Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:9]1=[O:18].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH2:13]2)[C:9]1=[O:18]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=C1N(c2ccccc2Cl)CCC12CCCNC2
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N(c2ccccc2Cl)CCC12CCCN(c1ccc(C(F)(F)F)cn1)C2
Temperature: 180 °C

Procedure:
A mixture of 2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one (16.0 mg, 0.0000604 mol, which was prepared by using a procedure that was analogous to that used for the synthesis of example 92, steps 1-4), 2-chloro-5-(trifluoromethyl)pyridine (13 mg, 0.000072 mol) and N,N-diisopropylethylamine (0.032 mL, 0.00018 mol) in N-methylpyrrolidinone (0.4 mL, 0.005 mol) was irradiated with microwaves to heat the reaction mixture to 180° C. for 20 min. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 410.2/412.2 (M+H)+.
Reaction SMILES: O.[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O-:13])(=[O:12])=[O:11])=O.[Na+:14].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]([CH2:25]P(OC)(OC)=O)=[O:24]>O>[CH3:21][O:22][C:23]([CH:25]=[CH:2][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O-:13])(=[O:12])=[O:11])=[O:24].[Na+:14]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COC(=O)C=Cc1ccccc1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
A mixture of sodium 2-formylbenzenesulfonate hydrate (31) (tech., purity 75%; 1.33 g, 4.79 mmol), potassium carbonate (1.32 g, 9.56 mmol), and trimethyl phosphonoacetate (1.05 g, 5.77 mmol) in water (2.5 ml) was vigorously stirred at ambient temperature for 1 hour. The precipitate was filtered and carefully washed with methanol. The methanol extract was evaporated to give the title compound (0.66 g, 52%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.72 (3H, s); 6.43 (1H, d, J=16.0 Hz); 7.18-7.96 (4H, m); 8.83 (1H, d, J=16.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH2:14].[C:15](Cl)(=[O:25])[C:16]1[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:18](Cl)=[O:19].CCN(C(C)C)C(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: COc1cc(Br)c(CCN)cc1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Br)c(CCN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-4,5-dimethoxylbenzeneethanamine (3.5 g 13.2 mmol) was dissolved and stirred in 50 mL dry acetonitrile. 2.14 mL (1.1 equiv) phthaloyl dichloride and 7 mL (3 equiv) Hünig's base were added. The mixture was stirred at room temperature overnight. Acetonitrile was then removed, and the remaining product was taken up in dichloromethane and washed with basic water (pH=11). The aqueous wash was extracted with dichloromethane 3×15 mL. The organic fractions were combined and dried over sodium sulfate. Solvent was removed to give the crude product, which was then purified by column chromatography. Calculated yield: 1.8 g (34%).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:29]([OH:33])[C:30]#[C:31][CH3:32])[CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:29]([OH:33])/[CH:30]=[CH:31]/[CH3:32])[CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC#CC(O)c1cccc(OCc2ccccc2)c1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C/C=C/C(O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
To a cold solution of sodium bis(2-methoxyethoxy)aluminum hydride (65+ wt. % in toluene) (available from Aldrich) (14.8 mL, 49.1 mmol) in ether (60 mL) was added a solution of 93.A (6.20 g, 24.6 mmol) in ether (30 mL) dropwise under nitrogen at 0° C. The mixture was stirred for 5 minutes at 0° C., the cooling bath was removed, and stirring was continued for 3 hours at room temperature. The reaction was carefully quenched at 0° C. with EtOAc, diluted with saturated aqueous Rochelle salt, and extracted with additional EtOAc. The combined organics were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 93.B (5.37 g, 86% yield) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][C:11]2[CH:30]=[CH:29][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:3][CH:2]([O:4][C:5]1[CH:32]=[CH:31][C:8]([O:9][CH2:10][C:11]2[CH:30]=[CH:29][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CC(C)Oc1ccc(OCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(OCc2ccc(CN3CCNCC3)cc2)cc1
Reaction time: 8 h
Yield: 136.8 %

Procedure:
To a solution of tert-butyl 4-(4-{[4-(propan-2-yloxy)phenoxy]methyl}benzyl)-piperazine-1-carboxylate (5.42 g) in CH2Cl2 (41 mL) was added TFA (10 mL) at room temperature, then the reaction mixture was stirred for 8 hours. The reaction mixture was basified with 5 M aqueous NaOH, and extracted with CH2Cl2. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 1-(4-{[4-(propan-2-yloxy)phenoxy]methyl}benzyl)piperazine as a colorless solid (5.73 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.CN(C)/[CH:17]=[C:18](/[C:24](=[O:33])[C:25]1[CH:30]=[C:29]([I:31])[CH:28]=[CH:27][C:26]=1F)\[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][N:1]2[C:26]3[C:25](=[CH:30][C:29]([I:31])=[CH:28][CH:27]=3)[C:24](=[O:33])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cn(CC2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
