Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[CH:34][N:33]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:35]6[CH:36]=[CH:37][N:32]=[N:33][CH:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: NC1(c2ccnnc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.075 g, 0.186 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.094 g, 0.93 mmol, 5.0 eq) and BOP reagent (0.123 g, 0.278 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. the The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent, and further purified the product by prep HPLC. Yield: 0.050 g (52.00%). 1H NMR (400 MHz, CD3OD): δ 9.44 (s, 1 H), 9.15 (d, 1H), 9.11 (s, 1H), 8.02-7.94 (m, 2H), 7.86 (dd, J=2.3, 4.3 Hz, 2H), 7.73 (br s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H), 7.29 (t, J=8.9 Hz, 2H), 2.96 (s, 3H), 2.37 (s, 3H), 1.71 (s, 4H). 19F NMR (376.51 MHz, CD3OD): δ −78.16 (TFA), −113.29 LCMS: (ES+) m/z=521.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2OS(C(F)(F)F)(=O)=O>N1C(C)=CC=CC=1C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2[O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(OS(=O)(=O)C(F)(F)F)c2cc1OC
Reactant: O=C(Nc1ccc(O)cc1)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: Cc1cccc(C)n1
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 165 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) in anhydrous 2,6-lutidine (50 mL) was added trifluoromethanesulfonic acid 6,7-dimethoxy-quinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixture was heated at 165° C. in a sealed pressure tube with stirring for 18 h. The reaction mixture was concentrated on high vacuum to completely remove lutidine. The resulting solid material was dissolved in DCM (250 mL), and washed several times with 1 N sodium hydroxide to remove the excess phenol. The crude mixture was loaded on a silica gel flash column and eluted with 75% EtOAc-hexanes, affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (3.2 g, 44%). 1H NMR (400 MHz, d6-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15(m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:31])([F:29])[F:30])[C:9]=3[CH:17]=2)=[CH:19][CH:20]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=536.96 (M+H+); retention time=0.91 minutes.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])[C:16]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH:39]([F:41])[F:40])=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl>C(Cl)Cl.CO>[ClH:37].[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([O:38][CH:39]([F:40])[F:41])=[C:31]([C:16]2[C:17]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:18][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]=2)[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cn(C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid tert-butyl ester (600 mg, 0.97 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) was added. The mixture was allowed to stir at room temperature for 30 minutes. The solvent was evaporated and the residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a glass which was purified by HPLC (Method 3). Appropriate fractions were combined and evaporated to afford an off-white solid. The solid was dissolved in MeOH and 1.25M methanolic HCl (1 mL) was added. The solvent was evaporated, azeotroped three times with methanol and triturated with ethyl acetate to afford the title compound as an off-white solid (144 mg, 28%). LCMS (Method 5) [M+H]+=488.0, RT=2.93 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.0 Hz), 8.98 (d, 1H, J=9.9 Hz), 8.69 (dd, 1H, J=1.7, 4.3 Hz), 8.67 (s, 1H), 8.38 (s, 1H), 7.65-7.62 (m, 2H), 7.30 (dd, 1H, J=4.2, 7.2 Hz), 7.26 (t, 1H, J=73.6 Hz), 4.66-4.57 (m, 1H), 3.47-3.42 (m, 2H), 3.17-3.03 (m, 2H), 2.32-2.18 (m, 4H).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:41]1[CH:42]=[C:43]([S:47][C:48]2[C:53]([O:54][CH2:55][CH2:56][CH2:57][C:58]3[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=3)=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:44]=[CH:45][CH:46]=1>C1COCC1>[CH:1]1([O:6][C:45]2[CH:44]=[C:43]([S:47][C:48]3[C:53]([O:54][CH2:55][CH2:56][CH2:57][C:58]4[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=4)=[CH:52][CH:51]=[CH:50][N:49]=3)[CH:42]=[CH:41][CH:46]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Oc1cccc(Sc2ncccc2OCCCc2ccncc2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OC2CCCC2)cc(Sc2ncccc2OCCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
Cyclopentanol (0.11 g, 1.3 mmol) and triphenylphosphine (0.47 g, 1.8 mmol) are dissolved in THF (15 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (0.26 g, 1.3 mmol) and 2-(3-hydroxyphenylthio)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.30 g, 0.89 mmol) obtained in Example 13. The mixture is further stirred at room temperature for 30 minutes, and the reaction solution is concentrated under reduced pressure. The residue is extracted with a 10% aqueous hydrochloric acid solution (30 ml), and the aqueous layer is washed with chloroform (30 ml×2), and the pH value thereof is adjusted to pH 12 with potassium carbonate. The mixture is extracted with ethyl acetate (50 ml×2), and the organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give the title compound (0.26 g) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:13]1[N:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)[CH2:3][N:4]1[CH:9]2[CH2:10][NH:11][CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@@H:32]1[CH2:34][O:33]1>>[OH:1][CH:2]([C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=1)[CH2:3][N:4]1[CH:9]2[CH2:10][N:11]([CH2:34][C@H:32]([OH:33])[C:23]3[C:22]([CH3:21])=[C:30]4[C:26](=[CH:25][CH:24]=3)[C:27](=[O:31])[O:28][CH2:29]4)[CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: N#Cc1ccc(C(O)CN2C3CNCC2COC3)nc1
Product: Cc1c([C@@H](O)CN2CC3COCC(C2)N3CC(O)c2ccc(C#N)cn2)ccc2c1COC2=O

