Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:33][CH2:34][CH2:35][NH:36][S:37]([C:40]2[C:41]3[CH:42]=[CH:43][N:44]=[CH:45][C:46]=3[CH:47]=[C:48](Br)[CH:49]=2)(=[O:39])=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.O.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>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH:33][CH2:34][CH2:35][NH:36][S:37]([C:40]2[C:41]3[CH:42]=[CH:43][N:44]=[CH:45][C:46]=3[CH:47]=[C:48]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:49]=2)(=[O:39])=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(C(NCCNS(=O)(=O)c2cc(Br)cc3cnccc23)c2ccc(OC)cc2)cc1
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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(NCCNS(=O)(=O)c2cc(-c3ccccc3)cc3cnccc23)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
Add tetrakis(triphenylphosphine)palladium (0.816 g, 0.706 mmol) to a degassed mixture of phenylboronic acid (0.1.72 g, 14.1 mmol), cesium carbonate (9.20 g, 3.5928.2 mmol), and 7-bromo-isoquinoline-5-sulfonic acid (2-{[bis-(4-methoxy-phenyl)-methyl]-amino}-ethyl)-amide (3.93 g, 7.06 mmol) in toluene (75.0 mL) and water (100.0 mL). Warm to 100° C. for 2 hours, and cool to room temperature. Dilute with toluene (100 mL), separate layers, wash sequentially with water and brine, then dry with anhydrous MgSO4, filter and evaporate. Apply the residue to a cation exchange cartridge, wash the cartridge with methanol, and then elute with 2M methanolic ammonia. Evaporation affords the title compound (2.25 g, 58%). 1H NMR (DMSO): δ9.56 (s, 1H), 8.78(d, J=1.8 Hz, 1H), 8.70(d, J=6.2 Hz, 1H), 8.75(d, J=2.0 Hz, 1H), 8.45 (d, J=6.2 Hz, 1H), 7.91(d of t J1=1.3 Hz, J=7.0 Hz, 2H), 7.62(t of t, J1=1.7 Hz, J2=7.4 Hz, 2H), 7.53 (t of t, J1=1.3 Hz, J2=7.4 Hz, 1H), 7.04 (d of t, J1=1.7 Hz, J2=8.8 Hz, 4H), 6.72 (d of t, J1=1.7 Hz, J2=8.8 Hz, 4H), 4.44 (s, 1H), 3.68(s, 6H), 3.01 (t, J=6.1 Hz, 2H), 2.35 (t, J=5.9 Hz, 2H). LCMS: m/z 554 (M+H)+, 552(M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])[CH3:13]>N1C=CC=CC=1>[CH2:12]([O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:18])[CH3:13]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: Cc1cccc(N)c1C(N)=O
Solvent: c1ccncc1
Product: CCOc1ccccc1C(=O)Nc1cccc(C)c1C(N)=O

Procedure:
A mixture of 2-amino-6-methylbenzamide (UK Patent Application No 1,276,359; 5.49 g, 0.0365 mol), 2-ethoxybenzoyl chloride (7.67 g, 0.0415 mol) and pyridine (100 ml) was stirred at room temperature for 20 hours. The solvent was then removed by evaporation under vacuum and the residue dissolved in dichioromethane (200 ml). The solution was washed with saturated aqueous sodium carbonate solution (200 ml) and the aqueous phase back-extracted with further dichioromethane (2×100 ml). The organic solutions were combined, washed successively with 2N hydrochloric acid (3×100 ml) and brine (100 ml), then dried (Na2SO4) and evaporated under vacuum to give the title compound, which recrystallized from ethyl acetate as a colourless solid (6.86g, 63%), m.p. 166-168° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].CN(C)C=O.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])=[C:4]([Cl:11])[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Reaction time: 0.25 h

