Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.FC(F)(F)S(O[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=1)(=O)=O.C(=O)(O)[O-].[Na+].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)[CH:2]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc3ccccc3c2)CC1
Temperature: 25 °C
Yield: 76 %

Procedure:
3-Quinolineboronic acid (250 mg, 1.4 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (580 mg, 1.8 mmol) were combined and dissolved in a mixture of toluene (10 mL) and ethanol (1 mL). 2M aqueous sodium bicarbonate solution (1.5 mL, 3.0 mmol) was added to the mixture followed by lithium chloride (180 mg, 4.2 mmol). Nitrogen gas was bubbled through the mixture for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.07 mmol) was added to the mixture. Reaction was heated at reflux for 3.5 hours. Mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). Mixture was washed successively with water (2×30 mL) and brine (20 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the desired product as lightly colored oil in 76% yield. MS m/e (M−C4H8+H)+=255.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10])(=[O:3])[CH3:2].[Br:16]Br>O1CCOCC1>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=[CH:8][C:9]=1[Cl:10])=[O:3]
Reactant: CC(=O)c1cc(NS(C)(=O)=O)ccc1Cl
Reactant: BrBr
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(Cl)c(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-acetyl-4-chlorophenyl)methanesulfonamide (300 mg) was dissolved in dioxane (5 mL), and bromine (77 μL) was added dropwise with ice-cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was washed with a water/ethanol mixture (1:1) and then dried under reduced pressure to yield N-(3-bromoacetyl-4-chlorophenyl)methanesulfonamide (312 mg) as a colorless crystal.
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:39])[C@H:5]([CH2:20][C:21]1[CH:28]=[C:26]([I:27])[C:25]([O:29][C:30]2[CH:37]=[C:35]([I:36])[C:34]([OH:38])=[C:32]([I:33])[CH:31]=2)=[C:23]([I:24])[CH:22]=1)[NH:6][C:7](=[O:19])[CH2:8][O:9][CH2:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[C:40]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][CH2:41]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:39])[C@H:5]([CH2:20][C:21]1[CH:22]=[C:23]([I:24])[C:25]([O:29][C:30]2[CH:31]=[C:32]([I:33])[C:34]([OH:38])=[C:35]([I:36])[CH:37]=2)=[C:26]([I:27])[CH:28]=1)[NH:6][C:7](=[O:19])[CH2:8][O:9][CH2:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:40](=[O:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])[CH2:17][CH2:18]1)=[O:12]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCNCC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCN(C(=O)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(piperazinocarbonylmethoxyacetyl)thyroxine methyl ester Hydrobromide from step 5 (9.5 g, 0.01 mole) and succinic anhydride (2.0 g, 0.02 mole), in chloroform (400 mL) was added triethylamine (3.3 g, 0.033 mole). The slurry immediately begins to dissolve and the mixture was stirred overnight at room temperature. The next day the solid had all dissolved and the solution was washed with 5% HCl solution (3×100 mL), water (100 mL), saturated NaCl solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed on a rotary evaporator in vacuo. This material was further purified by chromatography using SiO2.
Reaction SMILES: FC(F)(F)[C:3]([N:5](C)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][NH:15][C:16]2[C:21](=[O:22])[N:20]([CH2:23][C:24]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][CH:32]=[C:31]4[CH3:37])=[O:25])[C:19]([CH3:38])=[CH:18][N:17]=2)[CH:8]=1)=O.C([O-])([O-])=O.[Na+].[Na+].O>CO>[CH3:37][C:31]1[C:30]2[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:24](=[O:25])[CH2:23][N:20]3[C:19]([CH3:38])=[CH:18][N:17]=[C:16]([NH:15][CH2:14][CH2:13][C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][NH:5][CH3:3])[CH:8]=4)[C:21]3=[O:22])[CH:29]=2)[NH:33][CH:32]=1
Reactant: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(CN(C)C(=O)C(F)(F)F)c4)c3=O)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
2,2,2-Trifluoro-N-methyl-N-[3-(2-{[5-methyl-4(2-{[(3-methyl-1H-indol-5-yl)methyl]amino}-2-oxoethyl)-3-oxo-3,4-dihydro-2-pyrazinyl]amino}ethyl)benzyl]acetamide (preparation 38) (40 mg, 0.07 mmol) was dissolved in hot methanol (15 ml) and treated with an aq. solution of Na2CO3 (0.6 ml, 0.46 mol) followed by an additional portion of water (1.5 ml). The resultant cloudy mixture was stirred at room temperature for 18 hr, then evaporated to dryness and dried. The resultant white solid was purified by chromatography (SiO2, gradient elution with 90:10 CH2Cl2:MeOH; 90:10:1 CH2Cl2:MeOH:NH3) to give the desired product (34 mg, 100%). 1H NMR (CDCl3) δ 2.15 (s, 3H), 2.30 (s, 3H), 2.50 (s, 3H), 2.90 (t, 2H), 3.60 (t, 2H), 3.90 (s, 2H), 4.50 (s, 2H), 4.75 (s, 2H), 6.70 (s, 1H), 7.00 (s, 1H), 7.05 (d, 1H), 7.20-7.40 (m, 5H), 7.45 (s, 1H). LRMS m/z=473.4 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6](I)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([C:31]#[C:30][CH2:29][OH:32])[CH:7]=1
Reactant: C#CCO
Reactant: Fc1ccc(Cl)cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: OCC#Cc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-fluoroiodobenzene (5.00 g), copper(I) iodide (74.3 mg), triphenylphosphine (256 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (404 mg), propargyl alcohol (1.27 ml), diisopropylethylamine (13.6 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.82 g) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:6][C:5]=2[NH:4][N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)n[nH]c2C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindazol-4-one (0.15 g), aminoguanidine hydrochloride (0.072 g), concentrated hydrochloric acid (0.062 ml), water (0.062 ml) and ethanol (30 ml) was stirred at 50° C. for 3 hours and at 80° C. for 1.5 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with diethylether. To the aqueous layer was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and to the residue was added 1N hydrochloric acid (1.5 ml). Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 20) (0.18 g) as colorless crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([CH:12]1[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][O:13]1)=O)C>C1COCC1>[OH:9][CH2:10][CH:12]1[CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][O:13]1
Reactant: CCOC(=O)C1CC(=O)CCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CC(O)CCO1
Temperature: 0 °C
Yield: 61 %

