Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7]>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: COCCN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COCCN(C)S(=O)(=O)c1ccc(N)cc1
Yield: 92.6 %

Procedure:
N-(2-Methoxyethyl)-N-methyl-4-nitrobenzenesulphonamide (Method 10; 3.88 g) was reduced by hydrogenation in ethanol (100 ml) over 10% palladium on carbon (400 mg) at 3 bar pressure. The catalyst was removed by filtration and the volatiles evaporated to give the title compound (3.2 g). M/z: 245.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16](B(O)O)=[CH:15][C:14]=3[CH:21]=2)([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:23]1[CH:38]=[CH:37][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:29]2)=[CH:25][C:24]=1[F:39]>>[F:39][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][C:23]=1[C:16]1[O:17][C:13]2[CH:12]=[CH:11][C:10]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([CH3:9])[CH3:8])=[CH:21][C:14]=2[CH:15]=1)[CH2:27][N:28]1[CH2:29][CH:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31]1
Reactant: CCOC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Reactant: CC(C)(c1ccccc1)c1ccc2oc(B(O)O)cc2c1
Product: CCOC(=O)C1CN(Cc2ccc(-c3cc4cc(C(C)(C)c5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B2, Step 2 and general procedure F from 5-(2-phenylpropan-2-yl)benzofuran-2-ylboronic acid and ethyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate to give ethyl 1-(3-fluoro-4-(5-(2-phenylpropan-2-yl)benzofuran-2-yl)benzyl)azetidine-3-carboxylate as a yellow foam. MS (ESI) m/z: Calculated: 471.2; Observed: 472 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]#[N:10])[CH:3]=1.[N:11]([O-])=O.[Na+]>Cl>[NH2:10][C:9]1[C:4]2[C:5](=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[NH:6][N:11]=1
Reactant: N#Cc1cc(Br)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: Nc1n[nH]c2ccc(Br)cc12

Procedure:
Twenty grams of 4-bromo-2-cyanoaniline is treated with concentrated hydrochloric acid and sodium nitrite; the resulting diazo compound is reacted with stannous chloride in concentrated hydrochloric acid at 0° C. Working up as in Example 2 gives 3-amino-5-bromoindazole.
Reaction SMILES: [CH2:1]([CH:4]([CH2:27][CH2:28][CH3:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH2:11][CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:2][CH3:3]>CCOCC>[CH2:27]([CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=1)[O:10][CH2:11][CH2:12][NH2:13])[CH2:28][CH3:29]
Reactant: CCCC(CCC)COc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1
Solvent: CCOCC
Product: CCCC(CCC)COc1cccc(OCCN)c1

Procedure:
Deprotection of 2-(2-(3-(2-propylpentyloxy)phenoxy)ethyl)isoindoline-1,3-dione following the method used in Example 18 gave Example 25 as a colorless oil. Yield (0.11 g, 82%): 1H NMR (400 MHz, DMSO) δ 7.11 (t, J=8.0 Hz, 1H), 6.42-6.48 (m, 3H), 3.85 (t, J=5.6 Hz, 2H), 3.78 (d, J=6.0 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 1.65-1.75 (m, 1H), 1.48 (brs, 2H), 1.20-1.40 (m, 8H), 0.85 (t, J=7.2 Hz, 6H).
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.C[Si]([C:15]#[N:16])(C)C.[CH:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:15]([C@H:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:16]
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: N#C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of L(+)-tartaric acid derivative shown in Table 1 (2 mmol) in a solvent shown in Table 1 (20 ml), a tetraalkyl titanate shown in Table 1 (2 mmol) was dropwise added and stirred for 30 minutes at room temperature. After evaporating volatile components off in the same manner as in Example 1, a solvent shown in Table 1 (20 ml) was added to the residue and stirred at room temperature to obtain a homogeneous solution. To the resulting solution, trimethylsilylcyanide (218 mg) and then benzaldehyde (212 mg) were added and stirred for 14 hours at room temperature. After the reaction, the reaction mixture was treated in the same manner as in Example 1. The product was analyzed by HPLC. The results are shown in Table 1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].[H-].[Na+].Br[CH2:16][CH:17]=[CH:18][CH3:19].O>C1(C)C=CC=CC=1>[CH2:16]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:17]=[CH:18][CH3:19]
Reactant: CC=CCBr
Reactant: CCOC(=O)NCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC=CCN(CC(OC)OC)C(=O)OCC
Reaction time: 1 h

