Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.C(OC([N:39]1[CH2:44][CH2:43][N:42]([C:45]2SC(=CC3C=C4C(=CC=3)N(CC3C=CC(C(O)(C)C)=CC=3C(F)(F)F)N=C4)C(=O)N=2)[CH2:41][CH:40]1[CH2:76][OH:77])=O)(C)(C)C>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][C@@H:40]5[CH2:76][OH:77])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)[C@@H](CO)C1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R) (4-Methyl-piperazin-2-yl)-methanol following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]([C:7]1([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:8]1)=[O:6]>CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:7]1([NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][CH2:8]1)[OH:6]
Reactant: COC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Solvent: CO
Product: COC(=O)CC(O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 41.1 %

Procedure:
To 2 (1.053 g, 4.09 mmol) in HPLC MeOH (20 mL) at −78° C. was added portion-wise KBH4 (764.3 mg, 14.2 mmol), and the resulting reaction mixture was stirred for 45 min before being warmed to −20° C., and being stirred for a further 30 min at that temperature. The mixture was then warmed to 0° C. and stirred for a further 2 h, after which the mixture was quenched with AcOH until the pH was below 7. The mixture was then concentrated in vacuo, and EtOAc (70 mL) was added followed by water (40 mL). The layers were separated and the aqueous phase was extracted with EtOAc (60 mL). The organic extracts were combined, washed with saturated brine (60 mL), dried (MgSO4) and concentrated in vacuo. Purification was performed by flash column chromatography on silica (eluant 3:7-4:6-1:1 EtOAc/Hexane) to give 3 (436 mg, 1.68 mmol, 41%) as a white solid (diastereoisomers 1:1 ratio).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8])=[O:3].[C:15]([O-:18])([CH3:17])=[CH2:16].[K+]>O1CCCC1>[C:2](=[O:3])([O:18][C:15]([CH3:17])=[CH2:16])[O:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:8]
Reactant: CC(C)=CCCC(C)CCOC(=O)Cl
Reactant: C=C(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)OCCC(C)CCC=C(C)C
Yield: 56.8 %

Procedure:
To a solution of 20.78 g (0.095 mole) of citronellyl chloroformate in 150 ml of tetrahydrofuran was added under a nitrogen atmosphere with cooling and stirring an aliquot (215 ml, 0.101 mole) of the solution of potassium isopropenolate described in EXAMPLE XVIII. The reaction temperature did not rise above 10° C. during addition. After addition was complete the cooling bath was removed and the mixture was poured into 400 ml of diethyl ether, and washed successively with one 300-ml portion and three 400-ml portions of water. The ether layer was separated and dried over magnesium sulfate. Removal of solvent under reduced pressure left a red, slightly viscous residue weighing 20.83 g, which on distillation through a rotary thin-film molecular still at 75° C. skin temperature and 0.10-0.13 mm pressure yielded 12.97 g (56.8%) of citronellyl isopropenyl carbonate as a colorless liquid. The identity of the compound was confirmed by spectral data.
Reaction SMILES: COC(=O)[C@@H](C1C=CC=[CH:8][C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)O.C(C(C(C([O-])=O)O)O)([O-])=[O:28].[Na+].[K+]>C1(C)C=CC=CC=1>[Cl:25][C:21]1[CH:20]=[C:19]([C@@H:7]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:8][OH:28])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@H](O)C1C=CC=CC1(OC1CCCCO1)c1cccc(Cl)c1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OC[C@H](OC1CCCCO1)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
Into toluene (15 ml) were added (R)-2-(3-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)-mandelic acid methyl ester (7.0 g) obtained in 2) above and then, under ice cooling and dropwise, a 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution (7.67 g). The resulting mixture was stirred at the same temperature for 1 hour. Then the reaction mixture was added into a 30% aqueous (+)−potassium sodium tartrate solution (27.6 g), the resulting mixture was stirred for 1 hour and then the organic layer was separated. The organic layer obtained was washed with water and further with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The desciccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (6.2 g, 98.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:26]2[CH2:27][CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCc4ccccc4C3)CC2C)cc1OC
Yield: 38.9 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 1,2,3,4-tetrahydroisoquinoline (487 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (210 mg, yield: 39%) as a white crystal. (cis:trans=1:1)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:25]([F:28])([F:27])[F:26])[N:6]2[CH2:23][CH2:22][N:21]([CH3:24])[C:8]3([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]3)[C:7]=12)#[N:2].[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[ClH:29].[CH3:24][N:21]1[CH2:22][CH2:23][N:6]2[C:5]([C:25]([F:28])([F:26])[F:27])=[CH:4][C:3]([C:1]#[N:2])=[C:7]2[C:8]21[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2
Reactant: CN1CCn2c(C(F)(F)F)cc(C#N)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCn2c(C(F)(F)F)cc(C#N)c2C12CCNCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 8-cyano-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (278.9 mg, 0.7 mmol) in DCM (4 mL) was added HCl in dioxane (2 mL of 4 M, 8.0 mmol). The mixture was stirred at room temperature for 30 min. The solvent was evaporated and the crude material was used directly in next step without further purification. ESI-MS m/z calc. 298.1, found 299.5 (M+1)+; Retention time: 0.88 minutes (3 minute run).
Reaction SMILES: O[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:23].C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:23][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(O)c2c1[nH]c1cc(C(F)(F)F)ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1cnc(Cl)c2c1[nH]c1cc(C(F)(F)F)ccc12
Temperature: 175 °C

