Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[F:13][C:14]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:15]=1[CH2:16]Br>C(O)C>[F:13][C:14]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:15]=1[CH2:16][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: Sc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1c(F)c(F)c(CSc2nc3ccccc3s2)c(F)c1F
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a slurry of 1.67 g of the 2-mercaptobenzothiazole in 18 ml of hot 95% ethanol was added 0.4 g of sodium hydroxide. After all materials had dissolved, the mixture was added to 2.79 g of 2,3,4,5,6-pentafluorobenzyl bromide. The mixture was stirred at 30°-32° C. for 1 minute, then poured into 75 ml ice-water. The product precipitated, was filtered and dried to yield 3.21 g, mp 58°-59.5° C. Recrystallization from aqueous ethanol yielded 2.19 g, mp 51°-53° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25]([O:27][C:28](=[O:37])[C@@:29]([CH3:36])([C:32]([NH:34][CH3:35])=[O:33])[NH:30][CH3:31])[CH3:26].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:25]([O:27][C:28](=[O:37])[C:29]([N:30]([CH3:31])[C:20]([C:19]1[CH:23]=[CH:24][C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)=[O:21])([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])[CH3:26]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@](C)(NC)C(=O)NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
DIPEA (1.0 mL) and 4-phenylbenzoyl chloride (0.50 g) were added in this order to a chloroform (10 mL) solution of O-ethyl-N,N2,2-trimethyl-3-oxoserinamide (Intermediate 9-1, 0.69 g), and the mixture was stirred for 5 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, whereafter the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=60/40→25/75) to obtain 4-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (colorless oil) (0.79 g, 66%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:10][NH2:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:19](=S)=[S:20].OO.Cl>O.CO>[F:1][C:2]1[C:3]2[N:4]([C:19](=[S:20])[NH:11][N:10]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)c(NN)n1
Reactant: S=C=S
Agent: Cl
Agent: OO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ncc(F)c2n[nH]c(=S)n12
Temperature: 15 °C

Procedure:
5-Fluoro-4-hydrazino-2-methoxypyrimidine (15.81 g, 0.100 mol), 47 g of methanol, 10.2 g (0,100 mol) of triethylamine, and 11.4 g (0.15 mol) of carbon disulfide were combined in a 250 mL flask under nitrogen at ambient temperature with stirring to obtain a yellow, heterogeneous mixture. The mixture was cooled to 15° C. with an ice bath. Hydrogen peroxide (12.5 g of 30 percent aqueous, 0.11 mol) was then added by means of a syringe pump, the syringe of which was inserted into the flask through a septum. The addition was made over a 1-hour period with stirring and cooling to maintain the temperature at about 15° C. The mixture was allowed to react and warm for 1 hour and the resulting heterogeneous orange mixture was vacuum filtered to remove the solid sulfur. The filtrate was cooled in an ice bath and acidified with 17.6 mL (0.11 mol) of 6.25N hydrochloric acid diluted with 125 mL of water. The resulting precipitate was recovered by vacuum filtration and dried under reduced pressure to obtain 18.81 g (94 percent of theory) of the title compound as an off-white solid melting at 166° C. with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[C:21](=[O:22])[C@H:20]([CH2:23][C:24]([OH:26])=O)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1([CH:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]2=[O:43])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[CH2:1]([N:8]1[C:21](=[O:22])[C@H:20]([CH2:23][C:24](=[O:26])[N:30]2[CH2:31][CH2:32][N:27]([CH:33]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][C:34]3=[O:43])[CH2:28][CH2:29]2)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][N:13]=[CH:12][C:11]=3[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@@H]1Cc2ccc3[nH]ncc3c2CN(Cc2ccccc2)C1=O
Reactant: O=C1Nc2ccccc2CC1N1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: O=C1Nc2ccccc2CC1N1CCN(C(=O)C[C@@H]2Cc3ccc4[nH]ncc4c3CN(Cc3ccccc3)C2=O)CC1
Yield: 21 %

