Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2].C[O-:34].[Na+:35].C([OH:38])C>CCOCC>[OH2:3].[OH2:38].[OH2:34].[OH2:3].[CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O-:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2].[Na+:35]
Reactant: CCO
Reactant: C[O-]
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)[O-])C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Product: O
Reaction time: 1 h

Procedure:
A mixture comprising 2.46 g of 5-{1-ethoxycarbonyl-1-[2-(3-phenylureido)thiazol-4-yl]methylene]rhodanine-3-acetic acid, 0.54 g of sodium methoxide and 30 ml of absolute ethanol was stirred for 1 hour under ice-cooling, then treated by ultrasonication at room temperature for 30 minutes. The reaction mixture was then poured into anhydrous ether and the crystalline product which precipitated out was collected by filtration, giving the desired compound as a reddish-brown powder.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23](=[O:24])[C:14]3=[CH:15][NH:16][C:17]4[C:22]([N:13]3[C:12]2=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:7][CH:6]=1)(=O)C.Cl>C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23](=[O:24])[C:14]3=[CH:15][NH:16][C:17]4[C:22]([N:13]3[C:12]2=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(-n2c(=O)c3c[nH]c4ccccc4n-3c2=O)cc1
Agent: Cl
Solvent: CCO
Product: O=c1c2c[nH]c3ccccc3n-2c(=O)n1-c1ccc(O)cc1
Reaction time: 2 h

Procedure:
2-(4-Acetoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (250 mg) wasadded to an ethanol solution (50 mL) saturated with HCl. The solution was stirred for 2 hours and the solvent was removed in vacuo to yield 2-(4-Hydroxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 41), m.p. 318°-322° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]23[O:16][C:15](=[O:17])[CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)=[O:8])=[CH:5][CH:4]=1.[NH:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23].C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl>[OH:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][OH:26])[C:15]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1([OH:16])[C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17]
Reactant: COc1ccc(C(=O)C23CCCCC2C(=O)O3)cc1
Reactant: OCCNCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)C2(O)CCCCC2C(=O)N(CCO)CCO)cc1

Procedure:
A solution of 26.03 g (0.100 mol) of 6-(4-methoxy-benzoyl)-7-oxa-bicyclo[4.2.0]octan-8-one in 200 ml of methylene chloride is added to 10.5 g (0.100 mol) of diethanolamine and 32 ml of N,N-diisopropylethylamine. The reaction mixture is heated at reflux for several hours and monitored by thin layer chromatography. Upon completion of the reaction, the mixture is cooled and poured into 1N hydrochloric acid solution. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated to give the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=3[Cl:29])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[O:5][C:4]([CH3:31])([CH3:30])[CH2:3]1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].CCN(CC)CC>C(Cl)Cl>[Cl:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[C:8]1[N:7]=[C:6]2[O:5][C:4]([CH3:31])([CH3:30])[CH2:3][CH:2]([NH:1][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]2=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(N)CC(C)(C)O3)c(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)C(C)(C)C)CC(C)(C)O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Step A (100 mg, 0.22 mmol) in 5.0 mL of CH2Cl2 was added pivaloyl chloride (32 μL, 0.26 mmol) and NEt3 (46 μL, 0.33 mmol). After stirring at rt for 16 h, the reaction mixture was concentrated. Chromatography on a Biotage 25+M cartridge using 1:1 v/v EtOAc/hexanes as the eluant afforded the product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15]O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[ClH:19].[CH3:1][N:2]([CH2:14][CH2:15][Cl:19])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CN(CCO)CCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(CCCl)CCc1ccc([N+](=O)[O-])cc1
Product: Cl
Temperature: 0 °C

