Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1CCNCC1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCNCC1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 95.1 %

Procedure:
A mixture of 7.7 g of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine, 12 g of N-methylpiperazine, 3.5 g of potassium carbonate, 150 ml of dioxane and 60 ml of water was heated overnight at 80°-90° C. and then evaporated. The residual gum was dissolved in dichloromethane, washed with water, dried, filtered and evaporated, giving 8.8 g of 2-[(N-methylpiperazinyl)methyl]-1,4-bis(phenylmethyl)piperazine.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:28]=[CH:27][C:7]2[N:8]=[C:9]([NH:17][C:18]3[C:23]([Cl:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[Cl:26])[C:10]3[CH:11]=[CH:12][NH:13][C:14](=[O:16])[C:15]=3[C:6]=2[CH:5]=1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[Br:3][C:4]1[CH:28]=[CH:27][C:7]2[N:8]=[C:9]([N:17]([C:18]3[C:19]([Cl:26])=[CH:20][C:21]([F:25])=[CH:22][C:23]=3[Cl:24])[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:10]3[CH:11]=[CH:12][N:13]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:14](=[O:16])[C:15]=3[C:6]=2[CH:5]=1
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(F)cc3Cl)nc3ccc(Br)cc3c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN(c1c(Cl)cc(F)cc1Cl)c1nc2ccc(Br)cc2c2c(=O)n(COCC[Si](C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of NaH (252 mg, 6.29 mmol) in THF (20 ml) was added 9-bromo-5-[(2,6-dichloro-4-fluorophenyl)amino]benzo[c]-2,6-naphthyridin-1(2H)-one (950 mg, 2.097 mmol) and the mixture was stirred for 5 min. [2-(Chloromethoxy)ethyl](trimethyl)silane (1.116 ml, 6.29 mmol) was added and the mixture was stirred at room temperature overnight. The solution was quenched with MeOH and concentrated under reduced pressure. The residue was purified by flash chromatography (0-30% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: BrCCCCBr
Reactant: C=CCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(=O)Oc2ccc(OCCCCBr)cc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
162.1 g (0.6 mol) of 4-hydroxyphenyl 4-allyloxybenzoate, known from U.S. Pat. No. 5,211,877, were dissolved in 3 l of methyl ethyl ketone, and 1.32 kg (6 mol) of commercial 1,4-dibromobutane, and 414 g (3 mol) of potassium carbonate were added. The mixture was heated to 80° C. with stirring and held at this temperature for 4 h. It was subsequently cooled, the remaining potassium carbonate was filtered off and the filtrate was concentrated. After the excess dibromobutane had been stripped off, the crude product was recrystallized twice from isopropanol. 4-(4-Bromobutoxy)phenyl 4-allyloxybenzoate was obtained in a yield of 90%. The ester shows the following phase behavior: C 64, N 81-85, isotropic.
Reaction SMILES: [Na].[F:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[C:10]=2[Cl:17])=[O:8])=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[Na+]>C(O)C>[F:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:21][C:22]([OH:24])=[O:23])=[C:11]([Cl:16])[C:10]=2[Cl:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(C(=O)c2ccc(F)cc2)c(Cl)c1Cl

