Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](O)=[CH:8][C:7]=1[OH:13])=[O:5].[C:19](=[O:22])([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[OH:13][C:7]1[CH:8]=[C:9]([O:22][CH2:19][C:2]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:3]=2)[CH:10]=[CH:11][C:6]=1[C:4]([C:3]1[CH:14]=[CH:15][C:16]([O:18][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][C:2]=1[OH:1])=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(c1ccc(OCc2ccccc2)cc1O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C

Procedure:
12.3 parts of 2, 2',4,4'-tetrahydroxybenzophenone are dissolved in 150 parts absolute ethanol. After adding 7 parts potassium carbonate and 17.1 parts benzyl bromide, the mixture is heated on reflux overnight. After cooling to room temperature the crystals are filtered off and washed with 300 parts ethanol and dried. The compound of Example 10 has the following formula: ##STR16## Yield: 19.8 parts (92.5% of theory). Melting point: 140-142° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:13]([Mg]Cl)([CH3:15])[CH3:14]>C1COCC1>[Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([OH:8])[CH:13]([CH3:15])[CH3:14])[CH:9]=1
Reactant: COc1cc(O)c(C=O)cc1Cl
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(O)c(C(O)C(C)C)cc1Cl
Reaction time: 0.5 h

Procedure:
The above prepared 5-chloro-2-hydroxy-4-methoxy-benzaldehyde (0.845 g, 4.53 mmol) was dissolved in 10 mL of abs. THF and treated at −15° C. with iPrMgCl (4.98 mL of 2M [THF], 2.2 eq.) and the mixture kept at this temperature for 0.5 h. Careful pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left 1.090 g of the title compound as light brown oil, almost perfectly pure according to TLC and NMR.
Reaction SMILES: C(O)C.[F:4][C:5]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:9]2.[H][H]>[C].[Pd].C(OCC)(=O)C>[F:4][C:5]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:9]2
Reactant: [H][H]
Reactant: CCC[C@H]1CC[C@H](C2=Cc3c(cc(F)c(F)c3F)C2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC[C@H]1CC[C@H](C2Cc3cc(F)c(F)c(F)c3C2)CC1

Procedure:
Ethanol (70 ml), ethyl acetate (30 ml) and 5% palladium-carbon (450 mg) were added to 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indene (4.5 g), and stirred for 1 hour in a hydrogen atmosphere. The reaction solution was filtered with celite, the filtrate was concentrated, and the residue was purified with a silica gel short column (hexane) to obtain 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indane (4.5 g). Moreover, this was then recrystallized from ethanol to obtain 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indane (4.5 g, purity: 99.8%). The melting point of this compound was 52° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:48][CH2:49][C:50]1[C:59](=[O:60])[C:58]2[C:53](=[N:54][CH:55]=[CH:56][CH:57]=2)[N:52]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:51]=1[C:67]1[O:68][CH:69]=[CH:70][N:71]=1>C(Cl)Cl>[O:68]1[CH:69]=[CH:70][N:71]=[C:67]1[C:51]1[N:52]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:53]2[C:58]([C:59](=[O:60])[C:50]=1[CH2:49][NH:48][C:14]([C:11]1[CH:12]=[CH:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:17])[CH:10]=1)=[O:16])=[CH:57][CH:56]=[CH:55][N:54]=2
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O
Reactant: O=C(O)c1ccn(Cc2ccccc2)c(=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2ncccc2c1=O)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 50 mL round-bottomed flask, 1-benzyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (21 mg, 0.93 mmol), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (23.0 mg, 0.148 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (20.0 mg, 0.148 mmol) and N,N-diisopropylethylamine were combined with methylene chloride (5 mL). The reaction mixture was stirred at room temperature for 10 min. After this time, 3-(aminomethyl)-2-(oxazol-2-yl)-1-phenyl-1,8-naphthyridin-4(1H)-one (intermediate B) was added. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was partitioned between methylene chloride and water. The organic phase was dried over sodium sulfate, then filtered and concentrated. The crude product was purified using flash chromatography (Isco, 0% ethyl acetate-hexanes ramped to 70% ethyl acetate-hexanes) to afford 1-Benzyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridin-3-ylmethyl)-amide as a light brown powder (12 mg). MS calcd. for C31H24N5O4 [(M+H)+] 530.2, obsd. 530.3
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[C:20]([OH:25])[CH:19]=3)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].COCCOC>[O-2].[O-2].[Mn+4]>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:19]4[N:30]=[C:26]([CH2:27][CH2:28][CH3:29])[O:25][C:20]=4[CH:21]=[CH:22][C:23]=3[CH:24]=2)=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccccc2)CC1
Reactant: CCCCN
Agent: [Mn+4]
Agent: [O-2]
Solvent: COCCOC
Product: CCCc1nc2c(ccc3cc(C(=O)N4CCC(Cc5ccccc5)CC4)[nH]c32)o1
Reaction time: 1 h
Yield: 124.5 %