Procedure:
89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise to 17.5 g (0.58 mol) of NaH (80% strength in paraffin oil) in 500 ml of absolute toluene at 80° C. The mixture is then stirred for one hour and 80 g (0.59 mol) of 1-bromo-2-butene are subsequently added dropwise at 80° C. The mixture is stirred at 80° C. overnight and cooled, the salts are dissolved with water and the aqueous phase is separated off and extracted with toluene. The toluene solutions are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH2:6][NH:7]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][NH2:7])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CN)ccc1OCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a stirred solution of tert-butyl 3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate (29.74 g, 82.97 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (50 mL, 649.0 mmol). The resulting brown solution was allowed to stir at room temperature. After 2 h, the reaction mixture was concentrated to dryness, and the residue was dissolved in water (250 mL). The acidic solution was extracted with diethyl ether (2×125 mL; organic phases discarded). The aqueous phase was then made basic with concentrated ammonium hydroxide. The basic aqueous phase was then extracted with dichloromethane (3×100 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 19.22 g (90%) of (3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(OO)(=[O:11])C.OO.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[N+:6]([O-:11])[C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cn1
Reactant: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(F)c[n+]1[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To the solution of 5-fluoro-2-picoline obtained in Step 4, at 0° C., was added, with vigorous stirring, a cold solution of 40% peracetic acid (prepared by carefully adding 50 mL of 30% hydrogen peroxide solution to 150 mL of glacial acetic acid). The reaction mixture was heated at reflux temperature (50° C.) for 4 days and then poured into 600 mL of ice water. The aqueous mixture was adjusted to pH 9 by the addition of potassium carbonate and then was stirred at ambient temperature for 4 hours. The aqueous solution was continuously extracted with methylene chloride for 24 hours and the methylene chloride extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 30.8 g (22% yield) of the title compound; MS DCI-NH3M/Z: 128 (M+H)+ base; 1H NMR (CDCl3) d 2.48 (s, 3H), 7.00 (ddd, 1H), 7.22 (dd, 1H), 8.22 (dd, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[C:13]1([CH:19](O)[CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CCCCC(O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCCC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
To a flame-dried flask containing a mixture of 811 mg of 4-hydroxycoumarin and 985 mg of 1-phenyl-1-pentanol in 30 mL of dioxane under an argon atmosphere is added 3.0 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether, acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 40% to 50% ethyl acetate in hexane to yield 193 mg of the title product as white crystals.
Reaction SMILES: C([NH:4][C:5]1[C:13]2[CH:12]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]3[O:10][C:9]=2[C:8]([C:18]([O:20]C)=[O:19])=[CH:7][C:6]=1[Cl:22])(=O)C.C(NC1C2C3CCCCC=3OC=2C(C(OC)=O)=CC=1Cl)(=O)C.C(NC1C2C3C=CC=CC=3OC=2C(C(OC)=O)=CC=1Cl)(=O)C>>[NH2:4][C:5]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:8]([C:18]([OH:20])=[O:19])=[CH:7][C:6]=1[Cl:22]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC1CCCCC21
Agent: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1oc1ccccc12
Agent: COC(=O)c1cc(Cl)c(NC(C)=O)c2c3c(oc12)CCCC3
Product: Nc1c(Cl)cc(C(=O)O)c2oc3ccccc3c12

