Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH:19](=[N+:26]([CH3:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:19]([N:26]([CH3:28])[CH3:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccccc2)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:14][C:13]([C:15]([C:50]4[C:55]([CH3:56])=[CH:54][C:53]([CH3:57])=[CH:52][C:51]=4[CH3:58])=[C:16]4[N:49]=[C:19]([C:20]([C:41]5[CH:46]=[CH:45][C:44]([CH2:47][OH:48])=[CH:43][CH:42]=5)=[C:21]5[NH:40][C:24](=[C:25]([C:31]6[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=6[CH3:39])[C:26]6[CH:27]=[CH:28][C:29]=2[N:30]=6)[CH:23]=[CH:22]5)[CH:18]=[CH:17]4)=[CH:12][CH:11]=3)=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:47]([C:44]1[CH:45]=[CH:46][C:41]([C:20]2[C:21]3[NH:40][C:24]([C:25]([C:31]4[C:32]([CH3:39])=[CH:33][C:34]([CH3:38])=[CH:35][C:36]=4[CH3:37])=[C:26]4[N:30]=[C:29]([C:9]([C:6]5[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=5)=[C:10]5[NH:14][C:13](=[C:15]([C:50]6[C:51]([CH3:58])=[CH:52][C:53]([CH3:57])=[CH:54][C:55]=6[CH3:56])[C:16]6[CH:17]=[CH:18][C:19]=2[N:49]=6)[CH:12]=[CH:11]5)[CH:28]=[CH:27]4)=[CH:23][CH:22]=3)=[CH:42][CH:43]=1)=[O:48]
Reactant: Cc1cc(C)c(-c2c3nc(c(-c4ccc(CO)cc4)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5ccc(CO)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)c(-c2c3nc(c(-c4ccc(C=O)cc4)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(-c5ccc(C=O)cc5)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A solution of 15 (0.190 g, 0.250 mmol) in CH2Cl2 (25 mL) was treated with pyridinium chlorochromate (216 mg, 1.00 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. After 90 min, the reaction mixture was poured on to a silica column (poured in CHCl3) and eluted with CHCl3/methanol (95:5) affording a purple solid (156 mg, 83%): 1H NMR δ −2.63 (brs, 2H), 1.84 (s, 12H), 2.63 (s, 6H), 7.29 (s, 4H), 8.28 (d, J=8.4 Hz, 4H), 8.41 (d, J=8.4 Hz, 4H), 8.71-8.78 (m, 8H), 10.39 (s, 2H); LD-MS obsd 755.24, calcd 754.3308 (C52H42N4O2); λabs 422, 515, 549, 594, 649 nm.
Reaction SMILES: O.[C:2]([O-:9])(=[O:8])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[NH4+].[NH4+].[C:12]1([CH3:22])[CH:17]=[CH:16]C(S(O)(=O)=O)=CC=1>C(O)CCC>[C:2]([O:9][CH2:22][CH2:12][CH2:17][CH3:16])(=[O:8])[CH2:3][CH2:4][C:5]([O:7][CH2:2][CH2:3][CH2:4][CH3:5])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])CCC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)CCC(=O)OCCCC

Procedure:
For the esterification reaction, a three-neck flask (500 ml) with a water separator is used, in which n-butanol, 52 g of diammonium succinate and 0.45 g of para-toluenesulfonic acid are initially charged. The mixture is brought to boiling with stirring. During the reaction, the dibutyl succinate formed is enriched in the flask (together with butanol). The water/n-butanol azeotrope and NH3 are distilled off via the top and condensed in the water separator. The condensate is separated into a butanol phase and a water phase. The butanol phase is recycled into the flask. The reaction ran for a total of 240 hours.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH2:4][C:5]1[N:6]([CH3:25])[C:7](=[O:24])[C:8]([O:15]C(=O)C2C=CC=CC=2)=[C:9]([C:11]([O:13]C)=O)[N:10]=1.COC(OC)CC#N.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>CO>[CH3:27][O:26][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[N:6]([CH3:25])[C:7](=[O:24])[C:8]([OH:15])=[C:9]([C:11]([NH:42][CH2:41][C:40]2[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=2)=[O:13])[N:10]=1
Reactant: COC(=O)c1nc(CC(OC)OC)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: COC(CC#N)OC
Solvent: CO
Product: COC(Cc1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C)OC

