Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccccc1C(F)(F)F
Yield: 111.8 %

Procedure:
A mixture of 10 g 2-trifluoromethyl phenol, 17 g potassium carbonate, 150 ml acetone and 7.7 ml iodomethane was heated under reflux for 2 hr. After cooling, the insoluble matters were removed by filtration, and the filtrate was evaporated. The resulting residue was dissolved in ethyl acetate, and washed with water and brine. It was dried over anhydrous magnesium sulfate, filtered, and evaporated to give 12.15 g of 2-trifluoromethyl anisole.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.Cl.[CH2:20]([O:22][C:23](=[O:27])[CH2:24][CH2:25][NH2:26])[CH3:21].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:26][CH2:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:27])=[O:9])=[C:5]([F:12])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCN
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(C#N)cc1F
Yield: 85.9 %

Procedure:
4-Cyano-2-fluorobenzoic acid (ABCR, 1.65 g, 10 mmol) was dissolved in DCM (40 mL). DMF (8 μl) was added at RT followed by oxalyl chloride (0.98 mL, 11.6 mmol). Once the gas evolution has ceased, the reaction mixture was evaporated to dryness. The residue was then dissolved in DCM (10 mL) and beta-alanine ethyl ester hydrochloride (1.54 g, 10 mmol) was added followed by dropwise addition of N-ethyldiisopropylamine (3.40 mL, 20 mmol) over 10 minutes. The reaction mixture was then washed with water and a saturated aqueous solution of NaHCO3, dried with MgSO4 and evaporated in vaccuo affording the title compound (2.27 g, 86%) as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.67 (t, J=5.0 Hz, 1H), 7.97 (dd, J=10.0, 1.3 Hz, 1H), 7.79 (dd, J=7.9, 1.4 Hz, 1H), 7.71 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.49 (m, 2H), 2.57 (t, J=6.9 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H). LC/MS (Method B): 263.2 (M−H)−. HPLC (Method A) Rt 2.68 min (Purity: 98.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[O:55][CH2:56][CH2:57]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:57][CH2:56][O:55][C:54]2[CH:60]=[CH:61][CH:62]=[C:52]([F:51])[CH:53]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCOc1cccc(F)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4cccc(F)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 59.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (66 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (92 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-fluorophenoxy)-1-propanol (52 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (63 mg, yield 55%).
Reaction SMILES: [CH2:1]([N:3]([C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])=[O:18])=[CH:15][C:10]=2[NH:9][N:8]=1)C(=O)C)[CH3:2].[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC(N(C)C)=O.CO>[CH2:1]([NH:3][C:7]1[C:11]2[CH:12]=[N:13][C:14]([NH:16][C:17]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])=[O:18])=[C:15]([F:29])[C:10]=2[NH:9][N:8]=1)[CH3:2]
Reactant: CCN(C(C)=O)c1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CCNc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N-Ethyl-N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (154 mg, 0.420 mmol) was dissolved in DMA (1 mL) and methanol (1 mL), charged with powdered Selectfluor® (164 mg, 0.462 mmol), and stirred at room temperature overnight. The reaction was then to heated to 55° C. for 8 h. The resulting crude residue was purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(3-(ethylamino)-7-fluoro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C19H21FN6O2 [M+1]+ 385. found 385.