Procedure:
A mixture of 1-hydroxy-7-(trifluoromethyl)-5H-pyrido[4,3-b]indole-4-carbonitrile in an excess of POCl3 was heated in a microwave apparatus at 175° C. for a period of 13 min. The reaction mixture was poured slowly into cold EtOAc and saturated NaHCO3. The organic phase was separated, dried over Na2SO4, filtered and evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]([NH:15][C:16](=[O:19])[CH2:17]Cl)([CH3:14])[CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=1.[K]>C1(C)C=CC=CC=1.O.Cl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:14])[CH2:9][C:10]([CH3:12])([CH3:11])[O:13][CH2:17][C:16](=[O:19])[NH:15]2)[CH:7]=1
Reactant: CC(C)(O)C[C@](C)(NC(=O)CCl)c1cc(Br)ccc1F
Agent: Cl
Agent: [Cl-]
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C[C@@](C)(c2cc(Br)ccc2F)NC(=O)CO1
Temperature: 23 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
To a solution of N-[(S)-1-(5-bromo-2-fluoro-phenyl)-3-hydroxy-1,3-dimethyl-butyl]-2-chloro-acetamide (intermediate A13A) (3.11 g, 8.5 mmol) in toluene (150 ml) at 23° C. was added dropwise a solution of potassium amylate (1.7 M in toluene; 25.0 ml, 42 mmol) within 10 min (slightly exotermic). The light brown solution was stirred at 23° C. for 2 h. Diluted with water, 1N HCl and brine and extracted twice with ethyl acetate. The organic layers were washed with sat. NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated to give a light brown oil, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound as an off-white solid (1.05 g, 37%). MS (ISP): m/z=330.0 [(M+H)+] and 332.0 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C[O-].[Na+].C([O:10][C:11](=O)[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:13](OCC)=[O:14])C.Cl>CO.O>[OH:10][C:11]1[C:12]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:13]([OH:14])[N:4]=[C:2]([SH:3])[N:1]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Reactant: NC(N)=S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2c(O)nc(S)nc2O)cc1
Yield: 41 %

Procedure:
To a solution of thiourea (13.69 g) in methanol (150 ml) is added a 28% solution of sodium methoxide in methanol (34.70 g) at 60° C., and thereto is further added (4-methylphenyl)malonic acid diethyl ester (32.62 g) at the same temperature. The reaction solution is refluxed for 8 hours. After cooling, water is added to the reaction solution, and the pH value of the solution is adjusted to pH 1 with hydrochloric acid under ice-cooing. The precipitated crystals are collected by filtration, and the residue is washed and dried to give 4,6-dihydroxy-2-mercapto-5-(4-methylphenyl)pyrimidine (12.53 g) as a crystal.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].O1C=CC=CC1=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[CH3:1][C:2]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1c(C)oc(C)c(C(=O)OCC)c1=O
Agent: O=c1cccco1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c(C)c(C(=O)OCC)c1=O

Procedure:
2,6-dimethyl-3,5-dicarboethoxy-N-phenyl-4-pyridone was prepared cording to Conrad and Guthzeit (M. Conrad and M. Guthzeit, Chem. Ber., 19, 19-26, (1886)), by reacting 2,6-dimethyl-3,5-dicarboethoxy-4-pyrone (said compound will be called hereinafter "the pyrone") and aniline in acetic acid. (m.p. 170°C).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[CH2:18][N:19]1[C:27]([C:28]2[N:32]([CH3:33])[CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)=[C:26]2[C:21]([N:22]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:23](=[O:38])[N:24]([CH3:37])[C:25]2=[O:36])=[N:20]1>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[CH2:18][N:19]1[C:27]([C:28]2[N:32]([CH3:33])[CH:31]=[C:30]([C:34]3[NH:35][N:3]=[N:2][N:1]=3)[CH:29]=2)=[C:26]2[C:21]([N:22]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:23](=[O:38])[N:24]([CH3:37])[C:25]2=[O:36])=[N:20]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(C#N)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2nnn[nH]2)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Temperature: 120 °C
Yield: 64.3 %

