Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=1[F:12].[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:27]=[CH:28][C:29]([N:32]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]([F:12])=[C:4]([CH:9]=3)[C:3]([O:2][CH3:1])=[O:13])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:30][CH:31]=2)=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccc(C#Cc2ccc(N)cc2)cc1
Reactant: CCCCCC=O
Reactant: COC(=O)c1cc(C=O)ccc1F
Product: CCCCCCN(Cc1ccc(F)c(C(=O)OC)c1)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Yield: 84.4 %

Procedure:
The title compound was prepared following procedure described in Example 49, step a) from 2-fluoro-5-formylbenzoic acid methyl ester (302 mg; 1.66 mmol), 4-(4-butylphenylethynyl)phenylamine (413 mg; 1.66 mmol) and hexanal (Aldrich, 600 μl; 4.97 mmol). Purification of the crude (890 mg) by flash chromatography using silicagel (EtOAc/c-Hex 5:95 then 10:90) afforded 700 mg (85%) of the title compound as a white powder. HPLC, Rt: 6.62 min (purity: 100%), LC/MS, M+(ESI): 500.3, 1H NMR(CDCl3) δ: 7.75 (dd, J=6.8, 2.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.9 Hz, 2H), 7.20 (m, 1H), 7.10 (d, J=8.3 Hz, 2H), 7.05 (dd, J=10.5, 8.6 Hz, 1H), 6.58 (d, J=7.9 Hz, 2H), 4.52 (s, 2H), 3.90 (s, 3H), 3.38 (t, J=7.8 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 1.57 (m, 4H), 1.30 (m, 8H), 0.87 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([NH2:30])(=[O:29])=[O:28].[OH-].[Na+]>ClCCCl.C(N(CC)CC)C>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([NH:30][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9])(=[O:29])=[O:28]
Reactant: NS(=O)(=O)c1cccs1
Reactant: Cn1cc(C(=O)O)cn1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NS(=O)(=O)c2cccs2)cn1
Temperature: 55 °C
Yield: 63.8 %

Procedure:
3.8 g of 1-methylpyrazole-4-carboxylic acid and 4.9 g of carbonyldiimidazole in 100 ml of 1,2-dichloroethane are heated at 55° C. for 3.5 h. 4.9 g of 2-thienylsulfonamide and 5.4 ml of triethylamine are added and then the mixture is heated at 55° C. for 13 h. After cooling, 40 ml of 10% strength aqueous NaOH solution are added and then the pH of the aqueous phase is adjusted to 1. The precipitate is removed and dried under reduced pressure. 5.2 g of N-(2-thienylsulfonyl)-1-methylpyrazole-4-carboxamide with a melting point of 174°-180° C. are obtained (active ingredient Example No. 103).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH-].[Na+].[CH3:10]I.Cl[C:13]([O:15][CH3:16])=[O:14].Cl>CO>[CH3:16][O:15][C:13]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4][CH3:10])=[O:14]
Reactant: COC(=O)Cl
Reactant: CI
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N[C@@H](CSC)C(=O)O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of L-cysteine (50 mg, 0.413 mmol) in methanol (0.4 mL) was treated with 1N NaOH (0.45 mL, 0.45 mmol) and methyl iodide (28.3 μL, 0.45 mmol) at 0° C. The mixture was warmed to 25° C. over 16 h, recooled to 0° C., and treated with 3N NaOH (0.45 μL, 1.3 mmol) and methyl chloroformate (64 μL, 0.83 mmol) at 25° C. for 4 h. The mixture was acidified with 2N HCl, and partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, and dried over MgSO4 and filtered. The solvents were evaporated to give the crude title compound (60 mg, 75%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[C:34]([F:35])=[CH:33][CH:32]=[C:31]([F:36])[C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[C:31]([F:36])=[CH:32][CH:33]=[C:34]([F:35])[C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Fc1ccc(F)c(CBr)c1Cl
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2c(F)ccc(F)c2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as in the preparation of compound 10, except that 2-chloro-3,6-di-fluoro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H NMR (400 MHz, CDCl3-CD3OD 10:1) δ ppm 6.98-7.06 (m, 2H), 6.90 (m, 2H), 5.31 (s, 1H), 5.01-5.20 (ABq, J=24.2, 14.4 Hz, 2H), 3.28-3.37 (m, 2H) 3.13 (s, 3H), 3.01-2.94 (m, 1H), 2.6-2.9 (m, 2H), 2.10 (m, 1H), 1.92 (m, 2H), 1.73 (s, 1H), 1.6-1.75 (m, 2H). MS (ES) [m+H] calc'd for C17H20ClF2N4O2, 385.1; found 385.