Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[OH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:24]2[CH2:25][CH2:26][CH:21]([OH:20])[CH2:22][CH2:23]2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 66.4 %

Procedure:
14.1 g of 1-bis(4-fluorophenyl)methoxy-2-chloroethane, 10.1 g of 4-hydroxypiperidine, 12 g of sodium carbonate and 0.2 g of sodium iodide were added to 200 ml of methyl isobutyl ketone, and the mixture was heated under reflux for 4 hours. At the end of this time, it was filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography. Elution with a 10:1 by volume mixture of ethanol and methylene chloride afforded 11.5 g (yield 66%) of the title compound as a pale yellow oily substance. p Infrared Absorption Spectrum (CHCl3), νmax cm-1 : 2920, 1600, 1505.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[Na:12].C1C(=O)[N:17](OC(ON2C(=O)CCC2=O)=O)[C:15](=[O:16])C1.C(OCC)(=O)C>CS(C)=O>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:15]([NH2:17])=[O:16])=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2].[Na:12]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC(=O)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 115 %

Procedure:
A solution of sodium sulfanilic acid (195 mg; 1 mmol) in dry DMSO (3 ml) was added dropwise to a solution of N,N′-disuccinimidyl carbonate (530 mg; 2 mmol) in dry DMSO (4 ml) and the resulting brownish solution stirred at room temperature for 20 hours. A solution of PAMAM 4.0 (EDA) (75 mg; 0.011 mmol) in dry DMSO (1 ml) added and the solution stirred for a further 18 hours. The solution was then concentrated under high vacuum (10−5 mmHg; 35°) to give a yellowish semi-solid. The crude product was dissolved in DMSO (4 ml) and the solution added to 200 ml of well stirred ethyl acetate. The precipitated white solid was collected by filtration and washed with ethyl acetate (2×) and ether (2×), then dried to give a white powder (275 mg). This material was further purified by gel filtration (Sephadex LH20; water) to give PAMAM 4.0 (EDA) terminated with 32 sodium 4-sulfophenylurea groups (106 mg). 1H nmr (D2O): δ 2.31; 2.55; 2.75; 3.19; 7.32 (d, J=9 Hz); 7.63 (d, J=9 Hz). 13C nmr (D2O): δ 36.3; 40.7; 43.3; 43.8; 53.7; 55.7; 123.3; 130.9; 140.9; 146.0; 161.4; 178.2; 178.6.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(C4CCNCC4)on3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(C4CCN(CCCCO)CC4)on3)ccc21

Procedure:
The preparation was carried out as already described starting from 130 mg of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)isoxazol-5-yl]piperidine and 83 μl of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[C:28]([CH3:35])=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[C:28]([CH3:35])=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1c(Cl)cccc1NN
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: Cc1c(Cl)cccc1-n1nccc1-c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-chloro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=447.3 (M+H)+
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]=[O:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13]([Mg]Br)#[CH:14].[NH4+].[Cl-]>C1COCC1>[S:1]1[C:5]([CH2:6][CH:7]([OH:8])[C:13]#[CH:14])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=CCc1cc2ccccc2s1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of crude 9-3 (8.77 g) in THF (100 mL) was added to a solution of ethynylmagnesium bromide (450 mL, 225 mmol, 0.5 M/THF) at 0° C. by cannula. The mixture was stirred for 1 h at 0° C. and for 1 h at room temperature. The reaction was then queched by addition of 200 mL saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (10% 20% ethyl acetate/hexanes) gave 8-4 (7.67 g, 37.9 mmol, 84% from 9-2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN1CCN(CCO[C:44]2[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=2)CC1>>[CH2:2]1[C:45]2[C:44](=[CH:50][CH:49]=[C:47]([NH:48][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:46]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-{[2-(4-methyl-1-piperazinyl)ethyl]oxy}aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.11 (s, 3H), 2.20-2.35 (m, 4H), 2.62 (t, 2H, J=5.8 Hz), 3.00-3.60 (m, 4H overlapping with H2O), 3.98 (t, 2H, J=5.8 Hz), 6.47 (d, 1H, J=5.1 Hz), 6.80 (d, 2H, J=9.0 Hz), 7.08 (t, 1H, J=6.9 Hz), 7.22 (t, 2H, J=8.0 Hz), 7.31 (d, 1H, J=7.5 Hz), 7.41-7.60 (m, 5H), 7.80 (d, 1H, J=8.1 Hz), 7.97 (s, 1H), 8.16-8.21 (m, 1H), 8.39 (bd, 1H, J=7.4 Hz), 8.81 (d, 1H, J=6.8 Hz), 9.31 (s, 1H), 10.91 (s, 1H); ESIMS (M+H)+=661.
Reaction SMILES: [C:1]12(C(O)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Mn]([O-])(=O)(=O)=[O:15].[K+]>[OH-].[Na+]>[C:1]12([OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: OC12CC3CC(CC(C3)C1)C2

