Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]C)=O)[N:6]2C.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].[CH3:21][O-].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([N:19]=[C:18]([NH2:20])[NH:17][CH3:21])=[O:14])[NH:6]2
Reactant: N=C(N)N
Reactant: COC(=O)c1cc2c(Cl)cccc2n1C
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(Cl)cccc2[nH]1
Yield: 82.6 %

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 2.00 g (8.94 mmol) of methyl 4-chloro-1-methyl-2-indolecarboxylate, 8.54 g (89.4 mmol) of guanidine hydrochloride and 50 ml of a methanol solution of 4.83 g (89.4 mmol) of sodium methoxide. Thus 1.06 g (41.3%) of 4-chloro-1-methyl-2-indoloylguanidine hydrochloride was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:22])([CH3:21])[CH:14]=[C:13]4[CH3:23])[CH:10]([OH:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1.[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>C(Cl)Cl>[CH2:27]([O:24][CH:10]1[C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:20]2[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9]1)[NH:16][C:15]([CH3:21])([CH3:22])[CH:14]=[C:13]3[CH3:23])[CH:26]=[CH2:25]
Reactant: C=CC[Si](C)(C)C
Reactant: COc1cccc2c1-c1ccc3c(c1C(O)O2)C(C)=CC(C)(C)N3
Solvent: ClCCl
Product: C=CCOC1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3
Temperature: 0 °C
Yield: 90.9 %

Procedure:
A three-necked round bottom flask was charged with the product from Example 6 (59.0 g, 0.182 mol) followed by CH2Cl2 (1.18 L). The resulting suspension was stirred briefly before adding allyltrimethylsilane (58 ml, 0.364 mol) all at once at room temperature. The suspension was cooled to 0° C. under nitrogen and was treated with BF3OEt2 (46.3 ml, 0.364 mol) dropwise keeping the reaction temperature below 2° C. After complete addition, the mixture was stirred at 0° C. for ˜1 hour. The completion of the reaction was monitored with HPLC until the starting material was consumed. The reaction mixture was poured into saturated NaHCO3 solution and stirred for 30 minutes. The organic layer was separated, washed with brine, dried over Na2SO4, treated with charcoal, filtered and concentrated to an oil. EtOH (200 ml) was added and the solution was concentrated to give a crystalline solid which was suspended with heptane at 0° C. for 2 hours before filtration to give a solid which was dried under reduced pressure at 45° C. to provide the title compound as a light yellow crystalline solid (60.1 g, 95.1%). Anal. Calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03; Found: C, 79.26; H, 7.12; N, 3.80, 1H NMR [(CD3)2SO] δ 1.16 (3H, s) 1.17 (3H, s), 2.18 (3H, s), 2.22 (1H, m), 2.46 (1H, m), 3.85 (3H, s), 5.01 (2H, m), 5.44 (1H, br s), 5.77 (1H, dd), 5.82 (1H, m), 6.10 (1H, br s), 6.52 (1H, d), 6.60 (1H, d), 6.70 (1H, d), 7.06 (1H, d), 7.06 (1H, t), 7.96 (1H, d); 13CNMR [(CD3)2SO] δ 23.8, 28.8, 28.9, 36.5, 49.7, 55.6, 73.4, 105.6, 110.5, 113.4, 113.4, 116.1, 116.4, 127.3, 117.3, 127.3, 127.7, 132.2, 133.8, 134.5, 145.8, 151.1, 156.4. MS (APCI) m/z: 348 (M+H)+.
Reaction SMILES: F[C:2](F)(F)OC1C=CC=CC=1CBr.C(O[N:19]1[CH2:24][CH2:23][C:22]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:38])([F:37])[F:36])([CH2:25][OH:26])[CH2:21][C:20]1=C=O)(C)(C)C.Cl.[C:42]([C:44]1[CH:58]=[CH:57][C:47]([CH2:48][N:49]2[C:53]([CH2:54][Cl:55])=[CH:52][N:51]=[C:50]2[CH3:56])=[CH:46][CH:45]=1)#[N:43]>>[ClH:55].[CH3:2][O:26][CH2:25][C:22]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:38])([F:36])[F:37])[CH2:21][CH2:20][N:19]([CH2:54][C:53]2[N:49]([CH2:48][C:47]3[CH:57]=[CH:58][C:44]([C:42]#[N:43])=[CH:45][CH:46]=3)[C:50]([CH3:56])=[N:51][CH:52]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)ON1CCC(CO)(Cc2ccccc2OC(F)(F)F)CC1=C=O
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: Cc1ncc(CCl)n1Cc1ccc(C#N)cc1
Agent: Cl
Product: COCC1(Cc2ccccc2OC(F)(F)F)CCN(Cc2cnc(C)n2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using the protocol described in Example 30, Step A-C using 2-(trifluoromethoxy)benzyl bromide in Step B, and in Example 52, Step B-E substituting N-tert-butoxycarbonyl-4-(3-methylbenzyl)-4-hydroxymethylpiperidine with N-tert-butoxy-carbonyl-4-(2-trifluoromethoxybenzyl)-4-hydroxymethylpiperidine in Step B, and substituting 1-(4-cyanobenzyl)-5-chloromethyl-imidazole hydrochloride salt with 1-(4-cyanobenzyl)-5-chloromethyl-2-methylimidazole hydrochloride salt in Step E.
Reaction SMILES: CS[C:3]1[N:4]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13][N:5]2[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.CN(C)C=O>[Zn].O>[C:18]1([N:15]2[CH2:14][CH2:13][N:5]3[C:3](=[N:8][C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=43)[NH:4][CH2:17][CH2:16]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC1=Nc2ccccc2N2CCN(c3ccccc3)CCN12
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(N2CCNc3nc4ccccc4n3CC2)cc1