Procedure:
5 g of 2,6-dichloropurine was added to the mixture of 1.54 g of sodium hydride and 100 mL of N,N-dimethylformamide in an ice bath, and stirred at the same temperature for 15 minutes. 6.81 mL of 2-(trimethylsilyl)ethoxymethyl chloride was added to the reaction mixture, and was stirred at the same temperature for 5 hours. The reaction mixture was added with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in the subsequent order, and then dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography, to obtain 6.18 g of 2,6-dichloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-1] as a light brown oily product.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:4][N:3]1[S:5]([C:8]1[CH:27]=[CH:26][C:11]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]([CH3:24])[C:22]([CH3:25])=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][N:29]([CH2:4][C:2]([NH:3][S:5]([C:8]2[CH:27]=[CH:26][C:11]([NH:12][C:13]3[N:18]=[C:17]([C:19]4[N:23]([CH3:24])[C:22]([CH3:25])=[N:21][CH:20]=4)[CH:16]=[CH:15][N:14]=3)=[CH:10][CH:9]=2)(=[O:7])=[O:6])([CH3:1])[CH3:28])[CH2:30][CH2:31]1
Reactant: C1COCCN1
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)N4CC4(C)C)cc3)n2)n1C
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC(C)(C)CN4CCOCC4)cc3)n2)n1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
2-[4-(2,2-Dimethylaziridin-1-ylsulphonyl)anilino]-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Example 47; 200 mg, 0.502 mmol) was dissolved on warming in morpholine (4.7 ml, excess) and stirred at room temperature for 3 days. The excess morpholine was removed in vacuo and the residue dissolved in EtOAc (40 ml) and washed with water (3×40 ml), dried the solvent evaporated in vacuo. The crude product was triturated with ether filtered washed with ether and air-dried to give the title compound (200 mg, 82%) as a white solid. NMR 1.03 (s, 6H), 2.27 (s, 2H), 2.38 (s, 3H), 2.47 (m, 4H), 3.52 (m, 4H), 3.95 (s, 3H), 7.05 (s, 1H), 7.2 (d, 1H), 7.63 (s, 1H), 7.72 (d, 2H), 7.88 (d, 2H), 8.43 (d, 1H), 9.86 (s, 1H); m/z 486.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:8]2[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: Cc1onc(C(=O)c2ccc(Cl)cc2)c1N
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1onc(C(=O)c2ccc(Cl)cc2)c1NC(=O)CBr
Reaction time: 1 h

Procedure:
Bromoacetyl bromide (39 g, 194 mmoles) was added slowly to a mixture of (4-amino-5-methylisoxazol-3-yl)-4-chlorophenylmethanone of Example Vb (22.9 g, 97 mmoles) in dichloromethane (200 ml) with 2N sodium carbonate (200 ml) and saturated sodium bicarbonate (300 ml) at 5° C. After stirring for 1 hour, the mixture was diluted with dichloromethane (400 ml) and water (400 ml). The organics were washed with water, saturated sodium chloride, dried (sodium sulfate) and evaporated to give 34 g of a solid. The residue (3.0 g) was flash chromatographed (25% ethyl acetate:hexane) to yield 2.4 g (80%) of a solid, melting point 107°-110° C.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6](F)[NH:5][C:4]=2[CH:3]=1.Cl.[CH3:15][C:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.C>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:22][C:16]3([CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:5][C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Reactant: CC1(N)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CCCCC1
Temperature: 50 °C
Reaction time: 20 h
Yield: 7.9 %

Procedure:
A mixture of 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 2.08 mmol), 1-methylcyclohexylamine hydrochloride (373 mg, 2.49 mmol) and triethylamine (0.58 ml, 4.16 mmol) in ethanol (3 ml) was stirred for 20 h at 50° C. and then for 22 h at 100° C. in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was triturated with water followed by adjustment to pH <2 with 4M hydrochloric acid. The crude product was isolated by filtration and dissolved in 1 N sodium hydroxide followed by treatment with decolourising charcoal. After filtration, the solution was acidified to pH <2 with 4M hydrochloric acid and the precipitate was filtered off and purified by chromatography (dichloromethane/methanol (19:1)). Recrystallisation from ethanol afforded 55 mg (8%) of the pure title compound; mp 218-219° C.; 1H-NMR (DMSO-d6): δ1.18-1.54 (m, 11H), 1.97-2.12 (m, 2H), 6.55 (br s, 1H), 7.12 (s, 1H), 10.60 (br s, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH2:13][OH:14])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[CH2:32](Cl)Cl.CCCCCC>>[CH:1]([C:4]1[C:5]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH:13]([OH:14])[CH3:32])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(COCc2c(C(C)C)cc(C(C)C)c(CO)c2-c2ccc(F)cc2)cc1
Reactant: ClCCl
Solvent: CCCCCC
Product: Cc1ccc(COCc2c(C(C)C)cc(C(C)C)c(C(C)O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared by subjecting the intermediate obtained in Step A to the procedures described in Example 244, Steps I-K. mp 84-86° C.; Rf=0.1 (80% CH2Cl2/hexane); 1H NMR (300 MHz, CDCl3): δ 7.39 (s, 1H), 7.27 (m, 2H), 7.09 (m, 6H), 4.76 (dq, J=1.5, 7 Hz, 1H), 4.22 (s, 2H), 4.03 (s, 2H), 3.89 (septet, J=6.6 Hz, 1H), 3.26 (septet, J=6.6 Hz, 1H), 2.35 (s, 3H), 1.66 (s, 1H), 1.40 (d, J=6.6 Hz, 3H), 1.26 (m, 12H); FAB-MS calcd for (C29H35FO2) 434, found 417 (M—OH); Anal. Calcd for C29H35FO2: C, 80.15; H, 8.12; F, 4.37. Found: C, 80.10; H, 8.30; F, 4.24; [α]22=+30.7.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CC#N
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A stirred solution of 7.1 grams (0.083 mole) of piperazine (commercially available) and 5.0 grams (0.028 mole) of 2-chloro-5-(trifluoromethyl)pyridine (commercially available) in 75 mL of acetonitrile was heated at reflux during a two-hour period. After this time the reaction mixture was allowed to cool to ambient temperature, and then it was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in 75 mL of methylene chloride and washed with two 50 mL portions of water. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 100% methylene chloride, then 5% methanol in methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.5 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:16][NH:15][C@H:14]([CH2:17][NH:18][CH2:19][C:20]([O:22]C)=O)[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C>CO>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:16][N:15]4[C:20](=[O:22])[CH2:19][NH:18][CH2:17][C@@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:3][CH2:4]1
Reactant: COC(=O)CNC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1CNC[C@@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reaction time: 18 h

