Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:10]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=O)[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]=1[CH3:14]>C(O)C>[CH3:8][C:9]1[CH:10]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]=1[CH3:14]
Reactant: Nc1ccccc1
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Solvent: CCO
Product: CC1=C(C)C(c2ccccc2C=Nc2ccccc2)C(C)=C1C
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Under a nitrogen atmosphere, aniline (31.5 mmol) was added dropwise to a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (30.0 mmol) in ethanol (90.0 mL) and the mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, the solvent was distilled off under reduced pressure to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-phenylamine (9.00 g, yield 100%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[C:12]([F:13])=[CH:11][C:10](F)=[CH:9][C:8]=2[F:15])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:36]=[C:35]([OH:37])[C:28]3[CH2:29][CH:30]([CH:32]([F:34])[F:33])[O:31][C:27]=3[CH:26]=2)=[O:24])=[N:18]1>>[CH3:16][N:17]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:36]=[C:35]([O:37][C:10]3[CH:11]=[C:12]([F:13])[C:7]([C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[C:8]([F:15])[CH:9]=3)[C:28]3[CH2:29][CH:30]([CH:32]([F:34])[F:33])[O:31][C:27]=3[CH:26]=2)=[O:24])=[N:18]1
Reactant: O=C(c1c(F)cc(F)cc1F)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C(F)F)C3)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3cc(F)c(C(=O)N4CCC4)c(F)c3)c3c(c2)OC(C(F)F)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 33, from azetidin-1-yl(2,4,6-trifluorophenyl)methanone (57.4 mg, 0.267 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (75 mg, 0.24 mmol) to give a white solid (20 mg, 16% yield). 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1 H) 7.25-7.35 (m, 1 H) 7.12-7.21 (m, 2 H) 6.71-6.82 (m, 1 H) 6.54 (d, J=8.34 Hz, 2 H) 5.73-6.12 (m, 1 H) 5.02 (d, J=8.08 Hz, 1 H) 4.23 (t, J=7.83 Hz, 2 H) 4.00-4.10 (m, 2 H) 3.78 (s, 3 H) 3.17-3.29 (m, 2 H) 2.36 (t, J=7.71 Hz, 2 H); LCMS for C24H20F4N4O4 m/z 505.00 and 506.00 (M+H)+; Anal. Calcd. for C24H20F4N4O4: C, 53.77; H, 4.01; N, 9.95; Found: C, 53.79; H, 3.91; N, 9.87.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:21][C:22]([NH:24][CH2:25][CH2:26]O)=[S:23])[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1>Cl>[S:23]1[CH2:26][CH2:25][N:24]=[C:22]1[NH:21][CH:10]([C:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)[CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(CC(NC(=S)NCCO)c2cccc3c2CCCC3)c1
Agent: Cl
Product: Cc1cc(C)cc(CC(NC2=NCCS2)c2cccc3c2CCCC3)c1
Yield: 88.5 %

Procedure:
A mixture of the above 1-[2-(3,5-dimethylphenyl)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)-ethyl]-3-(2-hydroxyethyl)-thiourea (1.21 g) and concentrated hydrochloric acid (20 ml) was heated under reflux for 2 hours. The hydrochloric acid phase was decanted carefully and the remainder dissolved in ethyl acetate and washed three times with potassium carbonate solution (5 wt % in water), three times with water and dried over sodium sulphate. The solvent was removed by evaporation and the remainder triturated with a solution of light petrol ether/ethyl acetate (10/1) and the precipitate separated by filtration to yield the product C.2 as an off-white solid (1.02 g)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH:17]4[CH2:19][CH2:18]4)[N:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])[CH2:21]1.C(=O)([O-])[O-].[K+].[K+].[F-].[Cs+]>O.Cl.COCCOCCOC>[CH:17]1([C:13]2[N:12]=[C:11]([C:9]3[NH:8][C:6]4=[N:7][C:2]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]6[CH2:29][CH2:30][CH2:31][CH2:32]6)=[O:27])[CH2:21]5)=[CH:3][N:4]=[C:5]4[N:10]=3)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:18]1
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Reactant: Brc1cnc2nc(-c3ccnc(C4CC4)n3)[nH]c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOCCOC
Product: O=C([C@@H]1CCCN(c2cnc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 150 °C

