Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]12[C:16]3[C:8](=[CH:9][C:10]([NH:17][C:18]4[N:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][N:19]=4)=[CH:11][C:12]=3[CH2:13][CH2:14][CH2:15]1)[CH2:7][CH2:6][CH2:5]2.I[CH3:30].[Cl-].[NH4+]>CN(C)C=O>[CH3:30][N:17]([C:10]1[CH:11]=[C:12]2[C:16]3[C:4]([CH3:3])([CH2:15][CH2:14][CH2:13]2)[CH2:5][CH2:6][CH2:7][C:8]=3[CH:9]=1)[C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:19]=1
Reactant: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4(C)CCC3)nc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(c1cc2c3c(c1)CCCC3(C)CCC2)c1ncc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A suspension of sodium hydride (60%, 0.008 g) in N,N-dimethylformamide (2 ml) was added with ethyl 2-[(5,6,6a,7,8,9-hexahydro-6a-methyl-4H-2-phenalenyl)amino]pyrimidine-5-carboxylate (0.034 g) dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with iodomethane (0.018 ml), and the mixture was stirred overnight. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was suspended in ethanol (5 ml), the suspension was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to obtain the title compound (0.028 g, yield: 85%) as colorless needles (melting point: >300° C.).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1CNc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 115.2 %

Procedure:
A solution of 2-bromomethyl-3-nitropyridine (2 g, 9.13 mmol) prepared in Step 2 of Preparation 1 and 4-fluoroaniline (0.87 ml, 9.13 mmol) in ethanol (15 ml) was stirred for 2 hours at 40° C. The reaction mixture was concentrated under reduced pressure to give 2.6 g of the titled compound as a brown solid. The product was used in the subsequent step without further purification.
Reaction SMILES: C(O[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[C:9]([OH:23])=[C:8]([C:24]([O:26][CH3:27])=[O:25])[N:7]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Pd].C(OCC)(=O)C>[OH:23][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:6]([CH3:5])=[N:7][C:8]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1nc(COC(C)=O)c2cc(Oc3ccccc3)ccc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 60 °C
Yield: 90 %

Procedure:
A reactor was charged with 1c (16.0 g), Pd/C (2.08 g), anhydrous Na2CO3 (2.56 g) and ethyl acetate (120 mL). The flask was vacuum-purged with nitrogen (3×) and vacuum-purged with hydrogen (3×). The flask was then pressurized with hydrogen and stirred at about 60° C. until completion of reaction. The flask was cooled to 20-25° C., the pressure released to ambient, the head space purged with nitrogen three times and mixture was filtered. The filtrate was concentrated. Methanol was added. The mixture was stirred and then cooled. Product precipitated and was filtered and dried in an oven (Yield: 90%, HPLC: 99.7%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[O:20]1[CH2:23][CH:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:27]3[CH2:28][CH2:29][CH:24]([CH:22]4[CH2:23][O:20][CH2:21]4)[CH2:25][CH2:26]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: C1CC(C2COC2)CCN1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 18 h
Yield: 56.8 %

Procedure:
A solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.0 g, 3.55 mmol), 4-oxetan-3-ylpiperidine (600 mg, 4.25 mmol) and molecular sieves (4 Å, powdered, 5 g) in anhydrous THF (25 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (1.5 g, 7.08 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 95:5 to 90:10) to afford the title compound as a white foam (0.82 g, 57%). LCMS (Method H): RT=2.38 min, M+H+=408.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][CH:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[CH3:18])[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCCC2C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 105 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (230 mg, 0.94 mmol), 2-methylpyrrolidine (Alfa) (799 mg, 9.4 mmol), K2CO3 (650 mg, 4.7 mmol) in H2O (1.5 mL) was stirred at 105° C. for 20 h. Upon cooling to room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×15 mL). The organic phase was washed with H2O (20 mL), saturated NaCl (20 mL), dried over Na2SO4, and concentrated with a rotary evaporator. Chromatography on silica gel with a gradient eluant of MeOH (0-10%):CH2Cl2 (100-90%) afforded 250 mg (93%) of the title compound as an off-white solid. Mp: 219-221° C. 1H NMR (CDCl3; 400 MHz): δ 1.39 (d, 3, J=6.3), 1.79 (m, 1), 2.22-2.07 (m, 3), 2.58 (s, 3), 3.90 (m, 1), 4.04 (m, 1), 4.59 (m, 1), 6.74 (s, 1), 7.38 (t, 1, J=7.4), 7.46 (t, 2, J=7.4), 7.63 (d, 2, J=7.4), 8.31 (s, 1). MS m/z: 293 (M+1), 291 (M−1). HRMS: Calcd for M+H: 293.1766. Found: 293.1770.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7](=[C:11]([Cl:15])[CH:12]([Cl:14])[Cl:13])[C:8](Cl)=[O:9].Cl>>[CH2:1]([O:5][C:8](=[O:9])[C:7]([Cl:6])=[C:11]([Cl:15])[CH:12]([Cl:14])[Cl:13])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(Cl)=C(Cl)C(Cl)Cl
Reactant: CCCCO
Agent: Cl
Product: CCCCOC(=O)C(Cl)=C(Cl)C(Cl)Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
An agitated flask is charged with 0.5 mole of n-butanol and heated under stirring to 50° C. Within 30 minutes, 60.6 g (0.25 mol) of 2,3,4,4-tetrachloro-2-butenoic acid chloride is added dropwise to the charge, and the latter is agitated for 30 minutes at 80° C. During this step the main quantity of the thus-formed hydrogen chloride is driven off in the gaseous phase. Subsequently, the reaction mixture is fractionated without neutralization over a 10 cm column under vacuum, thus obtaining 64.4 g (0.23 mol) of 2,3,4,4-tetrachloro-2-butenoic acid n-butyl ester; b.p. 95° C./0.6 mbar; nD20 --1.5050. Yield: 92% of theory.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3]1.[OH-].[Na+].Cl.Cl.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>O.C(O)C>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([N:6]3[CH2:5][CH2:4][O:3][C:2]3=[O:1])=[CH:17][CH:16]=2)=[O:13])[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(N2CCOC2=O)cc1
Reactant: Cc1ccc(N2CCCNCC2)c(C)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: O
Product: Cc1ccc(N2CCCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)c1
Temperature: 50 °C
Yield: 10.6 %