Reaction SMILES: [Br:1][C:2]1C=CNN=1.O[CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO[C:38](/[N:40]=[N:41]/[C:42](OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:42]=[N:41][N:40]([CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:38]=1
Reactant: O=C1CCCN1CCO
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: Brc1cc[nH]n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCN1CCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-bromopyrazole (5 g, 34 mmol), 1-(2-hydroxyethyl)pyrrolidin-2-one (5.75 g, 51 mmol), PPh3 (13.38 g, 51 mmol) in THF (100 mL) was added DEAD (8.89 g, 51 mmol) and the reaction mixture was stirred at RT overnight. The mixture was concentrated, co-evaporated with Et2O then dissolved in Et2O and cooled in a fridge for 3 hrs whereupon Ph3P═O precipitated out. The mixture was then filtered and concentrated to afford title compound 162 (8.78 g, 100% yield) which was used in the next step with no additional purification. MS (m/z) 259.12/261.12 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl[S:12]([OH:15])(=O)=[O:13].[NH4+:16].[OH-].Cl>CC(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([NH2:16])(=[O:15])=[O:13])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: [OH-]
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
Following the procedure of J. Med. Chem. 2006, 49, 1173, a solution of commercially available 2-fluoronitrobenzene (10.00 g, 70.87 mmol) and chlorosulfonic acid (21 mL) were heated to reflux for 18 hours at 95° C. and then cooled to room temperature. The solution was then added dropwise over a 1 hour period to a solution of iPrOH (225 mL) and concentrated aqueous NH4OH (54 mL) at −35° C. and stirred for 0.5 hours. The solution was maintained at −35° C. while concentrated aqueous HCl was added until the pH was acidic. The solution was then evaporated to remove some iPrOH, water was added and the solution was evaporated again to remove most of the iPrOH. More water was added, the solution was filtered and the solid was washed with 1 N aqueous HCl and water to give the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH:11]2[OH:26])=[CH:6][CH:5]=1.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][CH:11]2[O:26][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:8][CH:9]=1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CC(O)C1c1ccc(Cl)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
37 mg (0.85 mmol) of sodium hydride (55% dispersion in refined oil) were added to a solution of 200 mg (0.56 mmol) of tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-hydroxy-5-propyl-piperidine-1-carboxylate and 188 mg (0.85 mmol) of 2-bromomethylnaphthalene in 10 ml of dimethylformamide and the reaction mixture was stirred at room temperature for 5 hours. For the working-up, the reaction mixture was evaporated in an oil pump vacuum, the residue was partitioned between water and ether and thereafter the separated aqueous phase was extracted five times with 50 ml of ether each time. The combined ether extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 96:4 mixture of toluene and ethyl acetate as the eluent. There were obtained 215 mg (77% of theory) of tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-naphthalen-2-ylmethoxy-5-propyl-piperidine-1-carboxylate as a colourless oil; MS: 494 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:24])=[C:9]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:25])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:24])=[C:9]([CH:19]([CH2:37][CH2:36][CH3:40])[C:20]([O:22][CH3:23])=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:25])[CH3:2]
Reactant: CCc1c(C)sc2nc(C)c(CC(=O)OC)c(-c3ccc(C)cc3)c12
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc(C)c(CC)c2c1-c1ccc(C)cc1
Yield: 58.5 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.200 g; 0.566 mmol), LHMDS 1N in THF (0.635 mL; 0.635 mmol), 1-iodopropane (0.090 mL; 0.923 mmol) in DMF (8 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.131 g (59%) of the title compound as a white solid. ESI/APCI(+): 396 (M+H); 418 (M+Na).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([N+:16]([O-:18])=[O:17])[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2].[C:19]1([C:25](=O)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:34][C:35]([NH2:37])=[O:36].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([CH:14]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:37][C:35](=[O:36])[NH:34]2)[CH:11]=[C:10]([N+:16]([O-:18])=[O:17])[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1C(=O)OC