Procedure:
When the procedure of Example 15 is followed however methyl 1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate is replaced by methyl 1-acetylamino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylate or methyl 1-acetylamino-2-chlorodibenzofuran-4-carboxylate then the captioned products are prepared.
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH:4]([C:14]([O:16]CC)=[O:15])[CH2:3]1.O[Li].O.O>C1COCC1>[CH3:11][C:10]([O:9][C:7]([N:6]1[CH:2]([CH3:1])[CH2:3][CH:4]([C:14]([OH:16])=[O:15])[CH2:5]1)=[O:8])([CH3:12])[CH3:13]
Reactant: CCOC(=O)C1CC(C)N(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC1CC(C(=O)O)CN1C(=O)OC(C)(C)C

Procedure:
1-(1,1-Dimethylethyl) 3-ethyl 5-methyl-1,3-pyrrolidinedicarboxylate (1.0 g, 3.89 mmol, an estimated 3:1 mixture of cis/trans isomers) and LiOH.H2O (228 mg, 5.44 mmol, 1.4 equiv) was stirred in THF (5 mL) and water (2 mL) as a two-phase mixture at room temperature for 18 hours. The mixture was concentrated in vacuo, and the resulting residue was taken up in 15 mL of water, acidified with cold 2N HCl, and extracted with 2×50 mL of EtOAc. The organic were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (1.03 g) as an oil. LC-MS (ES) m/z=230 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:21])=[CH:18][CH:17]=3)=[CH:15][C:6]1=2
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)C(=O)CN3)cc1
Product: O=C(NCCN1CCCC1)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)C(=O)CN3)cc1
Yield: 25 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (35 mg) was reacted with N-(2-aminoethyl)pyrrolidine as in General Procedure 8 to give the title compound as a white solid (25% yield). M.p. 235° C. (dec), LCMS: m/z=492.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.81-18.5 (m, 4H), 2.55-2.65 (m, 4H), 2.72-2.80 (m, 2H), 3.58-3.62 (m, 2H), 4.68 (s, 2H), 4.99 (s, 1H), 5.23 (s, 2H), 6.85-6.95 (m, 2H), 7.02-7.08 (m, 1H), 7.07 (s, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.1 Hz, 2H), 8.03 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: CO.Cl.C(O[C@H]1[C@H](C)O[C@@H]([O:15][C@@H:16]2[C@@H:32]([CH3:33])[C:31](=[O:34])[O:30][C@H:29]([CH2:35][CH3:36])[C@:28]3([CH3:37])[C@H:24]([N:25]([NH:39][CH2:40][CH2:41][C@H:42]([N:44]4[CH:48]=[C:47]([C:49]5[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=5)[N:46]=[CH:45]4)[CH3:43])[C:26](=[O:38])[O:27]3)[C@@H:23]([CH3:55])[C:22](=[O:56])[C@H:21]([CH3:57])[CH2:20][C@:19]([O:59][CH3:60])([CH3:58])[C@H:18]([O:61][C@@H:62]3[O:71][C@H:70]([CH3:72])[CH2:69][C@H:68]([N:73]([CH3:75])[CH3:74])[C@H:63]3[O:64][C:65](=[O:67])[CH3:66])[C@H:17]2[CH3:76])C[C@@]1(C)OC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CCOC(C)=O>[C:65]([O:64][C@@H:63]1[C@@H:68]([N:73]([CH3:75])[CH3:74])[CH2:69][C@@H:70]([CH3:72])[O:71][C@H:62]1[O:61][C@@H:18]1[C@@H:17]([CH3:76])[C@H:16]([OH:15])[C@@H:32]([CH3:33])[C:31](=[O:34])[O:30][C@H:29]([CH2:35][CH3:36])[C@:28]2([CH3:37])[C@H:24]([N:25]([NH:39][CH2:40][CH2:41][C@H:42]([N:44]3[CH:48]=[C:47]([C:49]4[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=4)[N:46]=[CH:45]3)[CH3:43])[C:26](=[O:38])[O:27]2)[C@@H:23]([CH3:55])[C:22](=[O:56])[C@H:21]([CH3:57])[CH2:20][C@:19]1([O:59][CH3:60])[CH3:58])(=[O:67])[CH3:66]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](OC(C)=O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(NCC[C@@H](C)n3cnc(-c4cccnc4)c3)C(=O)O[C@]12C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(NCC[C@@H](C)n3cnc(-c4cccnc4)c3)C(=O)O[C@]12C
Temperature: 45 °C