Procedure:
To ethyl 4-(2-oxooxazolidin-3-yl)benzoate (0.235 g) described in Preparation Example 12 were added 1N aqueous sodium hydroxide solution (1.3 mL) and ethanol (5 mL), and the mixture was stirred at 50° C. 1N hydrochloric acid (1.3 mL) was added, 1-(2,4-dimethylphenyl)-[1,4]diazepane hydrochloride (0.241 g) described in Preparation Example 88, 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (0.277 g) and N-methylmorpholine (0.13 mL) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (41.8 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([C:20]#[N:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: C1CCOC1
Product: NCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21

Procedure:
6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalene-1-carbonitrile was dissolved in 100 mL of dry tetrahydrofuran (THF), and the mixture was stirred while cooling in an ice bath. Borane-THF complex (40 mL) was added to the cold, stirring solution, and the reaction mixture was stirred under nitrogen for 15 hours at room temperature. The reaction mixture was carefully quenched by addition of 20 mL of 20% HCl and 60 mL of methanol. The solvents were removed under reduced pressure, and the aqueous residue was treated dropwise with 1M NaOH until basic. The residue was extracted twice with 100 mL of EtOAc and the organic layers were dried (MgSO4) and evaporated. The crude product was acidified with dilute HCl in EtOH and recrystallized from EtOAc to yield 3.1 g of C-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methylamine as a hydrochloride salt. MS: 302 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=[O:15].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.IC1C=C2C(=CC=1)N=CC(C(N)=O)=C2NC1C=CC=C(OC)C=1>>[ClH:1].[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]2[C:11]([C:2]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([O:18][CH3:17])[CH:20]=3)=[C:3]([C:14]([NH2:16])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(Cl)ccc2c(Cl)c(C(N)=O)cnc12
Reactant: COc1cccc(N)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3ccc(I)cc23)c1
Agent: Cl
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)c(Cl)ccc23)c1

Procedure:
Intermediate 66 was prepared from Intermediate 68 using 3-methoxyaniline in a similar manner to Intermediate 14.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(O)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([C:2]3[CH:14]=[CH:13][CH:12]=[CH:4][CH:3]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1
Reactant: OC1(c2ccccc2)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)C(c1ccccc1)(c1ccccc1)c1cc(Br)ccc1-2

Procedure:
Next, 2,7-dibromo-9-phenyl-9H-fluorene-9-ol is dissolved in benzene, and benzene containing concentrated sulfuric acid is added into the solution and react for one hour. After the solution is cooled down, sodium carbonate is added into the solution. Next, a chloroform extraction is performed, and the organic layer is washed two times by water and dried by magnesium sulfate. Next, the rotary concentrator is utilized to remove the solvent, then chloroform and methanol are utilized to initiate a recrystallization reaction and produce 2,7-di bromo-9,9-diphenylfluorene.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](Cl)=[O:4].Cl.[F:20][C:21]([F:33])([C:29]([F:32])([F:31])[F:30])[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)=[O:23].CN1CCOCC1>C(Cl)Cl>[F:33][C:21]([F:20])([C:29]([F:30])([F:31])[F:32])[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:3]([CH:2]1[CH2:6][CH2:7][CH2:8][N:1]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:4])=[O:23]
Reactant: O=C(C1CCCN1)C(F)(F)C(F)(F)F
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)N1CCCC1C(=O)N1CCCC1C(=O)C(F)(F)C(F)(F)F