Procedure:
To a solution of 2-[N-methyl-N-(4-nitrophenethyl)amino]ethanol (8.0 g) in dry methylene chloride (75 ml) was added dropwise thionyl chloride (3ml) with stirring at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 16 hours. The resultant solid was filtered, washed with dry ether and dried to give a colourless product (7.1 g). Crystallisation from ethyl acetate/methanol gave the title compound, 6.0 g, m.p. 168°-169°.
Reaction SMILES: [F:1][C:2]([F:25])([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][N:4]1[CH2:8][CH2:7][C@H:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1.[OH:26]OS([O-])=O.[K+]>CO>[F:25][C:2]([F:1])([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([S:9]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:26])[CH2:5]1
Reactant: O=S([O-])OO
Reactant: Oc1ccc(S[C@H]2CCN(CC(F)(F)CCc3ccccc3)C2)cc1
Agent: [K+]
Solvent: CO
Product: O=S(c1ccc(O)cc1)C1CCN(CC(F)(F)CCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 108.5 %

Procedure:
(3S)-4-[1-(2,2-Difluoro-4-phenyl-butyl)-pyrrolidin-3-ylsulfanyl]-phenol (0.25 g, 0.688 mmol) was dissolved in MeOH (20 ml), cooled to 0° C. and treated with oxone (0.21 g, 0.34 mmol). After 4 hours stirring at 0° C., reaction mixture was quenched with saturated NaHCO3 (65 ml). Aqueous phase was extracted with CH2Cl2 (3 times). Combined organic phases were dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed by MPLC over silica gel (hexane-ethyl acetate, 98:2 to 50:50) to provide (3S,S-oxide R) or (3S, S-oxide S)-4-[1-(2,2-difluoro-4-phenyl-butyl)-pyrrolidine-3-sulfinyl]-phenol (140 mg, first fraction, 54%), MS: m/e=380.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81 %

Procedure:
The [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (90 mg, 0.21 mmol) obtained in Example 50, N-methylpiperazine (0.036 ml, 0.33 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (0.045 ml, 0.32 mmol) were dissolved in dichloromethane (5 ml). To the resulting solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture were added N-methylpiperazine (0.036 ml, 0.33 mmol), triethylamine (0.045 ml, 0.32 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=25:1 eluate was concentrated under reduced pressure to afford the title compound (86 mg, 0.17 mmol, 80%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:38]/[C:39](/[CH3:46])=[CH:40]\[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:39]([CH3:46])[NH:38][C:12]([CH3:14])=[C:11]1[C:10]([O:16][CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:23][CH2:24]1)=[O:15]
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1Cl
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1ccccc1Cl
Yield: 34.7 %

Procedure:
A mixture of o-chlorobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and ethyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl ethyl 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 76°-78° C. (sintering). Yield 34.7%. IR(Nujol) cm-1 : 3320, 1690, 1680. NMR (CDCl3)δ:1.17(3H,t,J=7, --CH2CH3), 2.20(6H, s, ##STR16## 4.20(1H,s,>N--CH<), 5.40(1H,s,C(4) --H), 6.37(1H,s,NH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>CCO.C(O)(=O)C>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[CH:22]=2)[CH:18]=[N:19]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=Nc1ccc3cn[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.3 %

Procedure:
To a mixture of 5-methylisatin (80.5 mg, 0.5 mmol) and 6-aminoindazole (66.5 mg, 0.5 mmol) in EtOH (2 mL) was added 1 drops of acetic acid. The resulting mixture was capped and microwaved 30 min at 120° C. After cooling to rt, it was stirred for 5 min at rt and the resulting precipitate was collected by suction filtration to give the title compound (35 mg, 28%) as an orange red solid. 1H NMR indicated a 80:20 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H, NH), 10.89 (s, 1H, NH), 8.10 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 7.07 (s, 1H), 6.81-6.74 (m, 2H), 6.17 (s, 1H), 2.49 (s, 3H, CH3); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[NH:5][C@H:6]1[C@@H:11]([CH3:12])[CH2:10][CH2:9][NH:8][CH2:7]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:2][O:3][C:4](=[O:13])[NH:5][C@H:6]1[C@@H:11]([CH3:12])[CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7]1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)N[C@@H]1CNCC[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@@H]1C
Reaction time: 60 h
Yield: 80.9 %