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1C(=O)OC
Yield: 58.1 %

Procedure:
To a mixture of methyl 2-ethoxy-4-formyl-6-nitrobenzoate (Intermediate 78) (100 mg, 0.4 mmol), 1,2-diphenylethanone (116 mg, 0.6 mmol) and urea (72 mg, 1.2 mmol) in ethanol (3 mL) was added conc. HCl (0.1 mL). Refluxed under N2 atmosphere overnight. Concentrated under reduced pressure, then purified by silica gel column chromatography (PE:EtOAc=10:1 to PE:EtOAc=1:1) to give methyl 2-ethoxy-6-nitro-4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)benzoate (110 mg, yield 58%). This was taken up in ethanol (5 mL) and aq. NaOH (0.5 M, 2 mL, 1 mmol) was added. The mixture was stirred under N2 atmosphere at 60° C. for 5 hrs. The reaction mixture was acidified with conc. HCl (3 mL), and then extracted with a solution (DCM:i-propanol=10:1, 30 mL×2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% TFA as additive) to give Compound 153 (58 mg, yield 55%). 1H NMR (DMSO-d6 400 MHz): δ 13.60 (s, 1H), 8.83 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.39 (s, 1H), 7.28-7.21 (m, 5H), 7.07-7.00 (m, 3H), 6.85 (d, J=6.8 Hz, 2H), 5.42 (d, J=2.4 Hz, 1H), 4.12-4.00 (m, 2H), 1.26 (t, J=7.0 Hz, 3H). MS (ESI): m/z 460.1[M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[O:4]1.O=[C:35]1[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[CH2:36]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:35]4[CH2:38][CH:37]([CH2:39][CH2:40][C:41]([O:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)=[O:42])[CH2:36]4)[O:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CNC3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of 7-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.5 g, 5.49 mmol), benzyl 3-(3-oxocyclobutyl)propanoate (1.66 g, 7.14 mmol) and HOAc (329 mg, 5.49 mmol) in DCE (40 mL) was added NaB(OAc)3H (2.33 g, 11 mmol) in one portion. Then the resulting reaction mixture was stirred at rt overnight. Saturated aqueous NaHCO3 (40 mL) was added to quench the reaction, then was extracted with DCM (50 mL×3), dried over anhydrous Na2SO4 and concentrated. The crude was purified by SGC (DCM:MeOH=100:1 to 50:1) to afford the desired compound (2.3 g, yield: 64%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.14 (d, J=2.5 Hz, 1H), 7.35-7.28 (m, 5H), 7.20 (d, J=4.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.64 (d, J=3.0 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 6.18 (d, J=2.5 Hz, 1H), 5.40-5.39 (m, 1H), 5.08-5.07 (m, 2H), 4.96-4.94 (m, 1H), 4.64 (s, 2H), 4.26-4.24 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.10-3.05 (m, 0.55H), 2.86-2.82 (m, 2H), 2.26-2.20 (m, 3H), 2.10-1.59 (m, 5H), 1.58 (s, 3H), 1.37 (s, 3H), 1.35-1.25 (m, 0.6H), 1.15-1.08 (m, 0.5H) ppm; LC-MS (m/z): 672.4 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[CH3:7][C:8]([CH3:10])=O.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH3:7][C:8]1([CH3:10])[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]1[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:14]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CNC(=S)NN
Reactant: CC(C)=O
Solvent: c1ccncc1
Product: CNC1=NN(C(=O)c2cccc(C(F)(F)F)c2)C(C)(C)S1

Procedure:
A 42 g. portion of 4-methylthiosemicarbazide was reacted with 200 ml. of acetone, and then with 32 g. of pyridine and 83.6 g. of 3-trifluoromethylbenzoyl chloride. The mixture was worked-up as described in Example 1 to obtain 77.5 g. of the desired product, m.p. 111°-115°, after recrystallization from nitromethane.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8](Cl)[N:7]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.[NH2:18][CH2:19][CH2:20][N:21]1[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:24](=[O:31])[NH:23][C:22]1=[O:32].C(N(C(C)C)CC)(C)C>C(O)(C)C>[S:1]1[C:5]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:18][CH2:19][CH2:20][N:21]3[C:25]4([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:24](=[O:31])[NH:23][C:22]3=[O:32])[N:7]=2)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: NCCN1C(=O)NC(=O)C12CCCCC2
Reactant: Clc1ncc(Br)c(-c2cc3ccccc3s2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)C2(CCCCC2)N1CCNc1ncc(Br)c(-c2cc3ccccc3s2)n1