Procedure:
Into a solution of 1.4 g. (0.06 g. atom) of sodium in 200 ml. of absolute alcohol, 16.0 g. (0.056 mole) of 4(4-fluorobenzoyl)-2,3-dichlorophenol was added and the mixture was stirred for thirty minutes at room temperature. The excess of alcohol was vacuum removed and the residue was washed with ether to obtain the sodium salt. The sodium salt of 4(4-fluorobenzoyl)-2,3-dichlorophenol was dissolved in 200 ml. of ethanol and 10.5 g. (0.06 mole) of ethyl bromoacetate was added and the reaction mixture was refluxed for 16 hours, filtered and the solvent was removed in vacuo. The residue was triturated with pet. ether and filtered to obtain a solid product. The product obtained was dissolved in 150 ml. ethanol and 50 ml. of 20% NaOH aqueous solution was added. The reaction mixture was refluxed for 1/2 hour and the solvent was partially removed in vacuo. The residue was dissolved in hot water and filtered. The hot filtrate was acidified with concentrated hydrochloric acid at 60° C. The resulting precipitate was collected by filtration and washed with water. Recrystallization from dichloroethane afforded 8.0 g. (47%) of the product; m.p. 174°-176°.
Reaction SMILES: [NH:1]([C:8](=[O:42])[CH:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[B-](F)(F)(F)[F:50].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1.C(OCC)(=O)C>[NH:1]([C:8](=[O:42])[C:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:24])=[CH:21][CH:20]=1)([C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11])[F:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reactant: F[B-](F)(F)F
Agent: CC(C)(C)[O-]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(F)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 18 %

Procedure:
tert-Butyl [2-({(4-[2-anilino-1-(anilinocarbonyl)-1-fluoro-2-oxoethyl]benzoyl}amino)phenyl]carbamate. To a solution of tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)phenyl]carbamate (59 mg, 0.10 mmol) in THF (2 mL) at room temperature was added potassium tert-butoxide (110 μL, 1 M in THF, 0.11 mmol). The solution was stirred for 5 min and Selectfluor™ (40 mg, 0.11 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h, diluted with ethyl acetate, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by reverse phase HPLC (30% to 100% MeCN in water) gave tert-butyl [2-({-4-[2-anilino-1-(anilinocarbonyl)-1-fluoro-2-oxoethyl]benzoyl}amino)phenyl]carbamate (11 mg, 18%) as a white solid: 1H NMR (600 MHz, CDCl3) δ 9.42 (s br, 1H), 9.11 (s br, 2H), 8.02 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.77 (d, J=7.9 Hz, 1H), 7.58 (d, J=7.6 Hz, 4H), 7.37 (t, J=7.6 Hz, 4H), 7.25-7.16 (m, 5H), 6.78 (s br, 1H); ESIMS calcd 605.2 (M++H), found 605.2 (M++Na).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.O.C([O-])([O-])=O.[Na+].[Na+].[C:20](O)(=O)[CH:21]([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]2[N:9]=[C:20]([CH:21]([CH3:23])[CH3:22])[NH:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CC(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Temperature: 120 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 5-bromo-3-nitrobenzene-1,2-diamine (prepared following the same procedure as for Example 1, 5.0 g) in isobutyric acid (20 mL) was stirred at 120° C. overnight. The mixture was cooled to room temperature and poured into water (100 mL). The pH was neutralized with aqueous Na2CO3 solution. It was then extracted with EtOAc and the organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:1 to afford the desired product as a yellow solid (4.7 g, 77%). 1H NMR (300 MHz, CDCl3) δ ppm 1.51 (m, 6H, J=6.9 Hz), 3.32 (m, 1H, J=6.9 Hz), 8.16 (d, 1H, J=1.5 Hz), 8.25 (d, 1H, J=1.5 Hz), 10.26 (br s, 1H); LC-MS: m/e=284 [M+1]+
Reaction SMILES: [Na].C([C:4](CC)(C([O-])=O)[C:5]([O-])=[O:6])C.[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]=[C:16]([C:20](=[O:22])[CH3:21])[CH2:15]1.[OH-].[K+]>C(O)C.O>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]2[CH:16]([C:20](=[O:22])[CH2:21][C:5](=[O:6])[CH2:4]2)[CH2:15]1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CC(=O)C1=CCCN(C)C1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCC2CC(=O)CC(=O)C2C1