Procedure:
To a cooled (0° C.), stirred suspension of LiAlH4 (3.42 g, 90.0 mmol) in anhydrous THF (50 mL) was added dropwise a solution of 4-oxo-tetrahydro-pyran-2-carboxylic acid ethyl ester (5.17 g, 30.0 mmol). After stirring for 1 hour, the reaction was quenched by the slow, sequential addition of water (3.4 mL), 15% NaOH (3.4 mL), and water (10.0 mL). The inorganic salt was filtered off and extracted with EtOAc repeatedly since the product was absorbed on the solid. Solvent removal afforded 2.42 g (61%) of yellow oil. The crude mixture was carried to the next step without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][N:16]=2)[C:11]([OH:24])=[C:10]([C:25](OCC)=[O:26])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C2C(=CC=CN=2)C(O)=C(C(OCC)=O)C1=O)C1C=CC=CC=1.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[S:62]([NH2:65])(=[O:64])=[O:63].NC1C=CC(Br)=CC=1S(N)(=O)=O>>[NH2:65][S:62]([C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[NH:55][C:25]([C:10]1[C:9](=[O:30])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[C:12]([C:11]=1[OH:24])=[CH:13][C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][N:16]=2)=[O:26])(=[O:63])=[O:64]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2cc(-c3ccccc3)cnc2n(Cc2ccccc2)c1=O
Agent: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Agent: Nc1ccc(Br)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1ccccc1NC(=O)c1c(O)c2cc(-c3ccccc3)cnc2n(Cc2ccccc2)c1=O