Procedure:
Methylene chloride (10 ml) was added to CBZ-L-Pro-Cl which was then reacted under argon with a suspension of 2-(2,2,3,3,3-pentafluoro-1-oxopropyl)pyrrolidine hydrochloride (compound from Example IC; 2.49 mmol) and N-methylmorpholine (0.54 ml; 4.98 mmol) dissolved in methylene chloride (7 ml). After 2.5 hours the reaction was concentrated and brought up in methylene chloride (1 ml) and the product purified by flash chromatography on silica gel column eluting with ethyl acetate/hexane (50:50). Product fractions were collected and concentrated to give the desired product (0.52 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:20][CH3:21])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2OS(C(F)(F)F)(=O)=O.[CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH2:23].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:25]([O:24][C:22]([C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[C:4]([O:20][CH3:21])[CH:5]=2)[N:10]=[CH:9][CH:8]=1)=[CH2:23])[CH2:26][CH2:27][CH3:28]
Reactant: COc1cc(F)c2nccc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(OCCCC)c1ccnc2c(F)cc(OC)cc12
Yield: 68.8 %

Procedure:
15.5 g (47.5 mmol) of 1,1,1-Trifluoro-methanesulfonic acid 8-fluoro-6-methoxy-quinolin-4-yl ester, 24.5 mL (0.19 mol) of butyl vinyl ether and 13.3 mL of triethylamine were takent up in 100 mL of DMF. 2.0 g (4.75 mmol) of dppp (1,3-bis(diphenylphosphino)propane) and 1.06 g (4.75 mmol) of Pd(OAc)2 were added and the contents heated to 60 C for 4 hrs. No starting material remained. Contents were rotary-evaporated to remove as much DMF as possible. Crude material was purified by flash chromatography on silica gel using 10% ethyl acetate/hexanes as the eluent to give 9.0 g (69%) of the desired product. 1H NMR (CDCl3, 400 MHz) 8.78 (d, 1H), 7.43 (d, 1H), 7.28 (m, 1H), 7.09 (d, 1H), 4.58 (d, 1H), 4.50 (d, 1H), 3.96 (t, 2H), 3.90 (s, 3H), 1.80 (m, 2H), 1.53 (m, 2H), 0.97 (t, 3H LCMS (M+H)+ 276.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: Cc1coc2ccc(C=O)cc12
Reactant: O=C1CSC(=O)N1
Product: Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-Methyl-benzofuran-5-carbaldehyde (intermediate 57) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2.[OH-].[NH4+]>S(=O)(=O)(O)O>[Br:6][C:7]1[CH:16]=[CH:15][C:14]([N+:1]([O-:4])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2
Reactant: Brc1cccc2cnccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=[N+]([O-])c1ccc(Br)c2ccncc12
Temperature: 0 °C

Procedure:
A solution of potassium nitrate (120 g, 1.2 mol) in conc. sulphuric acid (500 ml) was added to a mixture of 5-bromoisoquinoline (219.4 g, 1.05 mol) and conc. sulphuric acid (400 ml) at below 10° C. during 1.5 h. The reaction was poured out on ice (4 l) and was neutralised by addition of conc. ammonium hydroxide (2 l) and ice (4 l). The crystals were filtered and air dried. Yield 216.9 g (82%). Mp 129-130° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]#[N:25]>ClCCCl>[CH:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:22]2[N:18]([CH3:17])[C:19]([CH2:23][C:24]#[N:25])=[CH:20][CH:21]=2)=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6]
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: Cn1cccc1CC#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)c1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Temperature: 25 °C