Procedure:
Sodium azide (0.054 g) and ammonium chloride (0.044 g) were added to a solution of 5-[2-[(6-chloro-4-quinolinyl)methyl]-7-(cyclopropylmethyl)-4,5,6,7-tetrahydro-5-methyl-4,6-dioxo-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (0.083 g) in dimethylformamide (5 ml) at 0° C. The mixture was heated at 120° C. for 31 hour. The crude reaction was purified on preparative HPLC to give the title compound (0.058 g). Mass: 543.08 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:5][CH:6]=1.C(N(CC)CC)C.[CH3:21][C:22]1([CH3:31])[C:26]([CH3:28])([CH3:27])[O:25][B:24]([CH:29]=[CH2:30])[O:23]1.C(OCC)(=O)C>CN(C=O)C>[CH3:27][C:26]1([CH3:28])[C:22]([CH3:31])([CH3:21])[O:23][B:24](/[CH:29]=[CH:30]/[C:2]2[N:3]=[C:4]([CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[S:5][CH:6]=2)[O:25]1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Brc1csc(CN2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(/C=C/c2csc(CN3CCOCC3)n2)OC1(C)C
Temperature: 120 °C

Procedure:
To a solution of 4-((4-bromothiazol-2-yl)methyl)morpholine (125 mg, 0.5 mmol) and triethylamine (0.2 mL, 1.5 mmol) in DMF (1.5 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.15 mL, 1 mmol) and Pd(Ptert-Bu3)2 (8 mg, 0.002 mmol). The mixture was heated to 120° C. under microwave irradiation for 1 h. Ethyl acetate (50 mL) was added and the solution was washed with water (2×10 mL) and brine (10 mL), dried over MgSO4 and concentrated to an orange oil (165 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=18.0 Hz, 1H), 7.19 (s, 1H), 6.40 (d, J=18.0 Hz, 1H), 3.84 (s, 2H), 3.74 (bs, 4H), 2.61 (bs, 4H), 1.29 (s, 12H); MS ESI 337.1 [M+H]+, calcd for [C16H25BN2O3S+H]+ 337.2. [α]22.8°D=−169° (c 0.42, Methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][NH2:11])=[N:7][C:6]=2[CH:12]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][NH:11][S:21]([CH3:20])(=[O:23])=[O:22])=[N:7][C:6]=2[CH:12]=1
Reactant: NCc1nc2cc(Br)ccc2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
To a stirred solution of C-(5-Bromo-benzothiazol-2-yl)-methylamine (0.780 g, 3.209 mmol) in CH2Cl2 (12 mL) is added triethylamine (1.2 mL, 8.024 mmol). To above solution is added drop wise methane sulfonyl chloride (0.5 mL, 6.419 mmol) at 0° C. then stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo and the crude material is diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, concentrated and purified by combiflash using 50% ethyl acetate in hexane as an eluent to afford the title compound (0.45 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.03 (s, 3H), 4.60 (d, J=5.72 Hz, 2H), 7.64-7.67 (dd, J1=1.88 Hz, J2=8.72 Hz, 1H), 7.88 (d, J=8.68 Hz, 1H), 8.21 (t, J=6 Hz, 1H), 8.40 (d, J=1.88 Hz, 1H). LC-MS (m/z): [M−H]=320.8.
Reaction SMILES: [C:1]([C:9]1[C:10]2[CH2:21][CH2:20][CH2:19][CH2:18][C:11]=2[S:12][C:13]=1[NH:14][C:15](=[O:17])[CH3:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[Pd]>[C:1]([C:9]1[C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[S:12][C:13]=1[NH:14][C:15](=[O:17])[CH3:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Agent: [Pd]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1sc2ccccc2c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
To a stirred solution of 0.61 g (2.04 mmol) N-(3-Benzoyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-acetamide in 20 ml chloroform was added 1.2 g palladium on charcoal (10%). The mixture was stirred at room temperature for 15 minutes and then the solvent was removed in vacuo. The resulting powder was heated at 100° C. for 48 h and then suspended in ethyl acetate and dichloromethane. The suspension was filtered, and the organic phase was concentrated in vacuo to afford 0.26 g (44%) N-(3-benzoyl-benzo[b]thiophen-2-yl)-acetamide as a yellow solid. ES-MS m/e (%): 296 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]2[CH2:13][C@@H:12]([O:14][CH3:15])[CH2:11]2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C@H:10]2[CH2:11][C@@H:12]([O:14][CH3:15])[CH2:13]2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: CO[C@H]1C[C@@H](Nc2cc(F)ccc2N)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](n2c([C@H](C)NC(=O)OC(C)(C)C)nc3ccc(F)cc32)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-N2-(cis-3-methoxycyclobutyl)benzene-1,2-diamine (0.34 g, 1.6 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.33 g, 1.8 mmol) and HOAt (0.24 g, 1.8 mmol) in DCM (8 mL) was cooled to 0° C. under a nitrogen atmosphere. To this mixture was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.35 g, 1.8 mmol) portion wise and the mixture stirred at RT for 1 h. The reaction mixture allowed to warm to RT then partitioned between DCM (30 mL) and saturated aqueous solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the compound as a pink oil (0.348 g, 57%). The compound thus obtained was dissolved in AcOH (8 mL) and heated at 70° C. for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue partitioned between DCM (40 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) then concentrated in vacuo. The resulting dark brown residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as yellow oil (0.222 g, 38%). LCMS (Method B): RT 2.86 min [M+H]+ 364.03