Procedure:
A mixture of 6-bromo-2-(2-cyclopropylpyrimidin-4-yl)-1H-imidazo[4,5-b]pyrazine (86 mg, 0.3 mmol), (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone (95 mg, 0.4 mmol), potassium carbonate (98.4, 0.7 mmol), cesium fluoride (124 mg, 0.8 mmol) and diglyme (1.0 mL) was heated to 150° C. for 3 days. The mixture was diluted with water and aqueous hydrochloric acid (1N). The mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 419.3, HPLC retention time 2.44 min (Method A).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][C:10]3[N:11]2[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=2)[C:16]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].O>CCO.C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][NH:9][C:10]3[N:11]2[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=2)[C:16]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1ncc1ccc([N+](=O)[O-])cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCc1ccc([N+](=O)[O-])cc1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
To a solution of 8-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]quinazoline-3-carboxamide (240 mg, 0.57 mmol) in 10 mL of EtOH and 10 mL of DCM was added NaBH4 (86 mg, 2.26 mmol) at RT. After stirring at RT for 20 min, 10 mL of water was added. The mixture was concentrated. 5 mL of water was added and filtered. The cake was washed with tert-Butyl methyl ether (30 mL) and dried to afford 200 mg (83%) of 8-nitro-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 427.9.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:16][C:11]=2[CH2:10][N:9]([C:8]([O:7][CH2:6][C:5]2[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:32])[CH2:30][CH3:31])[CH:42]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:44]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid 4-chloro-benzyl ester and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:26]1([CH:38]=[CH:37][CH:36]=[CH:35][CH2:34]1)[CH:27]=[N:28][C:29](=O)[CH2:30][CH2:31][CH3:32])C>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:29]([CH2:30][CH2:31][CH3:32])=[N:28][C:27]([C:26]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCC(=O)N=CC1(OCC)C=CC=CC1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCc1nc(-c2ccccc2)nn1-c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
First, 7.4 g of 3-bromophenyl hydrazine hydrochloride and 80 mL of carbon tetrachloride were put into a 200-mL three-neck flask, 3.5 g of triethylamine (Et3N) was added dropwise to this mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 8.8 g of N-(1-ethoxybenzylidene)butyramide obtained in Step 1 of Synthesis Example 1 was added to this mixture, and the mixture was stirred at room temperature for 24 hours. After the stirring, this mixture was dissolved in chloroform and washed with water and saturated saline. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. This mixture was gravity-filtered, and the obtained filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography. As the developing solvent, dichloromethane was used. The obtained fraction was concentrated to give a solid. This solid was recrystallized with a mixed solvent of toluene and hexane to give 1-(3-bromophenyl)-3-phenyl-5-propyl-1H-1,2,4-triazole (white powder, 47% yield). The synthesis scheme of Step 1 is shown in (E-1) below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[NH:14]1.ClCCl.N1C=CC=CC=1.[F:32][C:33]([F:37])([F:36])[S:34]Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:34][C:33]([F:37])([F:36])[F:32])[C:15]([C:19]([O:21][CH3:22])=[O:20])=[N:14]1
Reactant: COC(=O)c1cc(=O)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 10 g (0.028 mol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(methoxycarbonyl)-pyrazol-5-one in 150 ml of dichloromethane containing 2.45 g (0.03 mole) of pyridine, cooled to -10° to 0° C., was added 3.75 ml (0.04 mole) of trifluoromethanesulfenyl chloride. The reaction mixture was allowed to stir overnight, then diluted with ethyl acetate and washed with water. The organic layer was dried and concentrated to afford 13.0 g of a tan colored solid. Recrystallization from hexane:methyl-t-butyl ether afforded 5.5 g of a product, m.p. 216.5°-217.5° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:3][N:4]([C@@H:12]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][NH:27][CH:26]=2)=[O:24])=[CH:18][CH:17]=1)[CH2:13][OH:14])C(=O)OC(C)(C)C>Cl.C(O)C>[OH:14][CH2:13][C@@H:12]([NH:4][CH2:3][C@H:2]([OH:1])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][NH:27][CH:26]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)[C@H](CO)Cc1ccc(NC(=O)c2cc[nH]c2)cc1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 20 %