Procedure:
To a suspension of 17.5 g. (0.131 mole) aluminum chloride in 60 ml. 1,2-dichloroethane is added 24 g. (0.131 mole) ρ-isopropylbenzoyl chloride. The resulting mixture is added slowly and dropwise to a chilled solution (0° C.) of 15.7 g. (0.131 mole) 1-methylpyrrole-2-acetonitrile in 100 ml. of 1,2-dichloroethane. After addition is complete, the mixture is stirred at room temperature for twenty minutes and heated at reflux for three minutes. The reaction mixture is then cooled and poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and a saturated solution of sodium chloride; dried over magnesium sulfate; and the solvent evaporated. The product, 5-(ρ-isopropylbenzoyl)-1-methylpyrrole-2-acetonitrile, is isolated from the residual oil by column chromatography. The column is packed with acid washed alumina and eluted with benzene, ether and ethylacetate. The product is found in the first compound-bearing fraction which absorbs ultraviolet light at approximately 250 m. It is purified by recrystallization twice in ether:pentane (9 g.; 20% yield), M.P. 59°-64° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH2:13].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]=3[CH2:34][CH3:35])[N:26]=[CH:25]2)[CH:18]=1>>[CH2:34]([C:33]1[N:32]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:31]=[CH:30][C:29]=1[C:27]1[N:26]=[CH:25][N:24]([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=2[CH3:23])[C:16]([NH:13][C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:28]=1)[CH3:35]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: COc1ccc(C(F)(F)F)cc1N
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(F)(F)F)ccc4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 154 was prepared from 2-methoxy-5-trifluoromethyl-phenylamine and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 546 [C30H26F3N5O2+H]+.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[NH:6]1[CH:10]=[CH:9][CH:8]=[N:7]1.C(O)C>[Pd]>[CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[NH2:5][C:10]1[CH:9]=[CH:8][NH:7][N:6]=1
Reactant: c1cn[nH]c1
Agent: [Pd]
Agent: CS(N)(=O)=O
Solvent: CCO
Product: Nc1cc[nH]n1
Reaction time: 3.5 h

Procedure:
To a nitrogen flushed solution of pyrazole methylsulfonamide (275.0 mg, 0.70 mmol), from step C, in 10 mL of ethanol was added solid palladium (10% on activated carbon, wet with <50% water, 550.0 mg). The suspension was degassed via house vacuum, then filled with hydrogen gas supplied by a gas balloon. The mixture was stirred for 3.5 h under a hydrogen atmosphere, and filtered through a layer of Celite. The solid residue and the filtration pad were rinsed with ethanol and ethyl acetate, the combined filtrate and rinsing were concentrated under reduced pressure to give 173.0 mg (95%) of amino-pyrazole methylsulfonamide as a solid (MH+=262.0).
Reaction SMILES: [Na].[CH:2]1([N:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18][OH:19])[N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:20]1([N:8]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][CH2:18][O:19][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:16]=2)=[O:10])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Brc1ccccn1
Reactant: O=C(Nc1nc(CCO)cs1)N(C1CCCCC1)C1CCCCC1
Agent: [Na]
Product: O=C(Nc1nc(CCOc2ccccn2)cs1)N(C1CCCCC1)C1CCCCC1

Procedure:
1,1-Dicyclohexyl-3-{4-[2-(pyridin-2-yloxy)-ethyl]-thiazol-2-yl}-urea was prepared from the sodium salt of 1,1-dicyclohexyl-3-[4-(2-hydroxyethyl)-thiazol-2-yl]-urea (50 mg, 0.14 mmol; 0.5 mmol NaH, DMF as solvent) and 2-bromopyridine (20 mg, 0.14 mmol). After aqueous workup, the resulting oil was purified on silica gel to give 1,1-dicyclohexyl-3-{4-[2-(pyridin-2-yloxy)-ethyl]-thiazol-2-yl}-urea in 20 mg (33%) yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:23])[CH2:18][CH2:17]2)[N:10]=1.[OH-].[Na+]>>[Cl:8][C:9]1[N:14]=[C:13]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:12]=[C:11]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:34])([F:33])[F:35])=[O:23])[CH2:18][CH2:17]2)[N:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2nc(Cl)nc(N3CCC(C(=O)NCc4ccccc4C(F)(F)F)CC3)n2)CC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
N-Methylpiperazine (0.31 mL, 2.7 mmol, 1.0 equiv) was added to the suspension prepared in step a. The resulting mixture was heated to 40° C. and treated with 1 N NaOH to maintain a pH of 9-10. The reaction mixture was stirred for 30 min and then used immediately in the next step without workup or purification. MS (ES+): m/e 498.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>O1CCCC1>[C:26]1([CH3:29])[CH:27]=[CH:28][C:23]([NH:22][C:15]([C:9]2[C:10]3[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=3[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=2[CH3:18])=[O:16])=[CH:24][CH:25]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Nc3ccc(C)cc3)c2nc1OC

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and p-toluidine 180 mg (1.68 mmol). Reaction was carried out in refluxing tetrahydrofuran for 50 hours, and the crude product was eluted through a flash column (7:3 hexanes:ethyl acetate), 200 mg (65%), mp 214-215° C.; 1H NMR (CDCl3): δ 8.33 (s, 1H), 7.69 (d, 2H, J=8.3 Hz), 7.65 (s, 1H), 7.15 (d, 2H, J=8.3 Hz), 4.17 (s, 3H), 4.03 (s, 3H), 2.58 (s, 3H), 2.32 (s, 3H); MS (APCI): m/z 383 (M+H).