Procedure:
A mixture of racemic cis (4-methyl-piperidin-3-yl)-carbamic acid methyl ester hydrochloride (7.35 mmol), benzaldehyde (818 μL, 8.09 mmol), diisopropylethylamine (3.9 mL, 22.1 mmol) and 4 Å molecular sieves (7 g) in DCE (50 mL) was stirred at ambient temperature for 5 hours before the addition of sodium triacetoxyborohydride (2.34 g, 11.03 mmol). The resulting mixture was stirred for 60 hours then filtered through Celite® and the filtrate concentrated under vacuum. The resulting residue was purified by Isolute® SCX-2 (gradient: DCM to 2M NH3 in methanol solution) then column chromatography on silica gel (gradient: 0 to 5% 2M NH3 in methanol solution in DCM) to afford 1.56 g (81%) of racemic cis (1-benzyl-4-methyl-piperidin-3-yl)-carbamic acid methyl ester as a clear oil. LCMS (Method H, ESI): RT=1.53 and 0.35 min, m+H=263.9; 1H NMR (400 MHz, CDCl3) δ: 7.31-7.23 (m, 5H), 5.42 (d, 1H), 3.78 (d, 1H), 3.66 (s, 3H), 3.45 (s, 2H), 2.80-2.77 (m, 2H), 2.20-2.12 (m, 1H), 1.94 (td, 1H), 1.72-1.48 (m, 1H), 1.38 (m, 2H), 0.90 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(OB(O)OC(=O)C)(=O)C.[CH:38]1([N:41]2[C:50]3[C:45](=[CH:46][C:47]([F:54])=[C:48](F)[C:49]=3[O:51][CH3:52])[C:44](=[O:55])[C:43]([C:56]([OH:58])=[O:57])=[CH:42]2)[CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[C:24]([NH:23][CH2:22][C@@H:20]1[O:19][C:18](=[O:27])[N:17]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3([OH:16])[CH2:15][CH2:14][N:13]([C:48]4[C:49]([O:51][CH3:52])=[C:50]5[C:45]([C:44](=[O:55])[C:43]([C:56]([OH:58])=[O:57])=[CH:42][N:41]5[CH:38]5[CH2:40][CH2:39]5)=[CH:46][C:47]=4[F:54])[CH2:12][CH2:11]3)=[C:2]([F:1])[CH:3]=2)[CH2:21]1)(=[O:26])[CH3:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCNCC3)c(F)c2)C(=O)O1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: CC(=O)OB(O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1c(N2CCC(O)(COc3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
In analogy to example 5 with 114 mg N-[{(5S)-3[3-fluoro-4-(4-hydroxy-piperidin-4-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}]-acetamide. (MW: 381.40 0.3 mmol), 127 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid diacetylborate (Sakurai, Nobuhiro; Sano, Mitsuharu; Hirayama, Fumihiro; Kuroda, Tsuyoshi; Uemori, Satoru; Bioorg. Med. Chem. Lett.; 8; 16; 1998; 2185-2190) (MW: 423.137, 0.3 mmol) and 38 mg of ethyl diisopropylamine (MW: 129.25, 0.3 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 137 mg, 69.5%. MS: 658.2 (M+H)+, 655.8 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]([NH:28]O)=[NH:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[H][H]>CO.[C].[Pd]>[F:33][C:31]([F:32])([F:34])[C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:30])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]([NH2:28])=[NH:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: [H][H]
Reactant: N=C(NO)c1ccc2c(ccn2-c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Agent: [Pd]
Solvent: CO
Product: N=C(N)c1ccc2c(ccn2-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c1
Yield: 27.4 %