3-(Aminomethyl)-1-N-Boc-pyrrolidine (2.5 g, 12.5 mmol) was added to the stock solution of (Z)-ethyl 3-(dimethylamino)-2-(3-iodobenzoyl)acrylate (Intermediate 24, 0.34M, 34 mL, 11.3 mmol). The reaction mixture was heated at 50° C. for 3 h. The solvent was removed in vacuo and the resulting residue was dried in a vacuum oven for 1.5 h. The residue was then dissolved in dimethylformamide (20 mL) and potassium carbonate powder (2.2 g, 15.8 mmol) was added. The reaction mixture was heated at 70° C. for 3 h then cooled to room temperature. Water (100 mL) was added and the suspension was extracted with 1:1 ethyl acetate: methyl tert-butyl ether (3×50 mL). The organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The residue was suspended in methyl tert-butyl ether (20 mL) and stirred at 40° C. for 1 h. The suspension was filtered and the solid dried to give 4.15 g (70% yield) of ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellowish powder.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:11][CH:12]=1.[C:18](=O)([O-])[O-:19].[Na+].[Na+]>CN(C)C=O>[CH:18]([C:15]1[S:14][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=2)=[CH:17][CH:16]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc(-c2cccs2)c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2cccc(Br)c2)s1
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (1.15 mL; 15.4 mM) was added slowly to stirring dimethylformamide (0.95 mL; 12.2 mM) at -10° under nitrogen. The resulting mixture was stirred for 15 mins. 2-(3'-bromophenyl)thiophene (2.12 g; 9 mM) was then added. The reaction mixture was then warmed slowly to 110° over a period of 1 hr. cooled and poured into ice, and cautiously neutralized with sodium carbonate. Extraction with ethyl acetate and drying the organic phase with anhydrous magnesium sulfate provided upon concentration 2.16 g of the desired aldehyde as an oily solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[C:7](O)=[CH:6]2.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[Cl:23])[NH2:19].CN1C(=O)CCC1.Cl>O1CCOCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[CH:7]=[C:6]2[NH:19][C:18]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:16]([Cl:15])[CH:17]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc2nc(O)c(O)cc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc2nc(O)cc(Nc3ccc(Cl)c(Cl)c3)c2c1
Yield: 23.9 %

Procedure:
6-Methoxyquinolinediol (2.5 g, 13.08 mmol) and 3,4-dichloroaniline (4.2 g, 26.25 mmol) were placed in a 100 mL Teflon vessel for use with an Ethos 1600 Lab Microwave. NMP was then added (9 mL), followed by HCl in dioxane (5 mL, 4 M). The slurry was irradiated to achieve a 200° C. temperature using a 400 W upper setpoint for 30 min. The mixture was cooled, suspended in methanol (20 mL), and filtered to afford 1.049 g of the title compound. 1H NMR (300 MHz, DMSO): 3.84 (s, 3H), 5.84 (s, 1H), 7.23 (td, ?H, J=8.88, 8.48 Hz), 7.35(tt, ?H, J=8.88, 2.42 Hz), 7.56(d, ?H, J=2.42 Hz), 7.66 (˜s, 2H), 8.71(s, 1H), 11.10(s, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:11][C:12](=O)[CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])(C)(C)C>CCOCC>[F:17][C:16]([F:19])([F:18])[CH2:15][O:14][CH2:13][CH2:12][OH:11]
Reactant: CC(C)(C)OC(=O)COCC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCOCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
To a suspension of LAH (750 mg, 19.7 mmol) in ether (40 ml) was added crude t-butyl-2,2,2-trifluoroethoxyacetate (2.0 g, 9.3 mmol) in ether (10 ml) at 0° C. The mixture was stirred for 45 minutes at 0° C. Then, the mixture was poured into ice-water and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crude 2-(2,2,2-trifluoroethoxy)ethanol (1.09 g, 81%). To a solution of crude 2-(2,2,2-trifluoroethoxy)ethanol (150 mg, 11.0 mmol) in dichloromethane (3 ml) was added triethylamine (110 mg, 1.1 mmol) and p-toluenesulfonylchloride (200 mg, 1.1 mmol). The mixture was stirred at room temperature for 2 days. The mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After concentration, silica gel column chromatography (n-hexane/ethyl acetate=5/1) gave 2-(2,2,2-trifluoroethoxy)ethyl p-toluenesulfonate (188 mg, 63%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=O)[CH2:27][CH2:26]3)=[CH:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[N:35]1(O)[C:39]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN>CN(C)C=O.C1COCC1.O>[CH3:39][NH:35][C:32](=[O:34])[CH2:31][N:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:21]2[S:20][C:19]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])=[N:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of {4-[(2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methyl]piperazin-1-yl}acetic acid (0.230 g) in N,N-dimethylformamide (4 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.066 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.093 g), and the mixture was stirred at 50° C. for 1 hr. A 2.0 mol/L solution of N-methylamine in THF (0.60 ml) was added to the reaction solution, and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and recrystallized from tetrahydrofuran-hexane to give the title compound (0.100 g, yield 42%) as colorless crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[N:24]1([C:30]2[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:17]1[N:15]2[N:16]=[C:11]([N:27]3[CH2:26][CH2:25][N:24]([C:30]4[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:39][CH:40]=4)[CH2:29][CH2:28]3)[CH:12]=[CH:13][C:14]2=[N:19][N:18]=1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
DIPEA (2.348 mL, 13.48 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2 g, 8.99 mmol) and ethyl 4-(piperazin-1-yl)benzoate (2.316 g, 9.89 mmol, CAS 80518-57-6) in DMF (20 mL). The resulting solution was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, then evaporated to dryness and redissolved in DCM (150 mL) and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was triturated with ether. The solid was collected by filtration and dried under vacuum to give ethyl 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]benzoate (3.40 g, 90%) as a solid.