Procedure:
Adamantane-1-carboxylic acid and potassium permanganate were reacted by oxidation using sodium hydroxide as a catalyst to obtain adamantan-1-ol, 4-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:22]([F:25])([F:23])[F:24])[CH:13]=2)[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1C(F)(F)F
Yield: 98.2 %

Procedure:
A solution of 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (265 mg, 0.67 mmol) in ethanol (5 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45–50° C. for 5 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (20 mL) and extracted with diethyl ether (1×40 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (249 mg, 97%) as a viscous oil: EI-HRMS m/e calcd for C17H21F3O4S (M+) 378.1113, found 378.1121.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Br)c1F)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 54.2 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.3 g, 6.5 mmol) prepared in Example 63a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 54%).
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[OH-].[K+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:16]=O)=[CH:11][CH:10]=1>C(O)C.C(OCC)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:16][CH2:5][C:3](=[O:4])[CH:1]=[CH:2]2)=[CH:13][CH:14]=1
Reactant: O=CC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C=CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C1C=CC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Reaction time: 24 h

Procedure:
1.7 cm3 of methyl vinyl ketone and 0.39 g of potassium hydroxide pellets dissolved in 3 cm3 of ethanol are successively added to a solution, cooled to 0° C., of 4 g of bis(4-fluorophenyl)acetaldehyde in 35 cm3 of ethyl ether. The temperature is left in the region of 20° C. for 24 hours. The mixture is concentrated to dryness under reduced pressure, 75 cm3 of dichloromethane are added and the mixture is washed with twice 75 cm3 of distilled water. After drying over magnesium sulphate and concentrating to dryness under reduced pressure, the residue is purified by flash chromatography on silica gel (30–70 μm), eluting with pure dichloromethane; 3 g of 4,4-bis(4-fluorophenyl)cyclohex-2-enone are thus obtained in the form of a pale yellow oil, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([O:17][C:25]3[CH:30]=[N:29][C:28]([CH:31]4[CH2:33][CH2:32]4)=[CH:27][N:26]=3)[CH2:16][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 2.323 g, 10 mmol) in tetrahydrofuran (60 mL) at room temperature was added potassium tert-butoxide (14 mL, 1 M in tetrahydrofuran). After 10 minutes, 2-bromo-5-cyclopropylpyrazine (2.249 g, 11.3 mmol) in tetrahydrofuran (3 mL) was added. The mixture was stirred at room temperature for 2 days. The mixture was concentrated and diluted with dichloromethane (200 mL). This solution was washed with water (30 mL), dried over sodium sulfate, and filtered. The organic phase was concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.78 (m, 3H), 2.08-2.38 (m, 5H), 2.70 (m, 1H), 2.83 (m, 2H), 3.53 (m, 3H), 5.24 (m, 1H), 7.28 (m, 5H), 8.12 (m, 2H); MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][NH:5][CH:6]=1.C1C=CC2N(O)N=NC=2C=1.C[CH2:21][N:22]=[C:23]=NCCCN(C)C.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[CH3:21][N:22]([CH3:23])[C:7]([C:3]1[C:2]([CH3:1])=[CH:6][NH:5][N:4]=1)=[O:9]
Reactant: Cc1c[nH]nc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c[nH]nc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a mixture of 4-methyl-1H-pyrazole-3-carboxylic acid (1.00 g, 7.93 mmol), HOBT (1.07 g, 7.93 mmol) and EDCI (2.27 g, 11.89 mmol) in DMF (10 mL) was added DIEA (2.74 mL, 15.86 mmol). After the mixture was stirred at room temperature for 16 hours, dimethylamine (2M in THF, 11.89 mL, 23.79 mmol) was added. The mixture was stirred at room temperature for 3 hours, then partitioned between EtOAc (300 mL) and water (30 mL). The organics was washed with brine (3×30 mL) and the combined aqueous material was back extracted with EtOAc (2×50 mL). All organic extracts were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% MeOH in CH2Cl2) to obtain the title compound as a brown oil (1.1 g, 92%). m/z (ES+) 154 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11](=[O:23])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:24]S(C)=O.[H-].[Na+].IC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11](=[O:23])[N:10]([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccc(F)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred and cooled (below 5° C.) mixture of 16 parts of ethyl 1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate, 200 parts of dimethyl sulfoxide and 200 parts of benzene are added 3.5 parts of a sodium hydride dispersion 50%. After stirring for 1 hour at a temperature below 5° C., there are added dropwise 10 parts of iodomethane at this temperature. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the layers are separated. The aqueous phase is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated, yielding 14.7 parts (88%) of ethyl 1-(4-fluorophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate as a residue.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.N1C=CC=CC=1>ClCCl>[F:15][C:16]([F:24])([F:25])[C:17]1[CH:18]=[CH:19][C:20]([NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
A suspension of 2.1 g of 5-chlorosulfonyl-2-oxindole, 1.6 g of 4-trifluoromethylaniline and 1.4 g of pyridine in 20 mL of dichloromethane was stirred at room temperature for 4 hours. The precipitate which formed was collected by vacuum filtration, washed twice with 5 mL of water and dried under vacuum at 40° C. overnight to give 2.4 g of crude product containing some impurities by thin layer chromatography. The crude product was chromatographed on silica gel eluting with ethyl acetate:hexane (1:2) to give 1.2 g (37% yield) of 5-(4-trifluoromethylphenylaminosulfonyl)-2-oxindole.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=2[S:10][CH:11]=1.[C:17](=[O:19])=[O:18]>CCOCC>[CH3:16][C:13]1[CH:14]=[CH:15][C:8]2[C:7]([C:17]([OH:19])=[O:18])=[CH:11][S:10][C:9]=2[CH:12]=1
Reactant: Cc1ccc2c(Br)csc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc2c(C(=O)O)csc2c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium (15 ml. of 1.0M solution in hexane) was added dropwise to a stirred solution of 3-bromo-6-methylbenzo[b]thiophene (3.0 g.) in dry ether (40 ml.) at -70° C. under an atmosphere of dry nitrogen. The mixture was stirred at -70° C. for 30 minutes and then an excess of crushed solid carbon dioxide was added. When all the carbon dioxide had evaporated, water (25 ml.) was added and the mixture was stirred for a few minutes. The organic layer was separated and washed with 2N.NaOH solution. The aqueous layer and NaOH extract were combined and acidified with concentrated hydrochloric acid. The solid was filtered off, washed with water, dried and crystallized from toluene to give 6-methylbenzo[b]thiophene-3-carboxylic acid (1.60 g.), m.p. 205°-209°.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)(C)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]2[N:4]=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CBr)c1
Solvent: CC(C)O
Product: CN1CCN(Cc2nnc(-c3ccccc3)cc2-c2cccc([N+](=O)[O-])c2)CC1
Yield: 50.7 %