Procedure:
Under argon, to a solution of 0.5 g (1.49 mmol) of 1-(4-benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indole-2-yl)methanone and 0.14 g (0.2 mmol) of n-butylamine in 100 ml of ethylene glycol dimethyl ether 10 g (115 mmol) of manganese dioxide is added portion-wise at 0° C. After stirring for 1 h, the reaction mixture is filtered, the filtrate is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and hexane:ethyl acetate=2:1 as eluent to yield 0.1 g (17.3%) of the title compound. Mp.: 195-196° C. (hexane—ethyl acetate).
Reaction SMILES: C1(C[O:8][C@H:9]2[C@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10]2)C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C@H:9]1[C@H:14]([NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: O=C(N[C@@H]1CCN(Cc2ccccc2)C[C@H]1OCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@@H]1CCNC[C@H]1O)c1ccccc1

Procedure:
A solution of 22.9 parts of trans-N-[3-(phenylmethoxy)-1-(phenylmethyl)-4-piperidinyl]benzamide in 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and suspended in trichloromethane. The whole was shaken with a dilute ammonium hydroxide solution and the layers were separated. The aqueous phase was evaporated and the solid residue was suspended in 5 parts of water. The product was filtered off and dried, yielding 6 parts of trans-N-(3-hydroxy-4-piperidinyl)benzamide; mp. 210° C. (compound 218).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@@:11]([C:14]([N:29]2[CH2:30][CH2:31][C:26]([OH:32])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:27][CH2:28]2)=[O:16])([CH:17]([CH3:19])[CH3:18])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentane-carboxylic acid (200 mg, 0.7 mmol), 4-phenylpiperidin-4-ol (140 mg, 0.81 mmol), and triethylamine (0.15 g, 1.5 mmol) in methylene chloride (4 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.42 g, 0.81 mmol). After being stirred overnight at room temperature, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The crude was carried on to the next step without purification. MS calculated for C25H38N2O4: (M+H) 431; found 431.2.
Reaction SMILES: [S-:1][CH2:2][CH2:3][CH2:4][CH3:5].[Na+].C(S)CCC.[H-].[Na+].C([O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:33]([CH2:34][CH2:35][C@:19]12[CH3:20])[C:32]1[CH:31]=[CH:30][C:29]([O:36]C(=O)C2C=CC=CC=2)=[CH:28][C:27]=1[CH2:26][C@H:25]3[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]OS(C)(=O)=O)(=O)C>O1CCCC1>[CH2:2]([S:1][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][C@@H:25]1[CH2:26][C:27]2[CH:28]=[C:29]([OH:36])[CH:30]=[CH:31][C:32]=2[C@@H:33]2[C@@H:24]1[C@H:21]1[C@@:19]([CH2:35][CH2:34]2)([CH3:20])[C@@H:18]([OH:17])[CH2:23][CH2:22]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[S-]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCCCCCCCOS(C)(=O)=O)Cc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCS
Solvent: C1CCOC1
Product: CCCCSCCCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 1 h