Procedure:
(S)-2-(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (80 mg, 0.24 mmol) and 3-(piperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one (75 mg, 0.32 mmol) were reacted in a manner analogous to the preparation of 4-chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e] inden-8-one. Material was obtained as white solid in 21% yield. MS m/e (M+H)+=543.3. 1H NMR (500 MHz, DMSO-D6): δ=13.01 (s, 1H), 10.13 (s, 1H), 8.21 (s, 1H), 7.36 (d, J=8.54, 1H), 7.19 (d, J=7.02, 1H), 7.11 (m, 2H), 6.90 (t, J=7.32, 1H), 6.82 (d, J=7.93, 1H), 5.36 (d, J=17.40, 1H), 4.61 (d, J=17.09, 1H), 3.84 (m, 1H), 3.57 (d, J=13.12, 1H), 3.47 (m, 2H), 3.38 (m, 1H), 3.32 (M, 1H), 3.09 (m, 1H), 3.02 (d, J=14.04, 1H), 2.985 (m, 2H), 2.85 (m, 1H), 2.75 (m, 1H), 2.65 (m, 3H), 2.50 (m, 2H), 2.31 (d, J=16.48, 1H), 0.71 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.ClCCN1CC[O:41]CC1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][O:41][CH2:31][CH2:30]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: ClCCN1CCOCC1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCN4CCCC4)c3)nn12
Agent: Cl
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(CCN4CCOCC4)c3)nn12

Procedure:
The title compound was prepared in analogy to the compound of Example 231 using 2-chlorethyl-morpholine hydrochloride instead of 1-(2-chlorethyl)pyrrolidine hydrochloride and with a second flash chromatography purification afterwards (tR 3.04 min (conditions 3), MH+=458.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.44 (s, 1H); 8.33 (d, 1H); 8.09 (m, 2H); 8.01 (d, 1H); 7.76 (d, 1H); 7.62 (m, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.54 (s, 2H); 4.28 (t, 2H); 3.50 (m, 4H); 2.72 (m, 2H); 2.39 (m, 4H)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:10](=[O:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 144.1 %

Procedure:
A solution of (3S)-N-[N-[3-[[(t-butyloxy)carbonyl]amino]-2-oxo-4-phenylbutyl]-L-phenylalanyl]-L-leucine, t-butyl ester (1.46 g, 2.45 mmol) in 15 ml of methanol was cooled to 0° C. Sodium borohydride (93 mg, 2.45 mmol) was added in portions over 5 minutes. After 15 minutes, the solvent was evaporated. The residue was taken up into ethyl acetate (100 ml), washed with water, dried (sodium sulfate) and evaporated to give 1.14 g of a slightly yellow gum. This material was combined with 1.73 g of material similarly prepared. The combined material (2.87 g) was purified by flash chromatography on 215 g of Merck silica gel (230-400 mesh), eluting with hexane-ethyl acetate (1.5:1), to give 2.11 g of the title compound as a colorless oil; TLC: Rf =0.19, 1.25:1 hexane-ethyl acetate.
Reaction SMILES: [Br:1]Br.[CH:3]1([O:9]/[N:10]=[C:11](/[C:17](=[O:19])[CH3:18])\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH2:15]([O:14][C:12](=[O:13])/[C:11](=[N:10]\[O:9][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1)/[C:17](=[O:19])[CH2:18][Br:1])[CH3:16]
Reactant: CCOC(=O)/C(=N\OC1CCCCC1)C(C)=O
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(=N\OC1CCCCC1)C(=O)CBr
Reaction time: 2 h

Procedure:
A solution of bromine (4.5 ml) in carbon tetrachloride (50 ml) was added dropwise to a mixture of ethyl (Z)-2-(cyclohexyloxyimino)-3-oxobutyrate (20.0 g), hydrogen bromide in acetic acid (45%, 1.0 ml) and carbon tetrachloride (150 ml) over 1.5 h, at room temperature. The mixture was stirred for 2 h, then the solvent removed in vacuo.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH:11]=[N:10][C:9]([CH:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[N:8]1>O1CCCC1>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([C:12]2([C:9]3[N:10]=[CH:11][NH:7][N:8]=3)[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(C(CCCCCl)c2nc[nH]n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(c3nc[nH]n3)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium tert-butoxide (1.10 g) in tetrahydrofuran (50 mL) is added dropwise to a solution of 4-[1-(1,2,4-triazolyl) -5-chloropentyl]benzonitrile (2.50 g) in tetrahydrofuran at 0° (ice-bath). The reaction is allowed to proceed at 0° for 30 minutes and is then allowed to warm to room temperature during 3 hours. The reaction is then quenched with water (100 mL) and the mixture is subsequently extracted with ethyl acetate (100 mL). The organic extract is extracted with 3 N hydrochloric acid (3×30 mL) and the combined acid extracts are made basic with 6 N sodium hydroxide. The crude product is extracted into ethyl acetate (3×30 mL) and the combined extracts are dried (MgSO4) and evaporated to afford 1-(4-cyanophenyl)-1-(1,2,4-triazolyl)cyclopentane. The compound is dissolved in acetone and treated with ethereal HCl to afford the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2O)=[O:9])=[CH:6][C:5]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[CH:23]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[CH3:17][C:13]1[C:12]2[O:9][C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]5)[CH:23]=4)[CH:6]=3)=[N:10][C:11]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(NC(=O)c2cc(-c3cnn(C4CCN(C)CC4)c3)cnc2N)c1O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2nc(-c3cc(-c4cnn(C5CCN(C)CC5)c4)cnc3N)oc12
Temperature: 200 °C
Yield: 57.6 %