Temperature: 170 °C

Procedure:
A mixture of 4-benzo[b]thiophen-2-yl-5-bromo-2-chloro-pyrimidine (318 mg, 1.0 mmol) and 1-(2-aminoethyl)-1,3-diaza-spiro[4.5]decane-2,4-dione (214 mg, 1.01 equiv.) in isopropyl alcohol (4 mL) was treated with diisopropylethylamine (192 μL, 1.1 equiv.) and heated at 170° C. for 17 min in a Personal Chemistry microwave reactor. Upon cooling, the product was obtained by filtration and washing with isopropyl alcohol, recrystallizing from hot isopropyl alcohol. MS (M+H)+ 500/502.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a solution of 4-(4-chloro-benzyl)-phenol (3.08 g, 14 mmol) in DMF (30 mL) at 0-5° C. was added 60% NaH (1.05 g, 26 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 14 mmol) in DMF (20 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (1.66 g, 30%).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15].C(N(CC)CC)C>CC(C)=O>[C:1]12([C:11]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N+:14]([O-:16])=[O:15])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1[N+](=O)[O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 22 h
Yield: 76.5 %

Procedure:
A solution of 1-adamantanecarbonyl chloride (17.95 g) in acetone (60 ml) was dropped into a solution of 2-nitroaniline (10.4 g) and triethylamine (12.6 ml) in acetone (50 ml), at ° under a nitrogen atmosphere. The mixture was stirred at 23° for 22 h; then further acetone (50 ml) was added. The mixture was heated at 70° for 3 h. The mixture was allowed to cool to 23°, then filtered; the brown solid obtained was crystallized from acetone to give the title compound as a yellow solid (17.3 g). T.l.c. CH-EA (10:2), Rf 0.67. M.p. 111°-4°.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH:2]3[C:14]4[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=4[C:8]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]3=4)[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCN(C(c3ccccc3)c3ccccc3)CC1)c1ccccc1-2
Reaction time: 20 h
Yield: 23.4 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (1.0 g, 4.26 mmol) was suspended in 10 ml of dry tetrahydrofuran, while cooling in an ice bath. 1-(Diphenylmethyl)piperazine (1.1 g, 4.26 mmol) dissolved in 10 ml of dry tetrahydrofuran was added over 10 min., thereafter triethylamine (0.59 ml, 4.26 mmol) in 3 ml tetrahydrofuran was added. The ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran to give 1.36 g of the crude product which was recrystallized two times from acetic acid to yield 0.45 g (20%) of the title compound as a hydrochloride. M.p. 212°14 216° C. 1H-NMR (DMSO-d6, δ): 2.5-3.3 (m, 8H), 4.64 (s, 1H), 5.62 (d, 1H), 7.1-7.9 (m, 14H), 11.25 (s, 1H), 11.74 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:38])[N:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-])=O)=[CH:29][C:28]=2[CH3:37])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Pd]>[NH2:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:22]2=[O:38])=[C:28]([CH3:37])[CH:29]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
970 mg (1.84 mmol) of the compound from Example 54A are dissolved in 20 ml of THF. 200 mg of palladium on carbon are then added, and the mixture is hydrogenated at RT in a hydrogen atmosphere under atmospheric pressure. The mixture is then filtered through kieselguhr, the filter cake is washed three times with THF and the filtrate is freed from the solvent. The reaction product (1.00 g) is reacted further without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:21][CH:22]([CH3:26])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:23](=[O:24])[CH:22]([Br:21])[CH3:26])=[O:5])[CH3:2]
Reactant: CC(Br)C(=O)Cl
Reactant: CCOC(=O)C1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: To 2.7 g of indoline-2-carboxylic acid ethyl ester and 3.4 g of powdered potassium carbonate in 30 ml of methylene chloride, 2.42 g of 2-bromopropanoyl chloride in 10 ml of methylene chloride are added during 2 minutes. The mixture is stirred at room temperature for 2 hours and then partitioned between 50 ml of water and 100 ml of diethyl ether. The organic layer is washed twice with 30 ml of 1N hydrochloric acid and 25 ml of saturated aqueous sodium chloride, dried and evaporated, to yield the 1-(2-bromopropanoyl)-indoline-2-carboxylic acid ethyl ester melting at 101°-103°.