Procedure:
A solution of sodium thiobutoxide [generated from butanethiol (0.045 g.) and a 60% dispersion of sodium hydride in mineral oil (0.02 g.)] in tetrahydrofuran (2 ml.) was added to a solution of 17β-acetoxy-3-benzoyloxy-7α-(11-methanesulphonyloxyundecyl)oestra-1,3,5(10)-triene (Example 24; 0.078 g.) in tetrahydrofuran (1 ml.) and the mixture was kept for 1 hour at laboratory temperature, neutralised with aqueous N-hydrochloric acid and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (3 ml.), dried and evaporated to dryness, and the residue was dissolved in methanol (3 ml.). Aqueous N-sodium hydroxide solution (1 ml.) was added and the mixture was kept at laboratory temperature for 18 hours, neutralised with aqueous N-hydrochloric acid and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (10 ml.), dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of toluene and ethyl acetate as eluant. There was thus obtained as an oil 7α-(11-n-butylthioundecyl)oestra-1,3,5(10)-triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloroaniline (400 mg, 3.13 mmol) in anhydrous dichloromethane (40 mL) were added 3-methoxybenzenesulfonyl chloride (648 mg, 3.13 mmol) followed by pyridine (297.2 mg, 3.76 mmol). The mixture was allowed to stir for 12 h at 25° C. 10% citric acid solution (20 mL) and water (20 mL) was added. The organic phase was dried (Na2SO4), and evaporated under reduced pressure yielding the title compound as solid which was used as such in the next step. Yield: 900 mg (96%). MS (m/e): 296 (M+−H); 1H-NMR (CDCl3, 400 MHz): δ 3.76 (s, 3H), 6.48 (brs, 1H), 7.0 (d, J=8.72 Hz, 2H), 7.06 (d, J=7.76 Hz, 1H), 7.21 (m, 3H), 7.32 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)Cl>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([Cl:14])=[O:5]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Cl)C(F)(F)F
Reaction time: 14 h

Procedure:
DMF (3 drops) was added to a solution of 3,3,3-trifluoro-2,2-dimethyl-propionic acid [889940-13-0] (179 mmol) in CH2Cl2 (160 mL) at rt. Slowly added a solution of oxalyl chloride (197 mmol) in CH2Cl2 (20 mL). After stirring for 14 h, the reaction mixture was carefully evaporated (500 mbar, 33° C.) to afford the title compound (volatile!) as a yellow solution.
Reaction SMILES: O[CH:2]([C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S-:17][C:18]#[N:19].[NH4+:20]>C(O)CC>[C:3]1([C:2]2[N:19]=[C:18]([SH:17])[NH:20][C:9]=2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: O=C(c1cccnc1)C(O)c1ccccc1
Reactant: [NH4+]
Solvent: CCCO
Product: Sc1nc(-c2ccccc2)c(-c2cccnc2)[nH]1
Yield: 44.3 %

Procedure:
3-Pyridyl α-hydroxybenzyl ketone (8.15 g; 38.3 mmoles) was reacted with 7.5 g (0.1 mole) of ammonium thiocyanate in 1-propanol heated at reflux to give 4.3 g of 4-phenyl-5-(3-pyridyl)-1H-2-imidazolethiol, m.p. 317°-323° recrystallized from DMF:H2O (2:1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CN(C)C=O>[C:28]([O:30][CH:31]([O:21][C:20](=[O:22])[CH2:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([C:6](=[O:7])[C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:23])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:29])[CH3:27]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OC(OC(C)=O)c1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 81 %

Procedure:
180 g (0.503 mol) of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid were dissolved in 900 ml of dimethylformamide, 35 g of triturated, anhydrous potassium carbonate were added and stirring was continued for 45 minutes at 50°C. 128 g (0.558 mol) of benzyl bromoacetate were then added and the mixture was stirred for 3 hours at 50°C. After evaporating the dimethylformamide under vacuum, the residue was dissolved in chloroform, washed several times with water, dried over sodium sulphate and then separated by chromatography on alumina. The eluate was concentrated by evaporation and the residue recrystallised from alcohol. The [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate which formed melted at 93°-94°C and the yield was 81% of the theoretical. This benzyl ester was converted as described in Example 1 or 2 into the free acid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][CH:13]([SH:17])[CH:14]([SH:16])[CH3:15].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>C1CCCCC1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]1[S:17][CH:13]([CH3:12])[CH:14]([CH3:15])[S:16]1
Reactant: O=Cc1ccco1
Reactant: CC(S)C(C)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC1SC(c2ccco2)SC1C
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Into a 100 ml reaction flask equipped with magnetic stirring bar, thermometer and reflux condenser and hot plate with magnetic stirring apparatus is placed 0.5 grams para-toluenesulfonic acid, 5 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. Over a period of 35 minutes, 4.8 grams (0.05 moles) of 2-furaldehyde is added to the reaction mass with stirring. The reaction mass is then heated to reflux and refluxed for a period of 7.5 hours with stirring while removing water to reaction. After the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated sodium chloride soution and dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled using a Microvigreux column yielding the following fractions:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([N:31]([CH2:34]C)CC)C.C[N:37](C)C=O>>[ClH:1].[C:34]([N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][CH2:15][N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=[C:2]([Cl:1])[C:11]=3[N:12]=[C:13]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:18][CH2:19]1)(=[NH:31])[NH2:37]
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Reactant: Clc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCC1CCNCC1
Product: Cl
Product: N=C(N)N1CCC(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1