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[F:19][C@H:20]1[CH2:37][C@@:35]2([CH3:36])[C@@H:31]([CH2:32][CH2:33][C:34]2=[O:38])[C@H:30]2[C@H:21]1[C@:22]1([CH3:40])[C:27]([CH2:28][CH2:29]2)=[CH:26][C:25](=[O:39])[CH2:24][CH2:23]1>O1CCCC1>[F:19][C@H:20]1[CH2:37][C@@:35]2([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]2[OH:38])[C@H:30]2[C@H:21]1[C@:22]1([CH3:40])[C:27]([CH2:28][CH2:29]2)=[CH:26][C:25](=[O:39])[CH2:24][CH2:23]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 3.0 g. of lithium tri-(tert.-butoxy)-aluminum hydride in 15 ml. of tetrahydrofuran is introduced into 2.0 g. of 11β-fluoro-4-androstene-3,17-dione in 5 ml. of tetrahydrofuran. After 45 minutes, the solution is poured into sulfuric ice water and extracted with methylene chloride. The crude product (1.5 g.) representing a mixture of 11β-fluoro-17β-hydroxy-4-androsten-3-one and 11β-fluoro-4-androstene-3β,17β-diol is stirred for 4 hours at room temperature with 1.8 g. of 2,3-dichloro-4,5-dicyano-1,4-benzoquinone in 50 ml. of dioxane. The solution is diluted with ether, washed repeatedly with 2N sodium hydroxide solution and water, and dried over sodium sulfate. After chromatography on silica gel with acetone/hexane, 1.2 g. of 11β-fluoro-17β-hydroxy-4-androsten-3-one is obtained; m.p. 160°-162°. UV: ε239 = 16,500 (methanol).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=O)[CH2:6][N:7]([C:14]([C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22]([OH:24])=[O:23])=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(NCC(OC)=O)C=CC=CC=1.Cl.NO>CO>[O:4]=[CH:5][CH2:6][N:7]([C:14]([C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22]([OH:24])=[O:23])=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CN(C(=O)[C@H]1CCCC[C@H]1C(=O)O)c1ccccc1
Agent: COC(=O)CNc1ccccc1
Agent: Cl
Agent: NO
Solvent: CO
Product: O=CCN(C(=O)[C@H]1CCCC[C@H]1C(=O)O)c1ccccc1
Temperature: 15 °C
Reaction time: 6 h

Procedure:
A solution of 1.32 g (33 mmoles) of NaOH in 32 ml of methanol, is added under stirring at a temperature of 10° C., with 3.19 g (10 mmoles), of cis-2-[[N-[2-methoxy-2-oxoethyl]-N-phenylamino]carbonyl]-cyclohexanecarbo xylic acid (prepared from the anhydride of the cis-1,2-cychlohexanbicarboxylic acid and methyl N-phenyl-aminoacetate according to a process like that disclosed in the example 2), and then with 0.764 g (11 mmoles) of hydroxylamine hydrochloride. The resulting suspension is maintained under stirring at 15° C. for 6 hours, then at rest for the night.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:18]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][C:11]2=[N:10]1.C(OCC)(=O)C.C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:32])=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:32][C:13]1[C:12]2=[CH:18][N:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[CH:16]=[CH:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2nn(-c3c(F)cccc3Cl)cc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Fc1cccc(Cl)c1-n1cc2c(Cl)nccc2n1
Temperature: 85 °C
Yield: 27 %

Procedure:
2-(2-Chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine 5-oxide (2.13 g, 8.1 mmol) was added to a solution of tetrabutylammonium chloride (2.24 g, 8.1 mmol) in phosphorous oxychloride (16 mL) and the reaction mixture was heated at 85° C. for 5 hours. The reaction mixture was cooled to room temperature and poured into a mixture of ethyl acetate and sodium hydrogen carbonate (sat. aq.). The organic phase was separated, washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (606 mg, 27% yield). 1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 8.12 (d, J=6.3 Hz, 1H), 7.57 (d, J=6.5 Hz, 1H), 7.55-7.50 (m, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.27 (m, 1H). LCMS (Method D): RT=3.29 min, m/z: 282 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:30]([F:33])([F:32])[F:31])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl.O>CO.C(O)(C)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]([O:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:30]([F:33])([F:32])[F:31])[N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(COc1cc(-c2ccc([N+](=O)[O-])cc2)nc2cccc(C(F)(F)F)c12)N1CCOCC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: Nc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3c(C(F)(F)F)cccc3n2)cc1