Procedure:
Methyl 2-(2,2-dimethoxyethyl)-5-benzoyloxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.0 eq.) (prepared from 3,3-dimethoxypropionitrile by procedure similar to those set forth in Examples 1 or 2) in dry MeOH was treated with 4-fluorobenzyl amine (2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo and residue triturated with Et2O to obtain the title product.
Reaction SMILES: C(O)C.O.[OH-].[Li+].C([O:9][C:10]([C:12]1[NH:38][C:15]2[N:16]=[CH:17][N:18]=[C:19]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[O:29])=[CH:23][CH:22]=3)[C:14]=2[CH:13]=1)=[O:11])C.Cl>O>[F:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28](=[O:29])[NH:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]3[C:14]4[CH:13]=[C:12]([C:10]([OH:11])=[O:9])[NH:38][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:22][CH:23]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ncnc3[nH]c(C(=O)O)cc23)cc1
Temperature: 42.5 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
After adding 7 ml of ethanol, 7 ml of water and 31 mg of lithium hydroxide monohydrate to 75 mg of the 4-{4-[3-(4-fluorophenyl)ureido]phenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester synthesized in Example 163 and stirring the mixture at 40-45° C. for 24 hours, it was neutralized with 2N HCl and concentrated to dryness to obtain 40 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:12][O:11][C@@H:10]([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@@H:10]([CH2:23][CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1COCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1CO
Reaction time: 18 h

Procedure:
Add 20% palladium hydroxide on carbon (Pearlman's catalyst) (92 mg) to a solution of 5-(S)-benzyloxymethyl-2-(S)-(2-cyclohexylethyl)-morpholine-4-carboxylic acid tert-butyl ester (211 mg, 0.51 mmol) in absolute ethanol (25 mL) and hydrogenate in a Parr shaker at 40° C. for 18 hours at 60 psi. Filter and concentrate to give the desired compound which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:19])[C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])=[O:4].[H][H]>O1CCCC1.[Ni]>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:19])[C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])=[O:4]
Reactant: COC(=O)COC(=S)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)COC(=S)c1cc(N)c(F)cc1Cl
Yield: 91.6 %

Procedure:
10.4 g of the resulting 2-chloro-4-fluoro-5-nitrothiobenzoic acid (methoxycarbonylmethyl) ester are hydrogenated with hydrogen under normal pressure in 150 ml of tetrahydrofuran at a temperature of from 20° to 25° C. in the presence of 2 g of Raney nickel catalyst. When the stoichiometric amount of hydrogen has been consumed, the catalyst is separated off and the solution is concentrated by evaporation to yield 8.6 g of 5-amino-2-chloro-4-fluorothiobenzoic acid (methoxycarbonylmethyl) ester having a melting point of from +88° to +89° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[C:7]3[CH2:8][C:9]([CH3:19])([CH3:18])[O:10][C:11]=3[C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:4]=2[N:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:42][C:43]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:44]=1[C:45](O)=[O:46]>C1COCC1>[Cl:42][C:43]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:44]=1[C:45]([NH:1][C:2]1[NH:6][C:5]2[C:7]3[CH2:8][C:9]([CH3:19])([CH3:18])[O:10][C:11]=3[C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:4]=2[N:3]=1)=[O:46]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: COC(=O)c1cc2nc(N)[nH]c2c2c1OC(C)(C)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)c1cc2nc(NC(=O)c3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of methyl 2-amino-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (1.00 g, 3.81 mmol) in THF (25 mL) was added EDCI.HCl (1.4 g, 7.62 mmol), HOBT (1.00 g, 7.62 mmol), 2-chloro-6-fluorobenzoic acid (1.32 g 7.62 mmol) and TEA (3 mL). The reaction mass was stirred for 18 h. The reaction mass was quenched in water extracted with 10% DCM: methanol. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on basic alumina eluting with 0.7% DCM: MeOH to afford 0.700 g of the desired product. 1HNMR (DMSO-d6): δ 1.43 (s, 6H), 3.02 (s, 2H), 3.58 (s, 3H), 6.08 (bs, 1H), 7.59-7.69 (m, 2H), 7.83 (q, J=6.6 Hz, 1H), 8.14 (bs, 2H); MS [M+H]+: 418.05.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][C:5]3(O)[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.CCN(S(F)(F)[F:19])CC>C1(C)C=CC=CC=1>[F:19][C:5]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:11][CH:3]([CH:2]3[NH2:1])[CH2:4]1)[CH2:6]2
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: CCN(CC)S(F)(F)F
Solvent: Cc1ccccc1
Product: NC1C2CC3CC1CC(F)(C3)C2
Temperature: 25 °C
Yield: 86.3 %