Procedure:
The title compound was prepared according to the procedure of Example 84C substituting ethyl 1-benzyl-6-phenyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate for the product of Example 84B and substituting 2-amino-benzenesulfonamide for the product of Example 84A. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.72 (s, 2 H) 7.28 (m, 6 H) 7.44 (m, 2 H) 7.54 (m, 3 H) 7.67 (m, 1 H) 7.85 (d, J=6.99 Hz, 2 H) 7.92 (dd, J=8.09, 1.47 Hz, 1 H) 7.99 (d, J=8.09 Hz, 1 H) 8.70 (d, J=2.21 Hz, 1 H) 9.17 (d, J=2.21 Hz, 1 H) 12.41 (s, 1 H) 16.80 (s, 1 H).
Reaction SMILES: NC1C=C(OC)C(OCCOC)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[C:48]2[CH:49]=[C:50]([O:55][CH2:56][CH2:57][O:58][CH3:59])[C:51]([O:53][CH3:54])=[CH:52][C:47]=2[N:46]=[C:45]2[N:60](CC=C)[NH:61][C:62]([CH3:63])=[C:44]2[N:43]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[C:48]2[CH:49]=[C:50]([O:55][CH2:56][CH2:57][O:58][CH3:59])[C:51]([O:53][CH3:54])=[CH:52][C:47]=2[N:46]=[C:45]2[NH:60][NH:61][C:62]([CH3:63])=[C:44]2[N:43]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OCCOC)c(OC)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COCCOc1cc(C(=O)c2ccccc2Cl)c(N)cc1OC
Product: COCCOc1cc2c(cc1OC)N=C1NNC(C)=C1N=C2c1ccccc1Cl

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-methoxyethoxy-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVkk) was prepared by reacting 0.0014 moles of (2-amino-4-methoxy-5-(2-methoxyethoxy)phenyl)-(2-chlorophenyl)-methanone (Xkk) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-methoxyethoxy-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVkk) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=413.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[S:38][CH2:39][C:40](=[O:42])[N:41]=2)[CH2:33][C@@H:32]1[CH2:43][OH:44])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[S:38][C:39](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:2]([F:1])=[CH:3][C:4]=3[C:20]([F:23])([F:22])[F:21])[N:8]=[CH:9]4)[C:40](=[O:42])[N:41]=2)[CH2:33][C@@H:32]1[CH2:43][OH:44])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2(R)-Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C:13]([CH2:15][C@@H:16]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C:25]([CH2:27][C@H:21]4[CH2:20][C:18](=[O:19])[C@H:17]3[C@@H:11]2[CH2:10][CH2:9]1)=[O:26])=[O:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].Cl>>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C:13]([CH2:15][C@@H:16]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C:25]([CH2:27][C@H:21]4[CH2:20][C:18](=[O:19])[C@H:17]3[C@@H:11]2[CH2:10][CH2:9]1)=[O:26])=[O:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: C[C@H](CCC(=O)[O-])[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Agent: Cl
Agent: [Na+]
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C

Procedure:
The reaction of sodium dehydrocholate with guanidyl-lysozyme hydrochloride in a manner analogous to that described in Example 9 gave the corresponding dehydrocholate of guanidyl-lysozyme.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14]Br.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCCCBr
Reactant: COc1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(N2CCCC2)c1

Procedure:
To a stirring solution of 3-methoxy-phenylamine (571 mg, 4.6 mmol) in anhydrous toluene (40 ml) was added 1,4-dibromo-butane (1.0 g, 4.6 mmol) and diisopropylethylamine (0.59 g, 4.6 mmol). The resulting solution was heated to reflux for 24 hours and then concentrated in vacuo. The crude material was purified by column chromatography over silica gel (silica gel 60, EM science, 5% EtOAc:hexanes) and the title compound was obtained as an oil (754 mg, 92%). MS(ES) m/e 178.4 ([M+H]+).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:9](=O)[CH:10]=[C:11]([CH3:16])[C:12](=[O:15])[C:13]=1[CH3:14].[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][C:13]1[C:12](=[O:15])[C:11]([CH3:16])=[CH:10][C:9](=[N:18][C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[C:8]=1[CH3:7]
Reactant: Nc1cc[nH]n1
Reactant: CC1=CC(=O)C(C)=C(C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC1=CC(=Nc2cc[nH]n2)C(C)=C(C)C1=O
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A 1.62 ml quantity of pyridine was dissolved in 60 ml of dichloroethane, and 0.55 ml of titanium tetrachloride was added thereto. The mixture was refluxed with heating for 15 minutes. Then, to the mixture were added 1.50 g of 2,3,5-trimethyl-1,4-benzoquinone and 0.83 g of 3-aminopyrazole, and the mixture was refluxed with heating for 2 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with chloroform. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:1), giving 0.52 g of 2,3,6-trimethyl-4-(3-pyrazolylimino)-2,5-cyclohexadien-1-one (Compound 37a) as a yellow solid. Table 3 below shows the structure and properties of Compound 37a.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10]O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][Cl:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CO)no1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(CCl)no1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.62 g of (5-t-butyl-isoxazol-3-yl)methanol was dissolved in 12 ml of dichloromethane, and 0.9 ml of thionyl chloride was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.69 g of 5-t-butyl-3-(chloromethyl)isoxazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:6][CH:7]=1)=[O:39]
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Reactant: O=C=Nc1ccccc1F
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Nc2ccccc2F)cc1