Procedure:
A 250 ml three necked flask, equipped with magnetic stirrer, reflux condenser and nitrogen inlet was charged with 80 ml ethanol. Thereafter, 2.28 g of sodium metal, freshly cut, was added and the mixture stirred till all the sodium had dissolved. Then, 12.33 g of diethylmalonate in 6 ml of ethanol, and 9.74 g of 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)ethanone (arecolone) in 6 ml of ethanol, were added to the warm solution and the resulting solution was stirred and heated to reflux for 5 hours. Then, 10.2 g of 85% potassium hydroxide pellets were added and the mixture heated to reflux for four hours. During this period a heavy precipitate formed. With the aid of 50 ml water, the mixture was transferred into a 500 ml flask and concentrated at 30° and 20 mm of pressure. The residue was again concentrated from 50 ml water. It was then taken up in 100 ml water. 45 ml 12N hydrochloric acid were added and the solution was heated to reflux for 2 hours. It was then cooled and concentrated on a rotovap at 40° and 20 mm of pressure.
Reaction SMILES: [CH:1]([C:3]([CH:5]=[CH2:6])=[O:4])=[CH2:2].[NH2:7][C@H:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH:28]=[C:27]([C:29]5[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=5)[CH:26]=[N:25]4)[CH:18]=3)[S:14][C:10]=2[CH2:9]1>C(Cl)Cl.CO>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([C:27]2[CH:26]=[N:25][N:24]([CH2:23][C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=3)[C:16]([NH:15][C:13]3[S:14][C:10]4[CH2:9][C@@H:8]([N:7]5[CH2:6][CH2:5][C:3](=[O:4])[CH2:1][CH2:2]5)[CH2:39][CH2:38][C:11]=4[N:12]=3)=[O:37])[CH:28]=2)=[CH:34][CH:33]=1)#[N:36]
Reactant: C=CC(=O)C=C
Reactant: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](N)CC5)c3)c2)cc1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(-c2cnn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](N4CCC(=O)CC4)CC5)c3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
Add a solution of divinyl ketone (0.08 g 1.03 mmol) in 1 mL of CH2Cl2 to a solution of N—((S)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-benzamide (0.47 g, 1.03 mmol) in 10 mL of CH2Cl2 and 10 mL of MeOH. Stir the solution for 3 h at room temperature and concentrate the mixture. Purify the residue via column chromatography eluting with 1-10% CH2Cl2/MeOH to give 0.16 g, 30% yield of 3-[4-(4-cyano-phenyl)-pyrazol-1-ylmethyl]-N—[(S)-6-(4-oxo-piperidin-1-yl)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide. Both 1 cms and NMR show that the product exists as a mixture of ketone and hydrate. MS, ES+ 555.70 (M+H2O+H), rt 1.21 min.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)[CH2:2]1.[F:16][CH:17]([F:35])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[N:27][N:26]=2)=[CH:21][CH:20]=1>>[F:35][CH:17]([F:16])[O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][C:28]([C:30]([N:1]3[CH2:2][CH:3]([O:5][C:6]4[CH:7]=[CH:8][C:9]([CH2:12][N:13]([CH3:15])[CH3:14])=[CH:10][CH:11]=4)[CH2:4]3)=[O:31])=[N:27][N:26]=2)=[CH:23][CH:24]=1
Reactant: CN(C)Cc1ccc(OC2CNC2)cc1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC(F)F)cc2)o1
Product: CN(C)Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccc(OC(F)F)cc4)o3)C2)cc1
Yield: 15.2 %

Procedure:
Using a similar protocol as described in Example 36 employing 33B (0.19 g, 0.92 mmol) and 37A (0.26 g, 0.92 mmol) as starting materials afforded 62 mg (15%) of 37 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.27 (s, 6H), 3.44 (s, 2H), 4.35 (dd, 1H), 4.66 (dd, 1H), 4.77 (dd, 1H), 5.10 (m, 2H), 6.62 (t, 1H), 6.75 (d, 2H), 7.28 (m, 4H), 8.19 (d, 2H), MS (APCI+) m/z 445 [M+H]+, LC purity: 94%.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28]>CN(C)C=O>[CH2:27]([C:9]1[O:10][C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:11]([OH:13])=[O:12])[CH3:28]
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1oc2c(c1C(=O)O)C(=O)CCC2
Temperature: 60 °C
Yield: 86.9 %