Procedure:
To a solution of the product from Example 174F (0.958 g, 2.79 mmol) in methanol (10 mL) was added triethylamine (2.337 mL, 16.77 mmol). The mixture was heated to reflux and stirred for 18 hours. The cooled mixture was concentrated in vacuo, and the crude product was purified by flash chromatography on a 12 g silica gel column, eluting with 2.5% methanol (containing 2 N ammonia) in dichloromethane for 3 minutes and then a gradient to 10% methanol (2 N ammonia) in dichloromethane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.15 (dd, J=9.2, 1.4 Hz, 2H), 5.47 (t, J=5.0 Hz, 1H), 4.05-3.88 (m, 1H), 3.87-3.69 (m, 1H), 3.26-3.01 (m, 4H), 2.67 (s, 1H), 2.34 (dd, J=12.7, 10.2 Hz, 1H), 2.24-2.03 (m, 2H), 1.73 (ddd, J=13.3, 11.9, 4.8 Hz, 1H), 1.03-0.88 (m, 2H), 0.82 (ddd, J=6.8, 4.7, 2.4 Hz, 2H); MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S.C(OCC)(=O)C>[Cl:12][CH2:13][CH2:14][C:15]([C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[C:8]=1[CH3:9])=[O:16]
Reactant: O=C(Cl)CCCl
Reactant: Cc1csc2ccc(F)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: S=C=S
Product: Cc1c(C(=O)CCCl)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-fluoro-3-methylbenzo[b]thiophene (9.97 g) and 3-chloropropionyl chloride (7.45 ml) in carbon disulfide (100 ml) was added AlCl3 (16.00 g) at 0° C. The mixture was stirred at room temperature for 2 hours, poured onto crushed ice, and diluted with ethyl acetate. The extract was washed with 1N HCl, water and brine, dried over MgSO4, and concentrated. The residue was washed with ethanol and hexane to give the titled compound as colorless crystals (12.75 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[N:12]([C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=3)[N:13]=[C:14]([CH2:25][OH:26])[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[N:8][CH:9]=1.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN(C=O)C>[N:32]1([C:38]([O:26][CH2:25][C:14]2[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([C:6]3[CH:7]=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=3)[C:11]3[N:12]([C:27]([CH2:30][CH3:31])=[CH:28][CH:29]=3)[N:13]=2)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)CCCCc1c(CO)nn2c(CC)ccc2c1-c1cncc(Br)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(COC(=O)N2CCOCC2)nn2c(CC)ccc2c1-c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a suspension of 60% NaH (695 mg) in DMF (3 mL) was added ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate 5 (200 mg) under ice-water cooling and the mixture was stirred at 0° C. for 0.5 hour. To this was added 4-morpholinecarbonyl chloride (659 mg) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (20:1-1:1) to give [4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl 4-morpholinecarboxylate as yellow oil (75 mg).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2>C(OCC)C>[CH2:1]([C:11]1([OH:15])[C:12]2[C:8](=[CH:7][C:6]([F:5])=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)[CH3:2]
Reactant: O=C1CCc2cc(F)ccc21
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC1(O)CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
292 ml (876 mmol) of a 3N solution of ethylmagnesium bromide in diethyl ether were added to 5.00 g (33.3 mmol) of 5-fluoroindan-1-one in 150 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to a saturated, ice-cold aqueous ammonium chloride solution, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 5.70 g (94% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4]([NH2:15])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[CH2:16]([C:18]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21])[CH3:17]>>[CH3:1][N:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4]([NH:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[CH:26][C:18]=2[CH2:16][CH3:17])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CCc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CC1CN(C)CC(N)(c2ccccc2)C1
Product: CCc1cc(C(F)(F)F)ccc1C(=O)NC1(c2ccccc2)CC(C)CN(C)C1