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:38][N:13]2[C:14]3[C:19]([C:20]([C:21]4[C:22](=O)[O:23][C:24](=[O:36])[C:25]=4[C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)=[C:12]2[CH2:11][CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40](C)C=O>N>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:38][N:13]2[C:14]3[C:19]([C:20]([C:21]4[C:22](=[O:23])[NH:40][C:24](=[O:36])[C:25]=4[C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)=[C:12]2[CH2:11][CH2:10]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CC(NC(=O)OC(C)(C)C)CC4)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CC(NC(=O)OC(C)(C)C)CC4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 85 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 5 ml of dimethylformamide and 5 ml of 33% aqueous ammonia was heated to 100° C. for 1 hour. The cooled mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried and evaporated. Crystallization from ethyl acetate/n-hexane gave 70 mg of 3-[7-t-butoxyformamido-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 159°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29]([CH3:58])=[C:30]([C:49]([O:56][CH3:57])=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:36]([CH:40]=1)[C:37](O)=[O:38]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29]([CH3:58])=[C:30]([C:49]([O:56][CH3:57])=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:36]([CH:40]=1)[C:37]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:38]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2cc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
p-Methoxyaniline (0.250 g, 2.03 mmol), triethylamine (0.206 g, 2.03 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.344 g, 2.03 mmol) were added to a methylene chloride solution (40 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.460 g, 1.02 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:2) and recrystallized from ether to obtain the titled compound (0.211 g, 0.379 mmol, 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:23][NH:24][CH3:25]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([N:24]([CH3:25])[CH3:23])[C:11]=2[CH2:10][CH2:9]1
Reactant: CNC
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21
Product: Cc1ccccc1N1CCc2c(N(C)C)nc3c(C)cccc3c21
Yield: 63 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (1.5 g. 4.9 mmol) and dimethylamine (33% in ethanol. 150 ml) were heated to 180° C. in a pressure vessel for 18 hours, then evaporated, taken up in dichloromethane, washed with sodium bicarbonate, dried and evaporated. Crystallisation from aqueous ethanol gave 1-(2-methylphenyl)-4-dimethylamino- 6-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (0.97 g, 63%), m.p. 120°-121°.
Reaction SMILES: [C@H:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(O[CH2:16][CH2:17][CH2:18][CH3:19])=O>CCCCCCCC>[CH2:16]([O:8][C:7]([C@@H:4]1[CH2:3][CH2:2][C@H:1]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[O:9])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CCCCOC=O
Solvent: CCCCCCCC
Product: CCCCOC(=O)[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
(The procedure described for the trans isomer in JCS Perkin I, 1999, 25, 3023 was used.) A mixture of cis-cyclohexane-1,4-dicarboxylic acid (TCI) (24.1 g, 140 mmol), butyl formate (700 ml, 623 g, 6.10 mol, 43.5 equiv.), and Dowex 50W×2 resin (50-100 mesh, 140 g) in octane (700 ml) was stirred under nitrogen in a 110° C. oil bath for 24 hours. The mixture was cooled to ambient temperature. The supernatant solution was decanted away from the resin. The resin was washed with ethyl acetate: hexane (1:1, five 150 ml portions), and the washings were added to the supernatant. The solution was evaporated under reduced pressure, the resulting residue diluted with toluene (25 ml), evaporated under reduced pressure, and dried to give crude cis-4-(butoxycarbonyl)cyclohexanecarboxylic acid (36.5 g) as a yellow oil: 1H NMR (CDCl3) 4.08 (2H, m), 2.53 (1H, m), 2.46 (1H, m), 1.92 (4H, m), 1.70 (4H, m), 1.61 (2H, m), 1.38 (2H, m), 0.93 (3H, t, J 7 Hz).