Procedure:
To the solution of 4-aminoadamantan-1-ol (800 mg, 4.79 mmol) in anhydrous toluene (6 mL) was added DAST (780 mg, 5 mmol) at 0° C. The reaction mixture was refluxed for 8 h. The mixture was cooled to rt and quenched with aq NaHCO3. The mixture was concentrated and extracted with CH2Cl2 (2×). The combined organic extracts were dried, filtered and concentrated to give 1-fluoro-4-aminoadamantane (700 mg), which was used without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[C:19]([CH2:21][C:22]4[C:23](=[O:34])[C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[C:26](=[O:29])[C:27]=4[CH3:28])[CH:18]=[CH:17][C:16]=3[O:35]C(=O)C)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:39])[C:15]3[CH:20]=[C:19]([CH2:21][C:22]4[C:23](=[O:34])[C:24]([O:32][CH3:33])=[C:25]([O:30][CH3:31])[C:26](=[O:29])[C:27]=4[CH3:28])[CH:18]=[CH:17][C:16]=3[OH:35])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(N4CCOCC4)nc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(N4CCOCC4)nc3)c2)=C(C)C1=O
Yield: 96.3 %

Procedure:
N-(6-Morpholinopyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.100 g, 0.187 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.089 g, 0.180 mmol, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.Cl[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:23]2[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1ccc2cccc(B3OC(C)(C)C(C)(C)O3)c2c1
Product: COc1ccc2cccc(-c3cnnc(Cn4ccnc4C)c3)c2c1

Procedure:
The title compound, MS: m/e=331.4 (M+H+), was prepared from 2-(7-methoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CN(C)[CH:21]=[O:22]>>[CH:21]([C:14]1[S:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:16][CH:15]=1)=[O:22]
Reactant: c1ccc(-c2cccs2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2ccccc2)s1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 35 mL of dimethylformamide was cooled to 0° C. and 7 mL of phosphorus oxychloride was added with stirring. The solution was allowed to warm to ambient temperature, and then a solution of 10.0 grams (0.0625 mole) of 2-phenylthiophene in 10 mL of dimethylformamide was added in one portion. The reaction mixture was heated to 80° C. where it stirred for 24 hours and then poured into 250 mL of an aqueous 10% sodium hydroxide solution containing 50 grams of ice. The resulting slurry was extracted with diethyl ether, and the extract was washed in succession with water, an aqueous solution saturated with sodium chloride, and water. The organic layer was concentrated under reduced pressure to a solid residue which was dried under high vacuum to yield 6.8 grams of 5-formyl-2-phenylthiophene.
Reaction SMILES: [CH:1]1([C:6]2[S:10][C:9]([NH:11][C:12]([C:14]3[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=3[F:20])=[O:13])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:25].[OH-]>C(Cl)Cl.C1COCC1>[NH2:25][S:21]([C:16]1[CH:17]=[CH:18][C:19]([F:20])=[C:14]([CH:15]=1)[C:12]([NH:11][C:9]1[S:10][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:7][N:8]=1)=[O:13])(=[O:23])=[O:22]
Reactant: O=C(Nc1nnc(C2CCCC2)s1)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(F)c(C(=O)Nc2nnc(C3CCCC3)s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To a 20 ml scintillation vial was added 3-{[(5-cyclopentyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}-4-fluorobenzenesulfonyl chloride (190 mg, 0.488 mmol) in a mixed solvent (DCM/THF=3 mL/1 mL). To this was added 1 ml of 7M NH4OH(NH3 28-30% w/w) . The reaction mixture was stirred vigorously at room temperature for two hours. After consumption of the starting material, the reaction solution was concentrated with a rotary evaporator. The product was dissolved with 1.0 mL of DMSO, was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 1% B to 99% B in 8.5 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-(aminosulfonyl)-N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide (amount 33 mg, 18.2%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[C:31]([C:33](=[O:38])[NH:34][CH:35]5[CH2:37][CH2:36]5)[CH:30]=[CH:29][C:28]=4[CH3:39])[CH:25]=3)[C:20](=[O:40])[N:19]([CH2:41][C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.N>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[C:31]([C:33](=[O:38])[NH:34][CH:35]5[CH2:36][CH2:37]5)[CH:30]=[CH:29][C:28]=4[CH3:39])[CH:25]=3)[C:20](=[O:40])[N:19]([CH2:41][C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)NC3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of step i) (0.1 g) in dichloromethane (9 mL) was added trifluoroacetic acid (1 mL) and the mixture stirred at room temperature for 1 hour. The reaction was basified by the addition of 0.88 ammonia and washed with water. The organics were dried over magnesium sulphate, filtered and concentrated to dryness to yield the title compound as a solid (0.08 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38]>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Product: CN(C)C(=O)CN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=591.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-N,N-dimethylacetamide.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1Cl
Temperature: 0 °C

