Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH2:12])[N:6]=1.[O:32]=[C:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]1[CH2:43][C:44](O)=[O:45]>>[CH3:1][C:2]1[N:3]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:44](=[O:45])[CH2:43][N:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:41][CH2:42][C:33]2=[O:32])[N:6]=1
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Reactant: Cc1nc(-c2sccc2N)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1nc(-c2sccc2NC(=O)CN2C(=O)CCc3ccccc32)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 2-(2-methyl-1-trityl-1H-imidazol-4-yl)thiophen-3-amine and 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid using protocol B (125 mg). Method [7] Retention time 7.33 min by HPLC (MH+ 609).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[N:5]1[C:12](Cl)=[N:11][C:9]([Cl:10])=[N:8][C:6]=1Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([NH:4][C:12]1[N:5]=[C:6]([NH:4][CH2:1][CH:2]=[CH2:3])[N:8]=[C:9]([Cl:10])[N:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCNc1nc(Cl)nc(NCC=C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
54.9 g (0.96 mole) of allylamine are added dropwise, in the course of 1.5 hours and while stirring, to a clear solution of 73.8 g (0.4 mole) of cyanuric chloride in 500 ml of toluene, the temperature being kept between 20° and 30° by applying gentle external cooling to the reaction vessel. After stirring for a further two hours at room temperature and for one hour at 50°, the mixture is cooled to 20°, and a solution of 16 g (0.4 mole) of sodium hydroxide in 70 ml of water is added dropwise at 20° in the course of 2 hours. After stirring for a further 2 hours at room temperature and for 6 hours at 60°, a further 16 g (0.4 mole) of sodium hydroxide in 70 ml of water are added dropwise in the course of 2 hours and stirring is continued for a further 5 hours at 60°. After the mixture has cooled to room temperature, 200 ml of water are added, and the precipitate is filtered off after stirring for approx. 30 minutes. The precipitate is thoroughly washed with water, thoroughly suction-drained and dried in vacuo at approx. 95°. The colourless 2,4-bis-allylamino-6-chloro-1,3,5-triazine thus obtained is analytically pure and has a melting point of 205°-206°; its water content is <0.3%. Yield 88.2 g (97.7% of theory).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C@:19]1([CH3:30])[O:23][C:22]2=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]2[CH2:20]1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][C:43]([CH2:44]O)=[CH:42][CH:41]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C.O>[CH3:1][N:2]([CH2:18][C@:19]1([CH3:30])[O:23][C:22]2=[N:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][N:21]2[CH2:20]1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:44][C:43]2[CH:42]=[CH:41][C:40]([C:39]([F:38])([F:48])[F:49])=[CH:47][CH:46]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)C[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCN(C(=O)OCc2ccc(C(F)(F)F)cc2)CC1)C[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
Tert-butyl (S)-4-[2-(N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylamino)-ethyl]piperazine-1-carboxylate prepared in Example 173 (300 mg, 0.71 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (2 ml) and triethylamine (2 ml). After stirring for 5 minutes at room temperature, the solution was concentrated under reduced pressure. The residue was dissolved in DMF (15 ml). To the solution, a mixture of 4-trifluoromethylbenzyl alcohol (373 mg, 2.12 mmol) and 1,1′-carbonyldiimidazole (344 mg, 2.12 mmol) in DMF (5 ml) stirred at room temperature for 3 hours was added followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over magnesium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) and crystallized from methylene chloride-isopropyl ether to afford 4-trifluoromethylbenzyl (S)-4-[2-(N-methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylamino)ethyl]piperazine-1-carboxylate (196 mg, yield 53%) as a white powder.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:36])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:35])[CH2:12][CH2:13][C@@:14]3([C@H:31]([OH:34])[CH2:32][NH2:33])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:38])[CH3:37])(=[O:3])[CH3:2].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[Cl:52][C:53]1[CH:60]=[CH:59][C:56]([CH:57]=O)=[CH:55][CH:54]=1.[BH4-].[Na+]>CO>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:36])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:35])[CH2:12][CH2:13][C@@:14]3([C@H:31]([OH:34])[CH2:32][NH:33][CH2:57][C:56]4[CH:59]=[CH:60][C:53]([Cl:52])=[CH:54][CH:55]=4)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:37])[CH3:38])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5([C@H](O)CN)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5([C@H](O)CNCc5ccc(Cl)cc5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask containing (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-amino-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (200 mg, 379 mmol) and methanol (15 ml) was added triethylamine (15 mg, 0.152 mmol), magnesium sulfate (68 mg, 0.168 mmol) and 4-chlorobenzaldehyde (64 mg, 0.455 mmol). The contents were allowed to stir at ambient temperature for approximately 2 hours. To the resulting mixture was added sodium borohydride (17 mg, 455 mmol) in a single portion and the reaction was allowed to stir at ambient temperature for two and a half days. The reaction was then charged with an additional 20% excess of the p-Cl-benzaldehyde and sodium borohydride and allowed to stir an additional 2 hours. Finally, the reaction was quenched with water, allowed to stir 15 minutes and solids filtered to provide title compound contaminated with impurities. LC/MS: m/z calculated 651.4. found 652 (M+1)+.