Procedure:
To a solution of 2-amino-N-(2-hydroxy-3-methyl-phenyl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxamide (80 mg) in acetic acid (1.3 ml) was added TFA (1.3 ml). The clear mixture was sealed into a microwave tube. The reaction was heated to 200° C. in a 300 W microwave for 20 minutes. The solvents were evaporated. The residue purified by preparative HPLC using a Waters X-Terra reverse-phase column and decreasingly polar mixtures of water (containing 1% acetic acid) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 3-(7-methyl-1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (44.0 mg) NMR Spectrum: (DMSOd6) 1.94-2.10 (m, 6H), 2.22 (s, 3H), 2.62 (s, 3H), 2.84-2.92 (m, 2H), 4.09-4.17 (m, 1H), 7.27 (d, 1H), 7.32 (dd, 1H), 7.63 (bs, 2H), 7.64 (d, 1H), 7.93 (s, 1H), 8.30 (s, 1H), 8.44 (d, 1H), 8.52 (d, 1H); Mass spectrum: M+H+ 389.
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1>CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(S)cc1
Reactant: C[Si](C)(C)C#CC(=Nc1ccccc1)SCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Fc1ccc(SC=CC(=Nc2ccccc2)SCC2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethyl N-phenyl-3-(trimethylsilyl)thiopropynimidate (0.91 g) was dissolved in methanol (15 mL), a small amount of potassium carbonate was dissolved thereto at room temperature, and the mixture was stirred for 1 hour. 4-fluorothiophenol (0.35 mL) was added thereto and further stirred for 5.5 hours. The reaction mixture was concentrated under reduced pressure, then the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1), medium pressure HPLC (hexane/ethyl acetate=99.2/0.8-98.5/1.5) to obtain cyclopropylmethyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.84 g).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:33]1[S:34][CH:35]=[CH:36][N:37]=1.O.[F-].[K+].[Br-].[Na+]>FC(F)(F)C1C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:21][CH3:22])[C:14]([C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(B2OC(C)(C)C(C)(C)O2)c1OC
Reactant: Brc1nccs1
Agent: [Pd]
Agent: [Br-]
Agent: [F-]
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2nccs2)c1OC
Temperature: 175 °C
Yield: 19.5 %

Procedure:
A mixture of methyl 6-(benzenesulphonylmethyl)-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (Intermediate 59, 0.284 g), tetrakis-(triphenylphosphine) palladium (0.05 g), 2-bromothiazole (0.267 g), potassium fluoride monohydrate (0.25 g) and sodium bromide (0.117 g) in α,α,α-trifluorotoluene (5 ml) was degassed and then heated in the microwave at 175° C. for 2 hours. Ethyl acetate was added and the mixture was filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl 6-benzenesulphonylmethyl-2-methoxy-3-(thiazol-2-yl)-benzoate (0.05 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2C=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[OH:22][NH3+:23]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:23][OH:22])[CH:7]([Cl:12])[CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: [NH3+]O
Reactant: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: ON=C1c2ncc(Cl)cc2C=CC1Cl

Procedure:
22.6 parts of 3,7-dichloroquinoline-8-carbaldehyde (Example 4) were dissolved in 300 parts of alcohol. 10.6 parts of sodium carbonate and 6.9 parts of hydroxylammonium chloride were added to this solution and the suspension was refluxed for 1 hour. 1,000 parts of water were then added and the precipitated solid was filtered off and dried. 23 parts of 3,7-dichloro-8-hydroxyiminoquinoline of melting point 202° C. were obtained. The yield corresponds to 96% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[O:11]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:21]([C:20]3[CH:23]=[CH:24][CH:25]=[C:18]([O:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:19]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ccccc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-phenoxybenzaldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(3-phenoxyphenyl)-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a yellow crystalline solid of melting point 205-207° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:11](OCCN1CCNCC1)C#C>>[CH3:11][O:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: OCCCN1CCNCC1
Reactant: C#CCOCCN1CCNCC1
Product: COCCCN1CCNCC1

Procedure:
The title compound was prepared from 1-piperazinepropanol in the same manner as in Preparation Example 9(1) to (4).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)[N:14]=[CH:15][C:7]=12.O.O.Cl[Sn]Cl.[OH-].[Na+]>CCO.Cl>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:13]1[C:8]2=[N:9][C:10]([NH2:12])=[N:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[C:7]2[CH:15]=[N:14]1
Reactant: Nc1nc(-c2ccco2)c2cnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(Cn2ncc3c(-c4ccco4)nc(N)nc32)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 115.9 %