Procedure:
To a solution of 25 ml of fuming nitric acid and 20 ml of sulfuric acid, 25 g of 2,4-dichlorobenzoic acid was gradually added. After completion of the heat generation, the reaction mixture was poured into ice water. Precipitated solid was washed with water and dried to obtain 23.0 g of the desired product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]([NH:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([CH3:27])[CH:21]=[CH:20]2)=O)=[N:11][CH3:12]>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]1[N:11]([CH3:12])[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([CH3:27])[CH:21]=[CH:20]3)=[N:14][N:13]=1
Reactant: CN=C(CCCC1OCCCO1)NNC(=O)c1ccc2nc(C)ccc2c1
Solvent: CCOC(C)=O
Product: Cc1ccc2cc(-c3nnc(CCCC4OCCCO4)n3C)ccc2n1
Yield: 9.1 %

Procedure:
2-Methyl-quinoline-6-carboxylic acid N′-(4-[1,3] dioxan-2-yl-1-methylimino-butyl)-hydrazide (1.28 g, 3.4 mmol) was heated in ethyl acetate (20 ml) for 4 h. The solvent was evaporated and the residue was purified by silica gel chromatography (eluent 20% MeOH:EtOAc) which gave the title compound as a brown solid (109 mg, 10%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>C1COCC1>[I:46][CH2:20][CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:3]2[CH:4]=[C:5]([O:11][CH3:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:15]1
Reactant: COc1cc(N2CCC(CCO)CC2)c(C)cc1[N+](=O)[O-]
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N2CCC(CCI)CC2)c(C)cc1[N+](=O)[O-]
Yield: 90.1 %

Procedure:
To 2-{1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}ethanol (32.6 g, 111 mmol), triphenylphosphine (32.0 g, 122 mmol), and imidazole (8.29 g, 122 mmol) in THF (554 mL) was added iodine (30.9 g, 122 mmol) in one portion, slowly due to observable exotherm. The reaction mixture was filtered through Celite® and washed with DCM. Purification by flash chromatography provided the crude title compound which was washed with saturated Na2SO3 to remove any residual iodine. The aqueous layer was back extracted with DCM. The combined organic layers were dried (MgSO4), filtered, and rotovapped down to give the title compound of step G (40.6 g, 100 mmol, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=0.5 Hz, 1H), 6.68 (s, 1H), 3.89 (s, 3H), 3.33 (t, J=7.5 Hz, 2H), 3.26 (d, J=12.4 Hz, 2H), 2.63-2.74 (m, 2H), 2.17 (s, 3H), 1.78 (q, J=7.1 Hz, 4H), 1.46-1.61 (m, J=7.2, 7.2, 7.1, 3.8 Hz, 1H), 1.30 (qd, J=12.0, 3.6 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[O:25]1[CH2:26][CH2:27][O:28][C:29]2[CH:34]=[C:33]([C:35]3[NH:22][C:21]4[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]5[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)[CH:32]=[CH:31][C:30]1=2
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5c(c4)OCCO5)nc3c2)cc1

Procedure:
Compound 184 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and benzo[1,4]dioxane-6-carboxaldehyde. [M+H]+ calcd for C24H22N4O3: 415.17; found: 415.47.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH3:17])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:14]=[CH:13]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>ClC1C=CC=CC=1Cl>[CH2:21]([O:20][C:18]([C:15]1[N:14]=[C:13]2[C:23](=[O:24])[NH:1][C:2]3[C:3](=[CH:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=3)[N:12]2[C:16]=1[CH3:17])=[O:19])[CH3:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1ncn(-c2ccc(C(F)(F)F)cc2N)c1C
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1C
Temperature: 180 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
A mixture of 1-(2-amino-4-trifluoromethylphenyl)-4-ethoxycarbonyl-5-methyl-1H-imidazole (12.3 g, 39.3 mmol), 1,1'-carbonyldiimidazole (7.0 g, 43.2 mmol) in 1,2-dichlorobenzene (250 ml) was stirred at 180° C. for 6 h under N2. The reaction mixture was cooled to room temperature. The precipitate was filtered off and washed with acetone to give 10.2 g (77%) of the title compound. M.p. >250° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[C:4]([CH3:12])[CH:3]=1.[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:19][CH2:18][S:15](=[O:17])(=[O:16])[CH2:13][CH2:14]2)([CH3:9])[CH3:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: Cc1cc(Br)ccc1C(C)(C)N
Solvent: CCO
Product: Cc1cc(Br)ccc1C(C)(C)N1CCS(=O)(=O)CC1
Temperature: 25 °C

Procedure:
A solution of 1-(4-Bromo-2-methyl-phenyl)-1-methyl-ethylamine (preparation 48, 544 mg, 2 mmol), vinyl sulfone (200 μl, 2 mmol) in EtOH (8 ml) is heated to 100° C. for 6 h and then allowed to cool to RT. EtOH is removed under HV and the residue is purified by flash chromatography (silicagel, CH2Cl2:EtOAc=1:0=>0:1) to afford the title compound as a pale pink solid, Rt=1.231 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 346 (M+1, 79Br)+.