Procedure:
To a stirred mixture of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (640 g, 3.55 mol), potassium carbonate (1.7 kg, 10.65 mol) and cesium carbonate (100 g, 0.32 mol) in N,N-dimethylformamide (9.0 L) is added iodoethane (1250 g, 8.01 mol). The mixture is heated at 60° C. for 2 h. After cooling to ambient temperature, the mixture is filtered, the solid is rinsed with ethyl acetate, and the filtrate concentrated in vacuo. Water (2 L) is added then extracted with ethyl acetate (2×2 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (642 g). A mixture of this ester (640 g, 3.07 mol) and ammonium acetate (426 g, 5.53 mol) in N,N-dimethylformamide (320 mL) is heated to 100° C. for 2 h. The reaction mixture is concentrated in vacuo, ice water (2.5 L) is added, and extracted with dichloromethane (2×3 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (357 g). A mixture of this ester (170 g, 0.82 mol) in ethyl alcohol (250 mL) and a solution of sodium hydroxide (165 g, 4.1 mol) in water (1 L) is heated at reflux for 1 h, then cooled in an ice water bath. Concentrated hydrochloric acid (350 mL) is added dropwise, the precipitate collected by filtration, rinsed with ice water (3×), and dried in a vacuum oven at 75° C. to afford 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (125 g). m.p. 269-270° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:22])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][S:39](Cl)(=[O:41])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@H:11]([NH:22][S:39]([CH2:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:41])=[O:40])[C:12]2[N:13]=[C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[S:15][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2cccs2)n1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C[C@H](NS(=O)(=O)Cc2ccccc2)c2csc(-c3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 2-(4-nitrophenyl)-1-(2-thiophene2-ylthiazol-4-yl)ethylamine, 8, (330 mg, 0.80 mmol) in CH2Cl2 (6 mL) at 0° C. is added diisopropylethylamine (0.30 mL, 1.6 mmol) followed by phenylmethanesulfonyl chloride (167 mg, 0.88 mmol). The reaction mixture is stirred at room temperature for 14 hours. The mixture is diluted with CH2Cl2 and washed with sat. NaHCO3 followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified over silica to afford 210 mg of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:27][CH2:26]3)=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])=[CH:10][N:9]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][C:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])=[CH:12][N:13]=1
Reactant: COC(=O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2Cl)nc1
Temperature: 60 °C
Yield: 81 %

Procedure:
The solid residue obtained in step A was dissolved in methanol (3 ml) and aqueous solution 2N NaOH (1 ml) was added. The mixture was heated at 60° C. for 2 hours, the solvent was evaporated and the solid obtained was suspended in water. The pH was taken to 6.5 and extracted with CHCl3. The crude mixture was purified over a SiO2 eluting with DCM/MeOH 2% affording 0.170 g (yield 81%) of the expected product.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]2)[N:11]=[CH:10][N:9]=1)(C)(C)C.C[Al](C)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[CH2:20]([N:17]1[CH2:16][CH2:15][N:14]([C:12]2[N:11]=[CH:10][N:9]=[C:8]([NH:7][C:6]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])[CH:13]=2)[CH2:19][CH2:18]1)[CH3:21]
Reactant: C1CCNCC1
Reactant: CCN1CCN(c2cc(NC(=O)OC(C)(C)C)ncn2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN1CCN(c2cc(NC(=O)N3CCCCC3)ncn2)CC1
Temperature: 120 °C
Yield: 18.5 %