Procedure:
6-(1-Hydroxy-2-(7-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)ethyl)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 18 starting from 6-[1-hydroxy-2-(3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)ethyl]pyridine-3-carbonitrile (INTERMEDIATE 18) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one [INTERMEDIATE 2].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:30])[C@@H:19]([N:21](C)[C:22](=O)OC(C)(C)C)[CH3:20])=[CH:4][N:3]=1.[ClH:31]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:30])[C@@H:19]([NH:21][CH3:22])[CH3:20])=[CH:4][N:3]=1.[ClH:31]
Reactant: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)NC
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl (1-((5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (L1, 910 mg) in 1,4-dioxane (10 mL), a 4.0 mol/L solution of hydrochloric acid in dioxane (7 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated under reduced pressure to obtain (S)—N-(5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)-2-(methylamino)propanamide (L3) hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]#[N:21])([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>>[ClH:22].[C:20]([C:11]1([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2cccnc2)CCNCC1

Procedure:
Prepare by the method of example 30.3 using 1-tert-butoxycarbonyl-4-cyano-4-(pyridin-3-yl)-piperidine (3 mmol) and HCl in dioxane (40 mmol, 4N). Concentrate the solvent in vacuo and dry under high vacuum to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([O:17][CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:19][C:20]1[C:21](B(O)O)=[CH:22][C:23]2[C:24]([CH3:33])([CH3:32])[CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[C:9]=1[C:21]1[C:20]([CH3:19])=[CH:29][C:28]2[C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25][C:24]([CH3:33])([CH3:32])[C:23]=2[CH:22]=1
Reactant: COc1ccc(C=O)c(F)c1S(=O)(=O)C(F)(F)F
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C=O)c(F)c1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A mixture of 2-fluoro-4-methoxy-3-trifluoromethanesulfonyl benzaldehyde (1.21 g, 4.01 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (1.08 g, 4.41 mmol) and potassium carbonate (2.22 g, 16.04 mmol) in 1,2-dimethoxyethane (30 mL) and water (2 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol) was added and the mixture heated at reflux under argon for 16 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (Biotage, eluent: ethyl acetate/hexane, 0.5:8.5) to give 0.87 g of 4-methoxy-2-fluoro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzaldehyde (62%). 1H NMR (500 MHz; CDCl3): δ1.26 (s, 6H), 1.32 (s, 6H), 1.69 (s, 4H), 2.07 (s, 3H), 3.85 (s, 3H), 7.07 (d, J=8.8 Hz, 1H), 7.07 (s, 1H), 7.19 (s, 1H), 7.90 (t, J=8.8 Hz, 1H), 10.25 (s, 1H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33]2[CH:38]=[N:37][N:36]=[C:35]([NH:39][C:40]3[CH:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])[N:34]2[C:51]=1[CH3:52])=[O:30])[CH3:27]>CN(C=O)C.O>[CH2:26]([O:28][C:29]([C:31]1[CH:32]=[C:33]2[CH:38]=[N:37][N:36]=[C:35]([NH:39][C:40]3[CH:45]=[C:44]([C:46](=[O:47])[NH:25][CH:22]4[CH2:24][CH2:23]4)[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])[N:34]2[C:51]=1[CH3:52])=[O:30])[CH3:27]
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc2cnnc(Nc3cc(C(=O)O)ccc3OC)n2c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cnnc(Nc3cc(C(=O)NC4CC4)ccc3OC)n2c1C
Reaction time: 8 h