Procedure:
In 4N hydrogen chloride in ethanol (2.0 ml), tert-butyl N-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(1H-pyrrol-3-ylcarbonyl)amino]benzyl]ethyl]carbamate (113.5 mg) was dissolved and the solution was stirred at room temperature for 30 hours. After concentration under reduced pressure, the residue was extracted with ethyl acetate (20 ml) and washed with saturated sodium hydrogencarbonate aqueous solution (20 ml). The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with brine, and dried over magnesium sulfate to give N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]-phenyl]-1H-pyrrole-3-carboxamide (18.2 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([NH:31][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN(C)CCN
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Product: CN(C)CCNc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following Example 70 and General Procedure C, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and N1,N1-dimethyl-1,2-ethanediamine were reacted to give 113bp. 1H NMR (400 MHz, CDCl3), δ: 7.23 (m, 1 H), 6.87-6.92 (m, 2 H), 6.67-6.74 (m, 2 H), 6.47-6.54 (m, 2 H), 4.93 (s, 2 H), 3.84 (m, 2 H), 3.31-3.39 (m, 5 H), 2.86 (s, 6 H). LCMS (ESI) m/z: 444.0
Reaction SMILES: [Cl-].C([Al+]CC)C.Cl.[CH3:8][NH:9][O:10][CH3:11].[Br:12][C:13]1[S:17][C:16]2=[C:18]([C:21]([O:23]C)=O)[N:19]=[CH:20][N:15]2[CH:14]=1.P([O-])([O-])([O-])=O>ClCCl>[CH3:11][O:10][N:9]([CH3:8])[C:21]([C:18]1[N:19]=[CH:20][N:15]2[CH:14]=[C:13]([Br:12])[S:17][C:16]=12)=[O:23]
Reactant: COC(=O)c1ncn2cc(Br)sc12
Reactant: CNOC
Agent: CC[Al+]CC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CON(C)C(=O)c1ncn2cc(Br)sc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Diethylaluminum chloride (0.9 M hexane solution; 1.1 ml, 1.07 mmol) was added to an ice cooled solution of N,O-dimethylhydroxylamine hydrochloride (104 mg, 1.07 mmol) in dichloromethane (4 ml), and, while gradually raising the temperature, the mixture was stirred for one hr. A solution of methyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (56 mg, 0.21 mmol) in dichloromethane (6 ml) was added thereto, and the mixture was stirred at room temperature for 21 hr. A phosphate buffer solution (5 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 10 min and was then filtered through Celite. The filtrate was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1→10:1) to give N-methoxy-N-methyl-2-bromoimidazo[5,1-b]thiazole-7-carboxamide (54 mg, 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][C:13](=[CH:16][O:17][CH3:18])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:19](/[CH:24](CO)[CH2:25][OH:26])=[CH:20]\[CH2:21][CH2:22][CH3:23].C1(C)C=CC=CC=1>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C@H:16]3[O:26][CH2:25][C@H:24](/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH3:23])[CH2:18][O:17]3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COC=C1CCC(c2ccc(C#N)c(F)c2)CC1
Reactant: CCC/C=C/C(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC/C=C/[C@H]1CO[C@H]([C@H]2CC[C@H](c3ccc(C#N)c(F)c3)CC2)OC1
Reaction time: 1 h

Procedure:
A mixture of 0.98 g of 2-fluoro-4-[4-(methoxymethylidene)cyclohexyl]benzonitrile (U.S. Pat. No. 4,784,471), 0.70 g of 2-(1E-pentenyl)-1,3-propanediol, 45 ml of toluene, 2 ml of water and 10 drops of 10 percent sulphuric acid was stirred at about 85° C. for 75 minutes, then heated to boiling for 1 hour, whereby moist solvent distilled off and was replaced by fresh toluene. The reaction mixture was treated with 12 drops of triethylamine and, after cooling, washed three times with 15 ml of water, dried over sodium sulphate, filtered and concentrated. Chromatography of the residue (1.86 g) on 50 g of silica gel with hexane/ethyl acetate (vol. 9:1) and two-fold recrystallization from 8 ml of hexane each time gave 0.65 g of pure 2-fluoro-4-[trans-4-[trans-5-(1E-pentenyl)-1,3-dioxan-2-yl]cyclohexyl]benzonitrile, m.p. (C-N) 91.2° C., cl.p. (N-I) 192.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(OCC)(=O)C>CS(C)=O>[CH3:13][C:4]1[CH:3]=[C:2]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: NCc1ccccn1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(NCc2ccccn2)c2cccc(O)c2n1
Temperature: 160 °C
Yield: 43.9 %