Procedure:
A suspension of 4-(2-furyl)-1-(3-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (396 mg, 1.18 mmol) in EtOH (5 mL) was heated to 50° C., treated with a solution of SnCl2.2H2O (798 mg, 3.54 mmol) in conc. HCl (1.8 mL), stirred at 50° C. for 2 h then heated at 70° C. for 2 h. The reaction mixture was cooled, basified (5-M NaOH) filtered and the resulting solid suspended in MeOH, treated with HCl in dioxan (4-M, 2 mL), diluted with diethyl ether and filtered to give the title compound (419 mg, 94%) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])[C:15]=4[CH3:31])=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1.[N:33]1C=CC=C[CH:34]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[O:18][N:17]=[C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH:33][CH3:34])=[O:25])[CH3:22])[C:15]=4[CH3:31])=[N:11][C:10]=3[CH:32]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)noc1-c1nc2cc(OCC3CC3)ccc2o1
Reactant: c1ccncc1
Product: CNC(=O)N[C@@H](C)COc1noc(-c2nc3cc(OCC4CC4)ccc3o2)c1C

Procedure:
Using tert-butyl [(1S)-2-({5-[5-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-4-methylisoxazol-3-yl}oxy)-1-methylethyl]carbamate, and in the same manner as in Example 16 (using pyridine instead of triethylamine), the title compound was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2([OH:22])[C:13]1[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1)#[N:2].CC(C)([O-])C.[K+].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl.CO>CN(C)C=O>[CH2:20]([O:19][C:14]1[C:13]([C:6]2([OH:22])[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[N:8]([S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[C:7]2=[O:12])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:21]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(O)C(=O)N(S(=O)(=O)c2ccccc2)c2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
2.50 g (7.79 mmol) of (−)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one (prepared as in example 1.2 and racemate resolution into the corresponding enantiomers as described above) were dissolved in 30 ml of dimethylformamide, resulting in a yellow solution. After cooling to 0° C., 1.00 g (8.94 mmol) of potassium tert-butoxide was added in portions so that the temperature was kept between 0° C. and 5° C. The solution changed in color from yellow to dark yellow. It was stirred for 30 minutes and, at 0° C., 1.07 ml (8.20 mmol) of benzenesulfonyl chloride were slowly added dropwise. The solution became turbid and pale orange in color. It was stirred while cooling in ice for one hour. The progress of the reaction was followed by thin-layer chromatography (dichloromethane/methanol 9:1). For working up, the reaction mixture was added dropwise to ice-water. During this, a precipitate separated out and was, after stirring for 5 minutes, filtered off and washed with water. The title compound (2.65 g, 6.09 mmol, 78%) was dried in a vacuum drying oven at 40° C. and used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1>C1COCC1>[F:1][C:2]1[C:7]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1C=C(c2cccnc2F)CCC1
Solvent: C1CCOC1
Product: O[C@H]1CCC[C@H](c2cccnc2F)C1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A mixture of 3-(2-fluoropyridin-3-yl)cyclohex-2-enone (1100 mg, 5.75 mmol) and 1,1′-bis(di-1-propylphosphino)ferrocene(1,5-cyclooctadiene)rhodium (i) tetrafluoroborate (412 mg, 0.575 mmol) in THF (40 mL) was stirred at 45° C. under an atmosphere of hydrogen gas for 5 h. The mixture was filtered through a Celite pad that was washed with THF. Concentration of the combined filtrated and washings under reduced pressure, followed by flash chromatography on silica gel (0% to 50% EtOAc in hexanes) afforded (rac)-trans-3-(2-fluoropyridin-3-yl)cyclohexanol as a colorless oil together with its cis-isomer. MS (ESI, pos. ion) m/z: 196.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[CH:13]([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH:13]([CH2:18][CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(Br)C(=O)OC
Reactant: Oc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(Oc1ccc2ncccc2c1)C(=O)OC
Reaction time: 18 h
Yield: 92 %

Procedure:
6-Hydroxyquinoline (25.1 g), methyl 2-bromobutyrate (32.3 g) and anhydrous potassium carbonate (23.0 g) in dry N,N-dimethylformamide (100 ml) were stirred at 100° C. for 3 hours then stored at ambient temperature for 18 hours. The mixture was added to water, extracted with ethyl acetate (three times) and the extracts combined, washed with water (four times) then dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the required product (39.0 g) as a red oil.