Procedure:
To a suspension of HOBt (30 mg, 0.20 mmol), EDCI (30 mg, 0.16 mmol), cyclopropyl amine (20 uL, 0.29 mmol) in DMF (0.5 mL) at RT was added 4-(5-carboxy-2-methoxy-phenylamino)-6-methyl-pyrrolo[1,2-d][1,2,4]triazine-7-carboxylic acid ethyl ester (13 mg, 0.035 mmol). The reaction was stirred overnight. Water (1 mL) was added and the precipitate collected. The product was purified by flash chromatography on silica gel (1-3% MeOH in CH2Cl2) giving the title compound, 7 mg, as a yellowish solid. HPLC (condition A) tR 4.37 min. MS m/z 410 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCCO)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: NC1CCCCC1
Solvent: CCOCCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCCCC1

Procedure:
A mixture consisting of 19.4 g of 2,4-dichloro-1-nitrobenzene, 40 g of cyclohexylamine and 100 ml of 2-ethoxyethanol is maintained at reflux for 12 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[OH:17])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>>[O:22]1[CH2:21][CH:20]1[CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: ClCC1CO1
Reactant: Oc1ccccc1Cc1cccc2[nH]ccc12
Product: c1ccc(OCC2CO2)c(Cc2cccc3[nH]ccc23)c1

