3:30])[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20]=1[CH2:21][CH2:22][CH3:23])=[O:15])=[CH:8]2
Reactant: BrBr
Reactant: CCCc1c(C(=O)N(C)Cc2ccc3cc(O)ccc3c2)cnn1-c1ccccc1
Solvent: CC(=O)O
Product: CCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(O)ccc3c2)cnn1-c1ccccc1
Reaction time: 48 h
Yield: 98.5 %

Procedure:
1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (6-hydroxy-naphthalen-2ylmethyl)-methyl-amide (3.2 g, 8 mmol), prepared in the previous step, was dissolved in 300 mL glacial acetic acid (with warming). A solution of bromine (0.41 mL, 8 mmol) in 50 mL of glacial acetic acid was added under nitrogen dropwise over 2 h to the reaction at room temperature. After the addition the reaction stirred for 2 days. The solvent was removed under reduced pressure and the residue diluted with methylene chloride. The organic layer was extracted two times with 5% NaHCO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.77 g, 98.5%) as a pink solid, mp 205-207° C.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:29][CH2:30][CH3:31])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][O:27][CH3:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.N12CCCN=C1CCCCC2>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:29][CH2:30][CH3:31])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([O:27][CH3:28])[C:6]([NH2:5])=[O:7])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNOC
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(OC)C(N)=O
Temperature: -16 °C
Reaction time: 1.5 h

Procedure:
Trimethylsilyl isocyanate (0.250 mL, 1.85 mmol) was added dropwise to a solution of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-O-methyl-hydroxylamine in dichloromethane (10 mL) cooled to −16° C. The reaction temperature was cooled to −20° C. over 10 minutes. After stirring for 1.5 hours, the reaction was warmed to 0° C. and stirred for an additional hour. A drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.250 mL, 1.85 mmol) was added to the reaction mixture and stirred for 3 days. The reaction mixture was diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate and stirred for 30 minutes. The layers were separated, and the organic layer was dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford 0.82 g of 1-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-methoxyurea as off-white crystals, mp 179-181° C. MS (APCI) m/z 371 (M+H+); Anal. calcd for C19H26N6O2: C, 61.36; H, 7.09; N, 22.60. Found: C, 61.08; H, 7.41; N, 22.69.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([C:15]2[S:22][C:21]([CH3:23])=[C:20]3[C:16]=2[CH2:17][C@H:18]2[C:24]([CH3:26])([CH3:25])[C@H:19]23)=[O:14])[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCC1CO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A solution of 3-(3-chloro-4-hydroxy-5-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (550 mg, 1.41 mmol, Intermediate 14) in isopropanol (10 mL) and 3 N aq. NaOH (4 mL) is treated with epichlorohydrine (0.88 g, 7.04 mmol). The dark red reaction mixture is stirred at 60° C. for 1 h. The mixture is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(3-chloro-5-methoxy-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (400 mg) as a pale yellow oil; LC-MS: tR=1.14 min, [M+1]+=447.21; 1H NMR (CDCl3): δ 6.85-6.81 (m, 1H), 6.71-6.67 (m, 1H), 4.13 (dd, J=4.1, 11.1 Hz, 1H), 4.01 (dd, J=5.9, 11.1 Hz, 1H), 3.83 (s, 3H), 3.44-3.36 (m, 1H), 3.08-2.75 (m, 8H), 2.37 (s, 3H), 1.92-1.86 (m, 2H), 1.11 (s, 3H), 0.70 (s, 3H).