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]([NH:19][CH3:20])=[O:18])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:20][NH:19][C:17]([C:9]1[NH:10][C:11]2[C:16]([C:8]=1[CH:6]=[CH2:1])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:18]
Reactant: CNC(=O)c1[nH]c2ccccc2c1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1c(C(=O)NC)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5M in hexanes) (48.6 mL, 121.7 mmol) was added dropwise to an ice-cooled solution of methyl triphenylphosphoniumbromide (43.5 g, 121.7 mmol) in THF (500 mL). The mixture was stirred at 0° C. for 1 h then at rt for 2 h. 3-Formyl-N-methyl-1H-indole-2-carboxamide (1.96 g, 9.7 mmol) in THF (100 mL) was added and the mixture stirred at rt for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate and washed twice with water. The organic phase was dried over magnesium bromide and evaporated in vacuo. The crude mixture was chromatographed over silica gel eluting with 40% ethyl acetate in hexanes to afford the title compound (730 mg (38%). 1H NMR (300 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.04 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.33 (d, J=18 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.09 (t, J=7.2 Hz, 1H), 5.77 (d, J=18.4 Hz, 1H), 5.27 (d, J=11.6 Hz, 1H), 2.81 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](O)=O)=[CH:9][C:4]=2[N:3]=[N:2]1.[NH2:13]C(N)=O.S(=O)(=O)(O)N>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:13])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: NS(=O)(=O)O
Product: N#Cc1ccc2[nH]nnc2c1
Yield: 11.3 %

Procedure:
1H-Benzotriazole-5-carboxylic acid (1.0 g, 6.13 mmol), urea (0.552 g, 9.2 mmol) and sulfamic acid (1.19 g, 12.3 mmol) were heated to 240° C. for 1 h. The solid was triturated with water and the solid refluxed with CH2Cl2 for 1 h and the remaining solid removed by filtration. The solvent was removed to give 1H-benzotriazole-5-carbonitrile 100 mg (14%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccccc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methoxybenzoic acid (6 g, 39.4 mmol) in 80 mL of acetonitrile was added N-bromosuccinimide (7.4 g, 41.4 mmol) in 20 mL of acetonitrile. The reaction mixture was warmed to ambient temperature and the mixture was allowed to stir for 16 hours. Additional N-bromosuccinimide (14.8 g, 82.8 mmol) was added and the reaction mixture stirred for an additional 48 hours. The mixture was quenched with 25 mL of H2O and the layers were separated. The aqueous layer was extracted with three 15 mL of portions of CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 50% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 248, 250 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][N:10]=[C:9]2[SH:19])=[CH:4][CH:3]=1.[F:20][C:21]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:22]=1[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][N:10]=[C:9]2[S:19][CH2:23][C:22]2[C:25]([F:30])=[CH:26][CH:27]=[C:28]([F:29])[C:21]=2[F:20])=[CH:6][CH:7]=1
Reactant: Fc1ccc(F)c(CBr)c1F
Reactant: CON(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CON(C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
A mixture of 1-(4-fluorophenyl)-2-mercapto-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (8) (153 mg, 0.54 mmol), 2,3,6-trifluorobenzyl bromide (71 μL, 0.54 mmol), and potassium carbonate (90 mg, 0.65 mmol) in acetone (5 mL) was heated at reflux for 3 h. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 1-(4-fluorophenyl)-N-methoxy-N-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxamide (9) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[F:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[F:43])[NH2:39].N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:39][C:38]1[CH:40]=[CH:41][C:42]([F:43])=[C:36]([F:35])[CH:37]=1)=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: Nc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccc(F)c(F)c3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 3,4-difluoroaniline (125 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10 1) to give the objective product as powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)c(C)n1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M43) (190 mg, 0.333 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a brown solid (97 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:12][C:11]2=[O:17])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (58.4 mg, 51%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH2:22]([S:24]([C:27]1[S:31][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:29][CH:28]=1)(=[O:26])=[O:25])[CH3:23]>>[CH2:22]([S:24]([C:27]1[S:31][C:30]([N:32]2[CH2:33][CH2:34][N:35]([C:10]([C:9]3[CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[O:12])[CH2:36][CH2:37]2)=[N:29][CH:28]=1)(=[O:26])=[O:25])[CH3:23]