Procedure:
A mixture of 2,3,4,5-tetrahydro-7-(methylthio)-3-phenyl-1H-[1,2,5]-triazepino[1,2-a][1,2,4]benzotriazine (0.5000 g), zinc dust (2.0 g), N,N-dimethylformamide (16 ml) and water (4 ml) was stirred magnetically and heated under reflux for 20 hours. The cooled mixture was filtered through Celite and the filter pad washed with N,N-dimethylformamide. The filtrate and washings were evaporated under oil pump vacuum to a syrup. The syrup was dissolved in dichloromethane and applied to the edges of 4 plates of Alox-100 uv254 (20×20 cm×1 mm). The plates were developed twice in dichloromethane and several times in chloroform. The major band was excised and the component eluted by stirring with methanol. The adsorbent was filtered and washed with methanol. The filtrate and washings were evaporated to a syrup. The syrup was extracted with dichloromethane and the solution was evaporated to a syrup which crystallized. The crystals were dissolved in dichloromethane and the solution was treated with charcoal and filtered through Celite. Evaporation gave a syrup which was crystallized from dichloromethane-heptane; wt. 0.127 g (30%), mp=155°-157°.
Reaction SMILES: [S:1]([Cl:5])([CH3:4])(=[O:3])=[O:2].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][C:16]([CH3:34])([C:18]2[N:22]([CH3:23])[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[N:20][N:19]=2)[CH3:17])=[C:11]([CH2:13][NH2:14])[CH:12]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[ClH:5].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][C:16]([CH3:34])([C:18]2[N:22]([CH3:23])[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:33])[F:32])=[N:20][N:19]=2)[CH3:17])=[C:11]([CH:12]=1)[CH2:13][NH:14][S:1]([CH3:4])(=[O:3])=[O:2]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1CN
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1CNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of mesyl chloride (44 μl) in dichloromethane (1 ml) was slowly added to a solution of 1-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]methanamine (200 mg) and triethylamine (98 μl) in dichloromethane (4 ml), followed by stirring at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution to cease the reaction, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=97:3) and dissolved in ethyl acetate, and 4M hydrogen chloride-ethyl acetate was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was washed with diisopropylether to obtain N-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzyl]methanesulfonamide monohydrochloride (148 mg), as an amorphous.
Reaction SMILES: [CH3:1][C:2]([Mg]Br)=[CH:3][CH3:4].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=1.[Cl-:26].[NH4+]>O1CCCC1>[ClH:26].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[C:17]1[N:18]=[CH:19][CH:20]=[C:21]2[C:3]([CH3:4])=[C:2]([CH3:1])[NH:23][C:22]=12
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1cccnc1N1CCc2ccccc2C1
Reactant: CC=C(C)[Mg]Br
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nccc2c1C
Product: Cl
Temperature: -20 °C
Reaction time: 4 h

Procedure:
1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution; 112 ml) was slowly added at −78° C. to a solution of 2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-nitropyridine (4.8 g, 18.8 mmol) prepared in Preparation 20 in anhydrous tetrahydrofuran (150 ml). The reaction mixture was stirred for 4 hours at −20° C. 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 1.3 g of the titled compound as yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13]
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COn1c(C(F)(F)F)nc2ncc(Cl)cc21
Reaction time: 12 h