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
4-{[2-(4-Nitrophenyl)-5-trifluoromethyl-4-quinolyl]oxyacetyl}morpholine (6.6 g) dissolved in methanol (=b 132 cc) is hydrogenated for three hours thirty minutes at atmospheric pressure in the presence of an 8N solution (6.6 cc) of gaseous hydrochloric acid in isopropanol and palladium (0.66 g) supported on charcoal (10% palladium). Distilled water (240 cc) is then added, the mixture is stirred for 10 minutes and the catalyst is thereafter filtered off. Normal aqueous sodium hydroxide solution (45 cc) is added an the precipitate is filtered off, washed with distilled water (3×100 cc) and dried under reduced pressure. The precipitate is dissolved while hot in a cyclohexane/ethyl acetate mixture (50:50 by volume). The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up on petroleum ether, filtered off and dried. 4-{[2-(4-Aminophenyl)-5-trifluoromethyl-4-quinolyl]oxyacetyl}morpholine (3.16 g,), m.p. 174° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH3:14])[C:7](=[O:20])[CH2:6][CH2:5]2.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28].N>CCO.C(Cl)Cl.CO.C(Cl)Cl>[O:20]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[NH:28])[CH:3]=2)[N:8]1[CH2:12][CH:13]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[CH3:14]
Reactant: CSC(=N)c1cccs1
Reactant: CC(CN1C(=O)CCc2cc(N)ccc21)N1CCCC1
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CC(CN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-1-(2-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (240 mg, 0.88 mmol) in 10 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (501 mg, 1.76 mmol) and stirred overnight at room temperature. The mixture was diluted with CH2Cl2 (10 mL) and argon was bubbled through the solution for 20 minutes. The solution was partitioned between CH2Cl2 (100 mL) and saturated sodium carbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow which was subjected to flash chromatography on silica gel using 2% MeOH/CH2Cl2 then 5-10% 2M NH3 in MeOH/CH2Cl2. A yellow solid was obtained (200 mg, 59.4%). 1H-NMR (DMSO-d6) δ: 7.71 (d, J=3.6 Hz, 1H), 7.57 (d, J=5.4 Hz, 1H), 7.08-7.06 (m, 2H), 6.72-6.71 (m, 2H), 6.41 (br s, 2H), 4.05 (dd, J=9.0, 13.8 Hz, 1H), 3.83 (dd, J=4.8, 13.8 Hz, 1H), 2.79-2.75 (m, 3H), 2.54-2.47 (m, 6H), 1.63 (br, 4H), 0.87 (d, J=6.3 Hz, 3H).
Reaction SMILES: C[O:2][CH:3]1[CH:8]([CH:9](OC)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH:5](OC)[O:4]1.O1CCOCC1.Cl.C(=O)(O)[O-].[Na+]>O>[CH:9](=[C:8]([CH2:7][CH2:6][CH:5]=[O:4])[CH:3]=[O:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1CCC(C(OC)c2ccccc2)C(OC)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCCC(C=O)=Cc1ccccc1

Procedure:
A mixture of 100 g. 2,6-dimethoxy-3-(α-methoxybenzyl)tetrahydropyran, 300 g. dioxane, 200 ml. water and 40 g. concentrated hydrochloric acid was stirred for 2 hours at 60°-70° C. The solution, which eventually became homogeneous and brown colored, was cooled, neutralized with sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted twice with ether and the combined organic phase was washed until neutral. The solvent was removed and the residue was distilled in vacuo to give 51 g. of the title compound; b.p. 132° C. (1 mm). Yield: 51 g. (73%) (distillation was accompanied by partial decomposition).