Procedure:
In 10 mL of methanol, 12 mg (0.025 mmol) of 1-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-N-hydroxy-1H-indole-5-carboxamidine was dissolved and the solution was subjected to hydrogenation catalytic reduction on 10% palladium carbon in a hydrogen atmosphere at room temperature for 14 hours. After removal of the palladium carbon by a membrane filter, the filtrate was concentrated under reduced pressure, and the obtained product was triturated from diethyl ether to obtain 3 mg (25%) of 1-{4-[3-(3-(trifluoromethyl)phenyl)-ureido]phenyl}-1H-indole-5-carboxamidine (Table 1, Compound No. 25).
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([OH:8])=O)=[CH2:2].[C:15]([C:22]1NC=CN=1)(C1NC=CN=1)=[O:16].C([CH:29](C([O-])=O)[C:30]([O-])=[O:31])C.C(C(C([O-])=O)C([O-])=O)C.[Mg+2].[Mg+2].Cl>C1COCC1>[CH:1]([C:3]1[C:4]([F:14])=[C:5]([C:6](=[O:8])[CH2:29][C:30]([O:16][CH2:15][CH3:22])=[O:31])[CH:9]=[C:10]([F:13])[C:11]=1[F:12])=[CH2:2]
Reactant: C=Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCC(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: C1CCOC1
Product: C=Cc1c(F)c(F)cc(C(=O)CC(=O)OCC)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a cooled solution (0° to 5° C.) of 3-ethenyl-2,4,5-trifluorobenzoic acid (6.0 g, 0.03 mol) in THF (100 mL) was added carbonyl diimidazole (4.9 g, 0.030 mol). The mixture was then stirred at room temperature for 1 hour, heated with magnesium bis-(ethyl malonate) (8.7 g, 0.03 mol) and refluxed for 3 hours. The reaction was allowed to cool, treated with 3N HCl (30 mL) and stirred for 1.5 hours at room temperature. The reaction was partitioned between ether and water. The organic layer was dried and concentrated to provide 7.65 g (93%) of the desired product. An analytical sample was obtained by preparative TLC (SiO2, 9:1 hexane/EtOAC)
Reaction SMILES: C(O[CH2:4][CH3:5])=O.[CH:6]([SH:9])([SH:8])[CH3:7].[CH2:10]([N:12]([CH2:33][CH3:34])[C:13]([NH:15][C@H:16]1[CH2:30][C@H:29]2[C@@H:19]([CH2:20][C:21]3[C:31]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]2=4)[NH:23]C=3)[N:18]([CH3:32])[CH2:17]1)=[O:14])[CH3:11].N>C(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.O.CO>[CH2:33]([N:12]([CH2:10][CH3:11])[C:13]([NH:15][C@H:16]1[CH2:30][C@H:29]2[C@@H:19]([CH2:20][C:21]3[C:31]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]2=4)[NH:23][C:7]=3[CH:6]2[S:9][CH2:5][CH2:4][S:8]2)[N:18]([CH3:32])[CH2:17]1)=[O:14])[CH3:34]
Reactant: CC(S)S
Reactant: CCOC=O
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
At room temperature under argon, 7 ml of ethyl formate and 3.6 ml (44 mmol) of ethanedithiol are added in succession to a solution of 6.8 g of 1,1-diethyl-3-(6-methyl-8α-ergolinyl)urea in 200 ml of chloroform. Thereafter 8.8 ml (80 mmol) of titanium(IV) chloride dissolved in 100 ml of chloroform is added gradually dropwise to the mixture. The latter is stirred for 20 hours at room temperature. Although the starting material is not as yet entirely converted at this point in time, the reaction mixture is worked up to avoid further formation of the disubstituted compound. For this purpose, the reaction mixture is cooled in an ice bath and combined, in sequence, dropwise with 50 ml of methanol and 40 ml of water. The mixture is then made alkaline with 25% ammonia solution and extracted with methylene chloride. The organic phases are washed with water and dried over magnesium sulfate. The evaporated residue is crystallized in boiling heat from methanol/ethyl acetate, thus obtaining 3.8 g of 1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]urea (42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=1[OH:16])=[O:10].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[N:22][C:21]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>>[Cl:19][C:20]1[CH:25]=[C:24]([O:16][C:15]2[N:14]([CH3:17])[N:13]=[C:12]([CH3:18])[C:11]=2[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[O:10])[N:23]=[N:22][C:21]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34]
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1Oc1nnc(Oc2c(C(=O)c3ccc(Cl)cc3Cl)c(C)nn2C)cc1Cl
Temperature: 130 °C
Reaction time: 14 h
Yield: 80.6 %