Procedure:
Synthesis in analogy to Example 6 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 1-fluoro-2-isocyanato-benzene to yield 1-(2-fluoro-phenyl)-3-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-urea. LC/MS at 254 nm; [M+H] 521; Rt 3.641 min.
Reaction SMILES: S(Cl)(Cl)=O.C([O:9][C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:14]=1[C:15]([OH:17])=[O:16])=O)(C)(C)C>O1CCCC1>[F:23][C:18]1[C:14]2[C:15](=[O:17])[O:16][C:10](=[O:9])[NH:12][C:13]=2[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=c1[nH]c2ccc(F)c(F)c2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
A solution of 108 ml of thionyl chloride in 300 ml of tetrahydrofuran was added dropwise while cooling with ice to a solution of 100 g (366 mmol) of 2-(tert.-butoxycarbonyl)amino-5,6-difluorobenzoic acid in 1.5 I of dry tetrahydrofuran, whereupon the mixture was stirred at room temperature for 16 hours. The brown solution was evaporated and the brown solid obtained was triturated with methylene chloride. The beige powder obtained was filtered off and dried in a high vacuum. There were obtained 56.5 g (77%) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione as a beige powder of m.p. >240°.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5](=O)[NH:4][C:3]1=O.[H-].[Li+].[Al+3].[H-].[H-].[H-]>>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC1(c2ccccc2)CC(=O)NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(c2ccccc2)CCNC1

Procedure:
3-Methyl-3-phenyl-pyrrolidine, which was synthesized by reducing 3-methyl-3-phenyl pyrrolidine-2,5-dione with aluminum lithium hydride, was used as the amine to carry out the reaction according to <method α>. A purification by silica gel column chromatography (hexane/ethyl acetate) was carried out, and, the title compound (7 mg) was obtained as a colorless solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:13]1[C:14]([N:21]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[C:22](=[O:24])[CH3:23])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=1)#[N:12]>C1COCC1>[NH2:12][C:11]1[C:13]2[CH:18]=[N:17][C:16]([S:19][CH3:20])=[N:15][C:14]=2[N:21]([CH:25]2[CH2:26][CH2:27][CH2:28]2)[C:22](=[O:24])[CH:23]=1
Reactant: CSc1ncc(C#N)c(N(C(C)=O)C2CCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc2c(N)cc(=O)n(C3CCC3)c2n1
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.78 mL, 0.781 mmol) was added, at RT, to a solution of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-N-cyclobutyl-acetamide (205 mg, 0.781 mmol) in THF (7.8 mL) and the resulting mixture was stirred for 1 h. The reaction mixture was then quenched with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (MeOH/DCM, 1/99 to 5/95 in 10 min) to afford 98 mg (48% yield) as a white solid. MS=263 [M+H]+.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13][C:14](OC)=[O:15])=[CH:7][CH:6]=1>>[OH:2][NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:29][CH:28]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)(=[O:20])=[O:19]
Reactant: NO
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1cccc(N)c1
Product: COc1ccc(CCN(CCC(=O)NO)S(=O)(=O)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.6 %

Procedure:
Freshly prepared NH2OH solution (1 M in MeOH) (0.6 mL, 0.6 mmol)) was added to methyl 3-[(4-methoxyphenethyl)-(3-aminobenzenesulfonyl)amino]propionate (110 mg, 0.28 mmol). After stirring at room temperature for 18 h, the reaction mixture was concentrated and taken up with 10 mL of water. The mixture was acidified to pH 3-4 by 1 N HCl solution and extracted with ethyl acetate (2×20 mL). Combined organic layers was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (10/1 methylene chloride/methanol) to give N-hydroxy-3-[(4-methoxyphenethyl)-(3-aminobenzene-sulfonyl)amino]-propionamide (33 mg, 0.08 mmol). NMR (360 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.72 (br s, 1H), 7.23-6.25 (m, 8H), 5.57 (br s, 2H), 3.70 (s, 3H), 3.33 (t, 2H), 3.24 (t, 2H), 2.65 (t, 2H), 2.24 (t, 2H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f7) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.