Procedure:
A mixture of the 4-chloro-2-methylquinolin-8-ol (2.00 g, 10.3 mmol) and 2-aminomethyl pyridine (3.35 g, 30.9 mmol) in DMSO (5 mL) was heated at 160° C. for 2 h under nitrogen atmosphere. The mixture was cooled, poured into ice/NaHCO3 and extracted with ethyl acetate and dichloromethane. Evaporation gave a crude mixture that was mixed with ethyl acetate. The yellow solid precipitated and was filtered and dried to give 1.20 g of 2-methyl-4-((pyridin-2-ylmethyl)amino)quinolin-8-ol (44%). MS (+APCI) 266 (M+). 1H-NMR (CDCl3, δ): 8.56 (m, 1H), 7.79 (t, J=6.0 Hz, 1H), 7.75 (dt, J=2.0, 7.6 Hz, 1H), 7.63 (dd, J=1.2, 8.4 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.25 (m, 2H), 6.96 (d, J=7.6 Hz, 1H), 6.29 (s, 1H), 4.62 (d, J=6.0 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:28](=[O:29])/[CH:27]=[CH:26]/[CH2:25][N:24]([CH3:31])[CH3:23])[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3,4-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 25A (65 mg, 0.19 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (45 mg, 0.27 mmol) to yield 24 mg (26%).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH2:12]([N:22]=[C:23]=[S:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:23]([NH:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[S:24])=[CH:7][CH:6]=1)=[O:2]
Reactant: CCCCCCCCCCN=C=S
Reactant: Nc1ccc(NNC=O)cc1
Product: CCCCCCCCCCNC(=S)Nc1ccc(NNC=O)cc1

Procedure:
Procedure (12.) was employed with 1-formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and decyl isothiocyanate (1.99 g, 0.01 mole). Yield 2.4 g (69%), m.p. 150°-152° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]=2[CH:2]=1)=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.FC1C=CC(F)=CC=1C(C1C(C(O)=O)=CN=CC=1)=O>[N+](C1C=CC=CC=1)([O-])=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:10]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:7]([OH:9])=[O:8])=[O:11]
Reactant: Fc1ccc(F)cc1
Reactant: O=C1OC(=O)c2cnccc21
Agent: O=C(O)c1cnccc1C(=O)c1cc(F)ccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccncc1C(=O)c1cc(F)ccc1F
Reaction time: 3 h
Yield: 84 %

Procedure:
3,4-Pyridine dicarboxylic acid anhydride (95.7 g, 0.67 mol) and AlCl3 (367.3 g, 2.67 mol) were simultaneously, but separately, added in five portions (one every 15') to boiling 1,4-difluorobenzene (650 mL, 90° C.). After about 1 hour from the last addition, the majority of the 1,4-difluorobenzene was removed by distillation at normal pressure until a thick mass was obtained. The temperature was lowered to 80° C. and nitrobenzene (150 mL) was added in order to dissolve the residual mass. While still hot, the resulting solution was cautiously quenched into ice-cooled and stirred water (1000 g of ice and 530 g of demineralized water) (i.e., slowly drop the solution into the ice water). Then concentrated HCl (37%, 160 mL) was added to the poured mixture at 0°-5° C. and stirring was continued for about 3 hours. A greasy beige precipitate (about 150 g wet) was collected by filtration while the aqueous layer was separated from nitrobenzene and extracted with AcOEt (6x500 mL). Nitrobenzene layer was diluted with petroleum ether (400 mL) and the resulting little amount of precipitate was collected by filtration (about 2 g). Combined extracts were concentrated under vacuum, and the residual crude solid (about 45 g), together with the previously collected precipitates, was suspended into a mixture of AcOEt/petroleum ether (1/1) (600 mL). After about 2 hours at room temperature the suspension was filtered and dried in vacuum to give the mixture of 4-(2',5'-difluorobenzoyl)nicotinic acid and 3-(2',5'-difluorobenzoyl) isonicotinic acid (147.3 g, 84% yield) as a pale beige solid.
Reaction SMILES: [OH-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[C:15]([C:27]([O:29]C)=[O:28])=[CH:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>O1CCOCC1>[Si:3]([O:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)n1CC(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)n1CC(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Aqueous sodium hydroxide solution (1 M, 1.78 mL) was added to a solution of methyl 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (375 mg, 0.89 mmol) in 1,4-dioxane (10 mL) and stirred at 70° C. for 2 h. The resultant brown solution was cooled to room temperature and concentrated in vacuo to ˜50% of its starting volume. The reaction mixture was acidified to ˜pH 4 by the addition of aqueous HCl (1 M, 1.78 mL) and extracted with EtOAc. The aqueous layer was further extracted with EtOAc (2×10 mL) The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid as a brown gum (70% purity, 270 mg, yield ˜95%) The mixture was used without further purification. ESI-MI m/z [M+Na]+ 432.0.
Reaction SMILES: ClC1C=CC2SC=C(C[N:10]3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[Cl-].[NH4+]>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH2:10])=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(N)=O
Yield: 43 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with ammonium chloride, the title compound was obtained as a colorless solid in 43% yield: mp 201-203° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.38-7.31 (m, 4H), 7.23-7.17 (m, 2H), 4.42 (s, 2H), 3.99 (t, J=9.0 Hz, 2H), 3.45 (t, J=9.0 Hz, 2H), 2.46 (s, 3H): MS (ES+) m/z 33.51 (M+1).