Procedure:
A solution of 0.75 g of 4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinoline, 0.40 g of 1H-pyrazole-1-carboxyamidine hydrochloride and 0.39 ml of triethylamine in 5 ml of N,N-dimethylformamide was stirred at room temperature for 19 hours. The reaction solution was concentrated and the residue was added with ethanol, and then the precipitated crystals were collected by filtration to give 0.51 g of colorless crystals. Recrystallization from ethanol gave colorless crystals having the melting point of from 270 to 273° C. (decomposition).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12](B4OC(C)(C)C(C)(C)O4)[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][N:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.O.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>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:38]4[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][N:39]=4)[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)nc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cn3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Yield: 45.2 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carboxamide (0.15 g, 0.31 mmol) and 6-bromonicotinaldehyde (0.047 g, 0.25 mmol) in dioxane/water mixture (2 mL+0.5 mL), Cs2CO3 (0.219 g, 0.239 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.031 g, 0.025 mmol) was added and argon was purged again for 10 min. Reaction mixture was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(5-formylpyridin-2-yl)-1H-indazole-4-carboxamide (0.053 g, 37%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[NH:17][C:16](=[O:18])[C:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)=[CH:14][N:13]=1.B(Br)(Br)Br.O.[Cl:33]CCl>>[ClH:33].[ClH:33].[ClH:33].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[NH:17][C:16](=[O:18])[C:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[CH:14][N:13]=1
Reactant: COc1cccc(Cc2cnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1
Reactant: ClCCl
Agent: BrB(Br)Br
Solvent: O
Product: Cc1[nH]cnc1CSCCNc1ncc(Cc2cccc(O)c2)c(=O)[nH]1
Product: Cl
Reaction time: 8 h

Procedure:
2-[2-(5-Methyl-4-imidazolylmethylthio)ethylamino]-5-(3-methoxybenzyl )-4-pyrimidone (2.35 g) was suspended in dry dichloromethane (30 ml) and boron tribromide (6.49 g) carefully added. The mixture was stirred in a dry atmosphere overnight. Careful addition of water (30 ml) was followed by separation of the two phases. The aqueous phase was treated in NaHCO3 which precipitated a tacky solid which was repeatedly washed with water until it became solid, when it was filtered and dried. Treatment with ethanolic HCl gave 2-[2(5-methyl-4 -imidazolylmethylthio)ethylamino]-5-(3-hydroxybenzyl)-4-pyrimidone dihydrochloride, m.p. 142°-144° (ex. ethanol)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]([NH2:28])=[O:27])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[C:6]=2[N:25]=1.[CH2:29](N1C2C(=CC=CC=2)C2C=C(C(N)=O)C(NC)=NC1=2)C>>[NH2:28][C:26]([C:3]1[C:2]([NH:1][CH3:29])=[N:25][C:6]2[N:7]([CH2:14][C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:16])[C:8]3[C:13]([C:5]=2[CH:4]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:27]
Reactant: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)OC(C)(C)C
Reactant: CCn1c2ccccc2c2cc(C(N)=O)c(NC)nc21
Product: CNc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)NC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
tert-butyl {(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xvi-b, 20 mg, 0.052 mmol) was alkylated according to procedure detailed in the preparation of 48, to afford tert-butyl {(1S)-2-[3-(aminocarbonyl)-2-(methylamino)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xxxii-a, 20 mg, 89%). NH4OAc QC conditions. M+H=398.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH2:28])=[O:29])=[CH:23][C:22]=1[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3
Reactant: COc1cc(F)c2nc(C)c3c(C)nc(Br)n3c2c1
Reactant: NC(=O)c1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(F)c2nc(C)c3c(C)nc(-c4cc(C(N)=O)ccc4F)n3c2c1
Yield: 10.5 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 2-fluoro-5-carbamoylphenylboronic acid (55 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (8 mg, 11% yield). EIMS 383.1 [M+H]+.