Reactant: CCS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C(F)(F)F)CC2)s1
Yield: 61 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-ethanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 32(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 61%). MS (m/e): 556.3 (M+H+, 100%), 573.3 (M+NH4+, 55%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])=[N:9][C:8]=1[CH3:28])C.C1(NC2CCCCC2)CCCCC1.CN1C=C(N)SC1.C(OC(=O)CS)C>>[CH:22]1([N:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:29])=[O:3])=[C:8]([CH3:28])[N:9]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=O)CSc1sc(NC(=O)N(C2CCCCC2)C2CCCCC2)nc1C
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCOC(=O)CS
Agent: CN1C=C(N)SC1
Product: Cc1nc(NC(=O)N(C2CCCCC2)C2CCCCC2)sc1SCC(=O)O

Procedure:
[2-(3,3-Dicyclohexyl-ureido)-4-methyl-thiazol-5-ylsulfanyl]-acetic acid ethyl ester prepared as described in general procedure (A) using dicyclohexylamine and 3-methyl-5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](OCC)=[C:9]([CH3:16])[C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:20][NH2:21].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:21][N:20]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=C(C)C(=O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: Cc1c(C(F)(F)F)n[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A solution of 5.5 g of 4-(4-chlorophenyl)-4-ethoxy-1,1,1-trifluoro-3-methyl-3-buten-2-one in 20 mL of MeOH was slowly treated with 0.70 mL of NH2NH2 and allowed to stir for two hours. Water was added to the reaction mixture and a precipitate formed. The solid was collected by filtration and washed with hexanes to yield 3.87 g of 5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole as a white powdery product: mp 139.0° C.; 1HNMR (CDCl3) δ 2.09 (s, 3H), 7.39 (m, 2H), 7.45 (m, 2H, 8.5 Hz), 11.75 (bs, 1H). 19 FNMR (CDCl3) δ -62.34 (3F). Anal. Calcd for C11H8 N2F3Cl: C, 50.69; H, 3,09; N, 10.57. Found: C, 50.68; H, 3.05; N, 10.81.
Reaction SMILES: C1[O:19][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)OC1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>C1COCC1>[CH:4]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=3)=[CH:14][N:13]=2)=[CH:9][CH:10]=1)=[O:19]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Oc2ccc(C3OCCO3)cc2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(5-amino-2-pyridyl)oxy]benzaldehyde ethylene acetal (5.27 g, 20.4 mmol) and triethylamine (3.41 mL, 24.5 mmol) in THF (80 mL) was added dropwise a solution of 3,4-dichlorobenzoyl chloride (4.49 g, 21.4 mmol) in THF (30 mL) under ice cooling. The resulting solution was stirred for 2 hours at the same temperature. The reaction solution was concentrated under reduced pressure, to the residue, 80% acetic acid (55 mL) was added, and the mixture was heated at 80° C. with stirring for 1 hour. The reaction solution was concentrated under reduced pressure and to the residue was added water, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated. The obtained solid was recrystallized from isopropanol, to thereby yield 5.63 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]3([C:21](=[O:22])[C:4]=2[CH:3]=1)[CH2:18][CH2:17][N:16](C#N)[CH2:15][CH2:14]3.C(O)(=O)C.[BrH:29]>Cl.O.CCOCC>[BrH:29].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]3([C:21](=[O:22])[C:4]=2[CH:3]=1)[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3
Reactant: N#CN1CCC2(CC1)C(=O)c1cc(Cl)ccc1Oc1ccccc12
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(Cl)ccc2Oc2ccccc2C12CCNCC2
Temperature: 25 °C

Procedure:
A homogeneous solution of 1.8 g of 2-chloro-1'-cyano-10,11-dihydro-11-oxospiro[dibenz(b,f)oxepin-10,4'-piperidine], Example 4, in 20 ml of 3 N hydrochloric acid and 10 ml of glacial acetic acid is stirred at 110°-120° C. for 16 hours and then the solution is permitted to cool to ambient temperature. Thereafter, the solution is diluted with 50 ml of water and then is rotary evaporated at 80° C. until 50 ml of water is removed and the dilution and evaporation process is repeated. The residue is diluted with 200 ml of water and the diluted solution is successively cooled in an ice bath, basified to pH 9 with a small amount of 58% ammonium hydroxide and extracted thrice with 80 ml portions of ether. The combined ether extracts are sequentially washed twice with two 80 ml portions of water and one 40 ml portion of saturated sodium chloride and then dried over magnesium sulfate and finally evaporated to dryness leaving an oil. The oil is dissolved in ether where it is converted to its hydrobromic acid salt. The salt is recrystallized from acetone to provide crystals of 2-chloro-10,11-dihydro-11-oxospiro[dibenz(b,f)oxepin-10,4'-piperidine]hydrobromide which lose their regular shape upon heating above 125° C. and the resulting glass melts at 223°-225° C.