Procedure:
In analogy to the procedure described for the synthesis of example 1, the title compound was prepared from (3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidin-3-ylamine (Example A.20) and 2-Ethyl-4-trifluoromethyl-benzoic acid (CAS: 854531-63-8). MS (m/e): 405.4 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[CH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-:17].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]2([O:17][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CO2

Procedure:
In analogy to example 11 step 1 with 4-methylene-azepane-1-carboxylic acid tert-butyl ester (MW: 211.307, 1.73 mmol), 1.16 g sodium bicarbonate (MW: 84.01 13.8 mmol) and 1.36 g of 80% m-chloroperbenzoic acid (MW172.57, 6.05 mmol) in 5 ml of dichloromethane. Yield: 250 mg, 63%. MS: 228.8 (M+H)+, 127.8 (M-(CH3)3COCO) method ESI+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].Cl.Cl[CH2:21][CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:21][CH2:22][CH2:23][NH2:24])[C:7]=1[CH2:13][CH3:14]
Reactant: NCCCCl
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CCc1nn(CCCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 84 %

Procedure:
The pyrazole of Example 11 (200 mg, 0.71 mmol) was mixed with 3-chloropropylamine hydrochloride (138 mg, 1.06 mmol). The resulting mixture was heated neat at 150° C., for 24 hours, under a nitrogen atmosphere. After cooling, the reaction mixture was partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogencarbonate solution (30 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0, by volume) gradually changing to dichloromethane:methanol:ammonia (90:10:1, by volume) to afford the title compound (203 mg) as a brown oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[CH3:15][CH:16]([CH3:24])[C:17](=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH:16]([C:17]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)=[CH:2][C:18]=1[C:19]([O:21][CH3:22])=[O:20])([CH3:24])[CH3:15]
Reactant: O=C(CCl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C(C)C
Yield: 36.5 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-4′-(trifluoromethyl)acetophenone (13.4 g) and methyl 4-methyl-3-oxopentanoate (7.2 g) to give the title compound (5.7 g, 36%) as an oil.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([NH2:16])=[O:15])[CH:10]=[CH:11][CH:12]=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][C:14]1[O:15][C:2](=[O:3])[S:4][N:16]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)Cc1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: O=c1oc(Cc2cccc(Cl)c2)ns1

Procedure:
7.32 g (55.9 mmol) of chlorocarbonylsulphenyl chloride and 7.90 g (46.6 mmol) of 2-(3-chlorophenyl)acetamide are stirred in 50 ml of toluene at 80° C. for 3 h. The crude product is reacted further without additional purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:22])[C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)=[CH:6][CH:5]=2.[Li+].[OH-]>C1COCC1.CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:22])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)C(C)c1ccc(-c2ccc3[nH]c(C)cc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2cc(-c3ccc(C(C)C(=O)O)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 16d (24 mg, 82 μmol) in THF (2 mL) and MeOH (0.5 mL) was added a 1.0N aqueous solution of LiOH (0.2 mL, 200 μmol) and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with a 25% aqueous solution of NH4OAc and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. Purification by flash chromatography (30:70:1 EtOAc/hexane/AcOH) gave 23 mg of the title compound as a light yellow gum.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[NH:11])OCC)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C(O)C.[CH2:20](N)[CH2:21][NH2:22]>CCOCC>[CH2:20]1[NH:11][C:7](=[C:6]2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3](=[O:2])[CH:13]=[CH:12]2)[NH:22][CH2:21]1
Reactant: NCCN
Reactant: CCOC(=N)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C1C=CC(=C2NCCN2)C=C1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of the imidate ester HCl 34 (650 mg, 2.63 mmol) in abs. ethanol was added ethylenediamine (0.53 ml, 7.89 mmol) at 0° C. and the mixture was stirred for 16 hrs at room temperature. Ether was added and the resulting precipitates were collected by filtration and dried in vacuo to give 490 mg (90% yield) of the desired cyclic amidine 35. 1H NMR (600 MHz, DMSO-d6) δ 8.38 (d, 1H, J=3 Hz), 7.45 (dd, 1H, J=9, 2.4 Hz), 3.79 (s, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([OH:10])=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:10]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCCO)c1
Reactant: Nc1ccccc1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)Nc3ccccc3)cc2OCCO)c1

Procedure:
Analogously to Example 74, by condensing 3-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonyl-amino)-benzoic acid with aniline there was obtained 3-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonyl-amino)-N-phenyl-benzamide.