Procedure:
109 mg (0.382 mmol) of (2,4-dichlorophenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone, 1.62 g (6.35 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2) and 107 mg (0.775 mmol) of potassium carbonate were mixed, and the mixture was stirred at 130° C. for 14 hours. The reaction mixture was cooled up to room temperature, and purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 155 mg (0.308 mmol, Yield: 80.6%) of (5-{[5-chloro-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-1,3-dimethyl-1H-pyrazol-4-yl) (2,4-dichlorophenyl)methanone.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:7]([CH3:21])[CH:6]=1)=[O:4].[OH-].[Na+].C(O)=O>CO.O>[CH3:21][N:7]1[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:19])([F:20])[F:18])=[C:9]([CH3:10])[C:5]([C:3]([OH:4])=[O:2])=[CH:6]1
Reactant: COC(=O)c1cn(C)c(-c2ccccc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: Cc1c(C(=O)O)cn(C)c1-c1ccccc1C(F)(F)F
Yield: 90.4 %

Procedure:
To a solution of 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.5 g, 8.4 mmol) in MeOH (20 mL) was added 4N NaOH (10 mL) and the mixture was heated to reflux overnight. Evaporation of solvent gave a solid, which was re-dissolved in water. The solution was acidified with formic acid. The resulting solids were collected by filtration, washed with water and then dried under high vacuum to afford the title compound as an off-white solid (2.15 g, 90%). MS (ES): 284 (MH+).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]([CH3:45])[CH3:44])[N:38]=1>>[CH3:44][N:43]([CH3:45])[C:39]1[N:38]=[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN(C)c1cccc(Br)n1
Product: C[C@@H](c1ccc(-c2cccc(N(C)C)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-6-(dimethylamino)pyridine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.39 min, m/z=474; 1H NMR (CD3OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.58 (d, 3H), 2.18 (s, 2H), 2.28 (m, 1H), 2.50 (2H), 3.12 (m, 1H), 3.34 (s, 6H), 5.59 (q, 1H), 6.99 (d, 1H), 7.18 (3H), 7.25-7.40 (5H), 7.57 (d, 2H), 7.98 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:8](C(O)=O)=[C:9](C(O)=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>N1C2C(=CC=CC=2)C=CC=1>[C:12]1([C:11]2[NH:10][CH:9]=[CH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1[nH]c(-c2ccccc2)c(-c2ccccc2)c1C(=O)O
Solvent: c1ccc2ncccc2c1
Product: c1ccc(-c2cc[nH]c2-c2ccccc2)cc1

Procedure:
A mixture of 20 g (0.065 mole) of 4,5-diphenylpyrrole-2,3-dicarboxylic acid in 80 ml quinoline was heated at reflux in an oil bath (bath ~230°) until gas evolution stopped (approx. one-half hour). The reaction mixture was cooled and most of the quinoline was removed by distillation (bp 58°@0.2 mm). The partially crystalline residue was chromatographed on 300 g Silic AR CC-7, eluting with toluene to give 12 g (85%) of faintly pink 2,3-diphenylpyrrole which could be further purified by recrystallization from ethanol/water or by sublimitation (~125°@0.2 mm) to give white solid, m.p. 132°-3°.