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (5 grams), 80 milliliters of acetone, 5 milliliters of methyl iodide, and 10 grams of anhydrous potassium carbonate were mixed, heated and refluxed with stirring for 12 hours. The reaction mixture was then filtered, evaporated and eluted off of a silica column with diethyl ether, yielding the desired 1-methoxy-6-chloro-2-(trifluormethyl)-1H-imidazo(4,5-b)pyridine product. It was recrystallized from petroleum ether (boiling at 60°-80°C.). The product so obtained melted at 91°-2°C.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].BrCC[C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16]([NH:18][C:19](=[O:20])[C:14]=12)=[O:17].C(=O)([O-])[O-].[K+].[K+].[C:30](#N)[CH3:31]>>[CH:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:30][CH2:31][N:18]2[C:19](=[O:20])[C:14]3[C:15](=[CH:21][CH:22]=[CH:23][CH:13]=3)[C:16]2=[O:17])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Reactant: CC#N
Reactant: CC(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-isopropylpiperidine (3.3 g, 20.2 mmol), 2-bromoethylphthalimide (5.4 g, 21.3 mmol), potassium carbonate (5.9 g. 45.4 mmol) and acetonitrile (100 ml) and was heated under reflux for 2.5 hours then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue partioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer extracted with further ethyl acetate (100 ml). The combined organic extracts were dried (Na2SO4) and the solvent removed by evaporation under reduced pressure. The resulting oil was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane changing to dichloromethane: diethyl ether (50:50, by volume) changing to diethyl ether to afford the title compound (3.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH:14][N:15]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(O[C:39]([CH:41]1[CH2:46][NH:45][CH2:44][CH2:43][N:42]1[S:47]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][C:58]#[C:59][CH3:60])=[CH:52][CH:51]=1)(=[O:49])=[O:48])=[O:40])C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:45]1[CH2:44][CH2:43][N:42]([S:47]([C:50]2[CH:51]=[CH:52][C:53]([O:56][CH2:57][C:58]#[C:59][CH3:60])=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH:41]([C:39](=[O:40])[NH:15][OH:14])[CH2:46]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of 0.14 g (0.8 mmol) of N-(tert-butoxycarbonyl)glycine dissolved in 3 mL of DMF was added 0.13 g (0.963 mmol) of 1-hydroxybenzotriazole hydrate (HOBT) followed by 0.203 g (1.06 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The resulting mixture was stirred at room temperature for 1 h and 0.191 g (0.522 mmol) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester in 3 mL of DMF was added dropwise. After stirring the reaction for 14 h the solution was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1) to provide 0.26 g (95%) of the sulfonamide, ethyl 4-{2-[(tert-butoxycarbonyl)amino]acetyl}-1-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-piperazinecarboxylate, as a clear oil. Electrospray Mass Spec: 524.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6]C(=O)C)([O-:3])=[O:2].Cl>CO>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: Nc1ccccc1[N+](=O)[O-]
Yield: 108.7 %