Procedure:
Using the procedure of Step A of Example 2, 10.0 g of the product of Step A and 3 times 17.56 m1 of epichlorhydrin were reacted to obtain 12.5 g of the desired product melting at 78° C. which was used as is for the following step.
Reaction SMILES: [CH2:1]([Br:4])[CH:2]=[CH2:3].Br[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1>C1COCC1.C(OCC)C>[CH2:8]([C:7]1[CH:6]=[CH:11][C:1]([Br:4])=[CH:2][CH:3]=1)[CH:9]=[CH2:10]
Reactant: C=CCBr
Reactant: Brc1ccc(Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
At 5° C., a solution of allylbromide (5.64 g, 46.6 mmol) in THF (40 mL) is slowly added to the Grignard reagent freshly prepared from 1,4-dibromobenzene (10.0 g, 42.4 mmol) and Mg-turnings (1.13 g, 46.6 mmol) in THF. The reaction mixture becomes slightly warm and a fine precipitate forms. Upon completion of the addition, the suspension is stirred at rt for 1 h before it is diluted with diethyl ether and washed with two portions of 1 N aq. HCl and one portion of water. The wash solutions are extracted twice with diethyl ether. The organic extracts are combined, dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 1-allyl-4-bromo-benzene (5.50 g) as a colourless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20](Cl)=[O:21])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].O>CCCCC>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:20](=[O:21])[C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][C:8]=2[F:12])[CH2:23][CH2:24]1)(=[O:15])[CH3:14]
Reactant: Fc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCCCC
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a slurry of 6.6 g of aluminum chloride and 20 ml of 1,3-difluorobenzene was added, with stirring at ambient temperature, 5.0 g of N-acetylisonipecotyl chloride. The reaction mixture was heated under reflux for 11/2 hrs and then poured onto 100 ml of ice and water. The mixture was extracted with chloroform. The chloroform fractions were combined, washed with water and dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate gave an oil. Trituration of the oil with pentane gave 4.65 g (65.9%) of product, mp, 100°-102°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[S:9][C:10]=1[CH:11]([OH:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][N:13]=1.CO>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[S:9][C:10]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][N:13]=1)=[O:20]
Reactant: COc1ccc(C(O)c2sc(NC(=O)OC(C)(C)C)nc2-c2ccco2)nc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(=O)c2sc(NC(=O)OC(C)(C)C)nc2-c2ccco2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Compound 296 (697 mg, 1.73 mmol) was dissolved in dichloromethane (10 mL), and DMP (848 mg, 2.00 mmol) was added thereto, followed by stirring at room temperature for 1 hour. Methanol (10 mL) was added to the reaction mixture, followed by stirring for 10 minutes, and the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 297 (632 mg, 91%).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][O:5][C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl.[C:19]([N:27]1[CH2:32][CH2:31][CH2:30][C:29]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([Cl:56])[CH:50]=2)([CH2:33][CH2:34][CH2:35]N2CCC(C(N3CCCC3)=O)CC2)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[OH2:2].[ClH:55].[C:19]([N:27]1[CH2:32][CH2:31][CH2:30][C:29]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([Cl:56])[CH:50]=2)([CH2:33][CH2:34][CH2:35][N:9]2[CH2:8][CH2:7][C:6]([O:5][CH2:4][CH2:3][OH:2])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10]2)[CH2:28]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Reactant: OCCOC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)N1CCCC(CCCN2CCC(OCCO)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
A mixture of 1 g of 4-(2-hydroxyethoxy)-4-phenylpiperidine hydrochloride, 1.7 g of the compound obtained in step B of EXAMPLE 1 and 0.65 g of K2CO3 in 15 ml of DMF is heated at 60° C. for 2 hours and the reaction mixture is then stirred overnight at RT. It is poured into water and extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product, m.p.=120-123° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH:11]2[CH2:16]CC[CH2:13][CH2:12]2)[C:5](=[O:10])[N:6](C)[C:7]=1[CH3:8].C1CCC(N2C(=O)NC3CCCC=3C2=O)CC1.BrC1C(=O)N(C(C)C)C(=O)NC=1C.C(N1C(=O)C(Cl)=C(C)NC1=O)(C)(C)C>>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH:11]([CH2:12][CH3:13])[CH3:16])[C:5](=[O:10])[NH:6][C:7]=1[CH3:8]
Reactant: Cc1c(Br)c(=O)n(C2CCCCC2)c(=O)n1C
Agent: Cc1[nH]c(=O)n(C(C)(C)C)c(=O)c1Cl
Agent: Cc1[nH]c(=O)n(C(C)C)c(=O)c1Br
Agent: O=c1[nH]c2c(c(=O)n1C1CCCCC1)CCC2
Product: CCC(C)n1c(=O)[nH]c(C)c(Br)c1=O

Procedure:
5-bromo-3-cyclohexyl-1,6-dimethyluracil; 3-cyclohexyl-5,6-trimethyleneuracil; 5-bromo-3-isopropyl-6-methyluracil; 3-tert-butyl-5-chloro-6-methyluracil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:49])([S:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21]>C(Cl)Cl>[F:49][C:13]([F:12])([S:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:9])[C:14]([F:34])([F:35])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Sc1ccccc1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccccc1-c1ccccc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 99.7 %

Procedure:
Under ice cooling, 3.57g (14.5 mmol) of m-chloroperbenzoic acid was added little by little to a solution of 8.76 g (14.5 mmol) of 2-(perfluorooctylthio)biphenyl in 50 ml of methylene chloride with stirring. The mixture was stirred overnight at room temperature. The precipitate in the reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane as an eluent to give 8.97 g (100%) of 2-(perfluorooctylsulfinyl)biphenyl as while crystals. The properties of the product were as shown below.