Procedure:
A mixture of 1.6 g (7.75 mmol) 6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-ylamine (intermediate 4), 2.03 g (9.3 mmol) di-tert-butyl dicarbonate and 1.17 g (11.6 mmol) NEt3 in 30 mL DCM was stirred at 50° C. in a sealed tube for 16 h. After evaporation of all volatiles the residue was purified with flash column chromatography on silica. The combined product fractions were evaporated to dryness to yield [6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid tert-butyl ester. MS(m/e): 308.4 (MH+). A mixture of 28 mg (0.09 mmol) [6-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-carbamic acid tert-butyl ester, 0.18 mL (0.36 mmol) 2M AlMe3 solution in toluene and 30 mg (0.36 mmol) piperidine in 1 mL toluene were heated to 120° C. for 16 h. After removal of all volatiles under reduced pressure the residue was taken up in methanol/NEt3 and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 5.3 mg (18%) of the title compound. MS (m/e): 319.1 (MH+).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH3:5].[NH2-].[Li+].[CH3:8][O:9][C:10]([CH3:16])([O:12]CC#C)[CH3:11].BrCC>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:1][C:2]#[C:3][CH2:4][CH3:5])[CH3:11]
Reactant: C#CCOC(C)(C)OC
Reactant: C=CC=CC
Agent: [Li+]
Agent: [NH2-]
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 101.9 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 20 minutes to 100 ml (4 mol) of liquid ammonia at −37° C. The mixture was stirred until no more lithium floated (after approximately 15 minutes). A dark cyan solution of lithium in liquid ammonia was obtained. 6.34 g (92 mmol) of piperylene (=1,3-pentadiene) were added portion wise within 30 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 10.1 g (71 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (89.7% GC) were added with a dropping funnel to the reaction mixture at −37° C. within 30 minutes. The reaction mixture was held at −37° C. for about 1 hour. 14.0 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 30 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. 50 ml of water were added to the reaction mixture at 22° C., and the mixture was vigorously stirred until all salt was dissolved. The water layer was extracted once with 50 ml of n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. 11.3 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 87.5% (yield 85.3% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:12]3[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=3[C:18](=[N:19][OH:20])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.COC1C=CC2C3C(N4CCNCC4)=NC4C(C=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[N:26]1([CH2:25][CH2:24][O:20][N:19]=[C:18]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([OH:1])[C:11]=3[C:12]3[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]2=3)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc2c(c1)C(=NO)c1c-2c(O)nc2ccccc12
Reactant: ClCCN1CCCC1
Agent: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: Cl
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCN1CCCC1)c1c-2c(O)nc2ccccc12
Yield: 46 %

Procedure:
6-Hydroxy-9-methoxy-11H-indeno[1,2-c]quinolin-11-one O-2-pyrrolidin-1-yl)ethyl oxime (6bb) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6c and 1-(2-chloroethyl)pyrrolidine·HCl were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 46%.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:4][CH:3]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.C(O)(=O)C>ClCCCl>[CH2:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])=[CH:19][CH:20]=1)[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(NCCc2ccccc2)cc1

Procedure:
A solution of 4-amino-N-quinolin-3-yl-benzamide (1.0 g, 3.8 mmol), phenylacetaldehyde (0.49 mL, 4.18 mmol), tetramethylammonium triacetoxyborohydride (2.0 g, 7.60 mmol) and acetic acid (a catalytic amount) in 1,2-dichloroethane (40 mL) was heated at reflux for approximately 18 hours. The resultant solution was cooled to room temperature and washed with a saturated solution of aqueous sodium bicarbonate. The solution was applied to a flash silica gel column, and the product was eluted with ethyl acetate (40% to 75%) in hexane to give the product, 0.67 g (48%), as a colorless solid. MS: m/z 368 (MH+). 1H NMR (DMSO-d6): δ 2.88 (t, 2 H), 3.35 (t, 2 H), 6.51 (br t, 1 H), 6.7 (d, 2 H), 7.20-7.27 (m, 1 H), 7.30-7.33 (m, 4 H), 7.55-7.67 (m, 2 H), 7.87 (d, 2 H), 7.95 (m, 2 H), 8.82 (d, J=2 Hz, 1 H), 9.15 (d, J=2 Hz, 1H) and 10.25 (s, 1 H).