Procedure:
A mixture of 1.32 g of an o-nitroacetoanilide compound having the formula (XXV), ##STR23## 5 ml of conc. hydrochloric acid and 50 ml of methanol was heated under reflux for 80 minutes. The reaction solution was concentrated, poured into ice water and alkalifled with potassium carbonate. After extraction with ethyl acetate, the organic layer was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 1.1 g of an o-nitroaniline compound [compound (306)] having the formula (XXIV).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[I-].[Na+].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][C:18]1[CH:27]=[CH:26][C:21]2[B:22]([OH:25])[O:23][CH2:24][C:20]=2[CH:19]=1)[C:12]#[N:13].[H-].[Na+]>O.CN(C)C=O>[CH:5]1([CH2:4][O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:27]=[CH:26][C:21]3[B:22]([OH:25])[O:23][CH2:24][C:20]=3[CH:19]=2)[C:12]#[N:13])[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(O)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
A solution of bromomethyl cyclopropane (0.544 mL, 5.61 mmol), sodium iodide (4.20 g, 28.05 mmol), and N,N-dimethylformamide (30 mL) under a nitrogen balloon were stirred at 70° C. for 3 hours. The reaction was cooled to room temperature and 3-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.500 g, 1.87 mmol) and more N,N-dimethylformamide (30 mL) was added. The reaction was cooled to 0° C. in an ice water bath and sodium hydride (0.224 g, 5.61 mmol) was added. The reaction was stirred under nitrogen balloon at 0° C. for 5 minutes and then at room temperature overnight. Water was added to quench excess sodium hydride and the solution was neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 3-(cyclopropylmethoxy)-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.225 g, 37% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.15 (d, J=4.5 Hz, 2H), 0.43 (d, J=7.6 Hz, 2H), 1.06 (septet, J=6.7 Hz, 1H), 3.90, (d, J=6.9 Hz, 1H), 4.91 (s, 2H), 6.95 (m, 2H), 7.13 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 9.12 (s, 1H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:32])=[C:22]([CH:31]=1)[C:23]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:46]1[C:48]2([CH2:53][CH2:52][CH:51]([CH2:54][OH:55])[CH2:50][CH2:49]2)[CH2:47]1>>[Cl:17][C:18]1[C:19]([O:55][CH2:54][CH:51]2[CH2:52][CH2:53][C:48]3([CH2:46][CH2:47]3)[CH2:49][CH2:50]2)=[CH:20][C:21]([F:32])=[C:22]([CH:31]=1)[C:23]([NH:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[O:24]
Reactant: CCS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1CCC2(CC1)CC2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CCS(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(ethylsulfonyl)-2,4-difluorobenzamide and to replace adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the title compound was obtained as a colorless solid (0.378 g, 46%): 1H NMR (300 MHz, CDCl3) δ8.59-8.47 (m, 1H), 8.13-8.05 (m, 1H), 6.75-6.66 (m, 1H), 3.97-3.86 (m, 2H), 3.66-3.55 (m, 2H), 2.02-1.72 (m, 5H), 1.48-1.40 (m, 3H), 1.35-1.22 (m, 2H), 1.01-0.89 (m, 2H), 0.37-0.15 (m, 4H); MS (ES+) m/z 404.1, 406.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:24]1([C:30]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[C:24]1([C:30]2([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:34][CH2:35]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=Cc1cccnc1)NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.4 g (16.0 mmol) 3-(3-pyridyl)-acrylic acid and 2.9 g (17.6 mmol) CDI are heated under reflux in 150 ml absolute THF under moisture exclusion. After an hour, this is cooled to RT and 6.0 g (19.2 mmol) 4-(4,4-diphenyl-piperidin-1-yl)-butylamine, dissolved in 25 ml absolute THF, are added dropwise. After addition, this is stirred for a further three hours at RT and left to stand overnight. The mixture is poured into 200 ml water and extracted three times each with 100 ml acetic acid ethyl ester by shaking. The combined organic phases are washed with saturated NaCl-solution, dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically pre-purified over silica gel with CHCl3/CH3OH (95/5). After removal of the solvent, crystallization occurs from 130 ml isopropanol: Colorless crystals with MP. 207-208° C.: Yield 2.0 g (28%).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]2[C:16]([C:17]=1O)=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O.C(C1C(C(F)(F)F)=NC2C(C=1Cl)=CC=CC=2)C1C=CC=CC=1>>[CH2:1]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]2[C:16]([C:17]=1[Cl:26])=[CH:15][C:14]([I:19])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(Cc2ccccc2)c(C(F)(F)F)nc2ccc(I)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: FC(F)(F)c1nc2ccccc2c(Cl)c1Cc1ccccc1
Product: FC(F)(F)c1nc2ccc(I)cc2c(Cl)c1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-benzyl-6-iodo-2-(trifluoromethyl)quinolin-4-ol (6.10 g, 14.2 mmol, Intermediate 71: step a) in phosphoryl trichloride (18 mL, 194 mmol) was heated at 110° C. for 3 hours, then concentrated in vacuo. After cooling down to room temperature, ice-water and DCM were added to the residue, and the mixture was basified at 4° C. by the addition of 50% aqueous NaOH and concentrated NH4OH to pH 9. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (silica gel, 2-6% EtOAc in heptanes), affording a mixture of the title compound and 3-benzyl-4-chloro-2-(trifluoromethyl)quinoline in ˜2:1 ratio.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH2:21].CC1C=CC=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1CCC(=Nc2c(Cl)cccc2Cl)CC1

Procedure:
A mixture of 171 parts of ethyl 4-oxo-1-piperidinecarboxylate, 162 parts of 2,6-dichlorobenzenamine, 800 parts of dimethylbenzene and 1 part of 4-methylbenzenesulfonic acid is stirred and refluxed with water-separator. The reaction mixture is evaporated, yielding 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate as a residue.
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: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(CC(OC)OC)n(C)c(=O)c1OC(=O)c1ccccc1
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: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(Br)c1
Product: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with 3-Bromo-phenylamine to produce N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[N:10]=O.[H][H]>>[NH2:10][C:3]1[CH:4]=[N:5][N:6]([CH2:7][CH2:8][OH:9])[C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1c(N=O)cnn1CCO
Product: Nc1cnn(CCO)c1N

Procedure:
contacting the alkanol solution of (IV) from step (vii) with hydrogen in the presence of an insoluble hydrogenation catalyst under hydrogenation conditions of temperature and pressure to produce a product solution of 4,5-diamino-1-(2′-hydroxyethyl)pyrazole in an alkanol; and