Procedure:
A mixture of 3-bromomethyl-4-(3-nitrophenyl)-6-phenylpyridazine (0.6 g), 1-methylpiperazine (0.36 g) in isopropyl alcohol (6 ml) was refluxed for 30 minutes. After evaporating the solvent, the residue was dissolved in methylene chloride (50 ml), washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 3-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-6-phenylpyridazine (0.32 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.CO[CH:13](OC)[CH2:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:13]=[CH:14][N:15]=[CH:5]2)=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1Br
Reactant: COC(CN)OC
Product: Cc1cc2ccncc2cc1Br

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 75, Step 1 starting from 3-bromo-4-methylbenzaldehyde (Aldrich, Cat. #4017458) and. aminoacetaldehyde dimethyl acetal. Analytic LCMS (M+H)+: m/z=221.95/223.95.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18]([CH3:26])=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9].N1C=CC=CC=1.[CH:42]([O:45][C:46](Cl)=[O:47])([CH3:44])[CH3:43]>ClCCl>[CH:42]([O:45][C:46]([N:14]1[CH2:15][CH2:16][CH2:17][CH:11]([N:7]([C:8](=[O:10])[CH3:9])[CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=2)[C:12]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([CH3:26])[C:13]1=2)=[O:47])([CH3:44])[CH3:43]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(C)cc(C(F)(F)F)cc21
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(C)cc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(9-methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.0210 g, 0.0410 mmol) and pyridine (0.0100 ml, 0.123 mmol) in dichloromethane (1.00 ml) was added 1M isopropylchloroformate (solution in toluene) (0.120 ml), 0.123 mmol) dropwise. The mixture was stirred at room temperature overnight. The solvents were evaporated on a rotavapor (rotary evaporator). Purification by silica gel chromatography (gradient eluent, 0-30% ethyl acetate in hexane) provided the titled compound (0.0180 g, 72%) as white crystalline. MS (ES+): 599 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10](=O)[CH2:11][CH:12]([CH3:14])[CH3:13]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:10]/[CH2:11][CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)CC=O
Solvent: ClCCl
Product: CC(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 98.3 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with isovaleraldehyde (Alfa) (0.43 g, 5 mmol) in CH2Cl2 at room temperature for 18 h to give [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.98 g, 98%).