Procedure:
To a reactor is charged methanol and 12N HCl (5 mol). The temperature is set at 30° C. and (3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-8-[[4-O-Acetyl-2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl]oxy]-4-ethyldecahydro-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-[[(3R)-3-[4-(3-pyridinyl)-1H-imidazol-1-yl]butyl]amino]-10-[[2-O-acetyl-3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-2H-Oxacyclotetradecino[4,3-d]oxazole-2,6,14(1H,7H)-trione (17) (1 mol) is added. The reaction is stirred to dissolve the solids, then it is heated to 45° C. until complete. Once the reaction is complete, the methanol is removed in vacuo, and the internal temperature is set at 20° C. The reaction is extracted between sodium carbonate (6 mol) in water and EtOAc. The aqueous layer is separated, and the organic layer is concentrated to low volume. The product (19) is then isolated.
Reaction SMILES: N1[C:6]2[CH2:7][CH2:8][NH:9][C:5]=2N=CC=1.[NH:10]1CCC[C@H:11]1[C:12](O)=O.[C:18](C1CCCN1N)#N>>[NH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][CH2:7][CH2:8][N:9]1[CH3:18]
Reactant: c1cnc2c(n1)CCN2
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: N#CC1CCCN1N
Product: CN1CCCC1CCN

Procedure:
In more detail, pyrazinopyrrolidine 1A is synthesized via a [3+2] cycloaddition chemistry. Conversion of L-proline 7 to cyano-1-aminopyrrolidine 8 without loss of stereochemistry, followed by reduction provides the chiral 2-aminoethyl-1-methyl pyrrolidine 2A in high yield. CX-3543 was found to have a formulated solubility of approximately 20 mg/mL.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH2:34]([N:36]([CH2:42][CH3:43])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)[CH3:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]2[CH2:40][CH2:41][CH:37]([N:36]([CH2:42][CH3:43])[CH2:34][CH3:35])[CH2:38]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CCN(CC)C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCN(CC)C1CCN(C(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)C1

Procedure:
5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (95 mg, 0.19 mmol) was coupled with diethyl-pyrrolidin-3-yl-amine (50.6 mg, 0.25 mmol) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) at rt for 3 days to give the titled compound.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12]([O:14]C2C=CC([N+]([O-])=O)=CC=2)=O)C=CC=CC=1.[CH:36]([NH2:40])([CH2:38][CH3:39])[CH3:37]>>[CH:36]([NH:40][C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:14])([CH2:38][CH3:39])[CH3:37]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(C)N
Product: CCC(C)NC(=O)SCCN

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (300 mg) and sec-butylamine (188 μl) were subjected to similar reactions to those described in References 2 and 4 to give 2-sec-butylaminocarbonylthioethylamine (crude formate: 227 mg). The product was dissolved in anhydrous methanol (5 ml). Triethylamine (342 μl) and mitomycin A (137 mg: 0.8 molar equivalent) were added to the reaction solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 30 (94 mg) in the form of grayish blue powders with a yield of 49%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:35][C:36](=[NH:38])[CH3:37]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:38]=[C:36]([CH3:37])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CC(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (596 mg, 2.00 mmol) in dichloromethane (8ml) was treated with 1,1′-carbonyldiimidazole (364 mg, 2.25 mol) and the solution was stirred at room temperature for 15 minutes. The N-hydroxyacetamidine (Chem.Ber.; 17; 1884; 2746) (148 mg, 2.00 mmol) was then added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was heated neat under a nitrogen atmosphere for 90 minutes. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound (385 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].B.C1COCC1>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)ccc1F
Temperature: 0 °C
Yield: 94 %

Procedure:
4-Fluoro-3-nitro-benzoic acid (185 mg, 1 mmol) was dissolved in THF (2 ml) and cooled to 0° C. under a nitrogen atmosphere. A Borane/THF solution (2 ml of a 1M solution, 2 mmol) was added dropwise, and the reaction mixture was heated to reflux for 1 h. The reaction was judged complete and quenched with 3N HCl (0.5 ml) and the solvent was removed under vacuum. The reaction mixture was partitioned between ethyl acetate and a sodium carbonate solution. The organic layer was washed with carbonate two additional times, and then it was washed with brine. It was dried over MgSO4, and the solvent was removed to yield the title product (160 mg (95%), 0.94 mmol). 1H NMR (DMSO-d6): δ=8.10 (s, 1H), 7.62 (d, J=7.3 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 4.82 (d, J=4.5 Hz, 2H).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[C:34]([O:38][C:39](=[O:42])[CH:40]=C)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:42])[CH2:40][CH2:33][N:30]1[CH2:31][CH2:32][CH:27]([O:26][C:10]2[N:9]=[N:8][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:17][CH:18]=3)[CH:11]=2)[CH2:28][CH2:29]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Product: CCCCc1nnc(OC2CCN(CCC(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine (Example 14, 0.244 mmol, 100 mg) and acrylic acid tert-butyl ester (2 mL) may be stirred at room temperature for 20 h. The organic solvent may be removed in vacuo and the residue is purified by column chromatography on silica gel using 1-2% of MeOH in DCM to give 3-{-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-propionic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:12][C:13]([CH3:15])=[O:14])=[C:8]([CH:11]=1)[CH2:9]Br)(=[O:3])[CH3:2].[CH2:16]([NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:17]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:12][C:13]([CH3:15])=[O:14])=[C:8]([CH:11]=1)[CH2:9][N:18]([CH2:16][CH3:17])[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:3])[CH3:2]
Reactant: CCNC1CCCCC1
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1CBr
Product: CCN(Cc1cc(C(C)=O)ccc1NC(C)=O)C1CCCCC1

Procedure:
5-Acetyl-2-acetamino-N-ethyl-N-cyclohexyl-benzylamine, m.p. 98-100° C was prepared from 5-acetyl-2-acetamino-benzyl bromide and N-ethyl-cyclohexylamine analogous to Example 8.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)[CH:3]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:22])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C)c1
Solvent: CO
Product: Cc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of ethyl 6-chloro-4-(3,5-dimethylphenylamino)pyridazine-3-carboxylate (104 mg, 340 μmol) in methanol was added ammonia in methanol (4.86 mL, 34.0 mmol) and stirred at 50° C. for 16 h. The mixture was concentrated to give 6-chloro-4-(3,5-dimethylphenylamino)pyridazine-3-carboxamide (90 mg, 325 μmol, 96%) as a brown solid, which was used directly without purification. 1H NMR (400 MHz, DMSO-d) δ ppm 10.84 (s, 1H), 8.72 (s, 1H), 8.08 (s, 1H), 7.12 (s, 1H), 6.98 (s, 2H), 6.98 (s, 1H), 6.93 (s, 1H), 2.30 (s, 6H); MS (EI/CI) m/z: 276.9 [M+H].
Reaction SMILES: FC1C(=O)NC(=O)NC=1.[C:10](Br)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19]([N:27]1[C:32](=[O:33])[C:31]([F:34])=[CH:30][NH:29][C:28]1=[O:35])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:10]([N:29]1[CH:30]=[C:31]([F:34])[C:32](=[O:33])[N:27]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:28]1=[O:35])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Br)c1ccccc1
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(F)c1=O
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1cc(F)c(=O)n(C(=O)c2ccccc2)c1=O
Yield: 11.7 %

Procedure:
In the same manner as described in Example 1 but using 2.6 g (0.02 mole) of 5-fluorouracil, 10 ml of absolute pyridine and 7.4 g (0.04 mole) of benzoyl bromide, 1.6 g of 3-N-benzoyl-5-fluorouracil (yield, 34%) and 270 mg of 1,3-di-N-benzoyl-5-fluorouracil (yield, 4%) were obtained.