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:7](=[O:19])[C:6]=2[N:20]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:7](=[O:19])[C:6]3[N:20]=[C:2]([C:38]4[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:30]5[O:29][C:28]([C:25]6[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=6)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:31]=5[CH:37]=4)[CH:3]=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: O=C1c2nc(Br)ccc2OCN1Cc1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccc(F)cc3)CO4)cc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[2,3-e][1,3]oxazin-4(3H)-one (110 mg, 0.33 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (149 mg, 0.30 mmol) and K3PO4.3H2O (237 mg, 0.89 mmol) in dioxane/H2O (5 mL/0.2 mL) were added Pd2(dba)3 (13 mg, 0.02 mmol) and X-phos (14 mg, 0.03 mmol) under N2. The mixture was stirred at 110° C. for 1 hour. Then it was filtered and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash gel chromatography (DCM:MeOH=100:1) to afford the product of 5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (170 mg, yield: 82%). 1H-NMR (CDCl3, 400 MHz) δ 7.94˜7.97 (m, 3H), 7.75˜7.77 (m, 1H), 7.62 (s, 1H), 7.42˜7.45 (m, 1H), 7.33˜7.36 (m, 2H), 7.19 (t, J=7.6 Hz, 2H), 7.05 (t, J=7.6 Hz, 2H), 6.05 (br s, 1H), 5.22 (s, 2H), 4.78 (s, 2H), 3.22 (s, 3H), 2.99 (d, J=4.8 Hz, 3H), 2.93 (s, 3H). MS (M+H)+: 633.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:19])[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:12]([CH3:19])[CH3:11])=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN(C)CC(C)(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(C)(C)CNC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminobenzoic acid (Aldrich; 4.0 g, 29.17 mmol) in DMF (100 mL) was added N,N,2,2-tetramethyl-1,3-diaminopropane (Aldrich; 5 mL, 31.38 mmol). An immediate solid precipitate formed. DIPEA (15 ml, 86.11 mmol) was added and the resultant suspension stirred HATU (13 g, 34.18 mmol) was added portionwise at such a rate and time interval as to maintain internal reaction temp <30° C.}. The resultant yellow solution was stirred at ambient temperature, overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.O.OP([O-])(O)=O.[Na+].[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OC(C)C)(=O)C.O>[OH:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:29])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: COC(=O)c1cc(O)cc(OC(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was added methyl-3,5-dihydroxybenzoate (1.0 eq), sodium phosphate mono-basic monohydrate (0.46 eq) and water (10.5 vols) under a nitrogen atmosphere. The temperature was adjusted to 20° C.±3° C. 10% w/w Sodium hydroxide was added to adjust the pH to pH 7.8±0.2. Benzoyl chloride (1.0 eq) was added drop-wise in small portions over 1-2 hours, and sodium hydroxide was added concurrently drop-wise in small portions over the same time period to maintain the reaction in a pH range of pH 7.8±0.2 and at a reaction temperature of 20° C.±3° C. The crude reaction mixture was agitated for a further 30 minutes, filtered, and then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05 eq), and adjusted to pH7.5 with 10% w/w sodium hydroxide. The crude solid was then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05 eq), and adjusted to pH6.5 with 10% w/w sodium hydroxide. The crude solid was then dissolved in iso-propyl acetate (8 vols) and water (2 vols) and the mixture agitated for at least 30 minutes to ensure the solid had dissolved. The mixture was filtered through a CUNO™ filter to remove a small amount of brown solid. The aqueous layer was separated off. Water (2 vols) was added to the organic layer and the batch agitated for at least 30 minutes. The aqueous layer was separated off and the organic layer was vacuum distilled, keeping the batch temperature below 40° C. to reduce the volume to 5-6 vols. Toluene was added then added (5 vols) and the mixture was vacuum distilled keeping the batch temperature below 40° C., reducing the volume to approximately 3.5 vols. The mixture was cooled to 15° C.±3° C. and agitated at this temperature for at least 30 minutes, then filtered, and the solid washed with toluene (1 vol). The product was dried at 20° C.-40° C. to give the desired product as a solid (corrected yield 40%-70%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19]CC2C=CC=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>[C].[Pd].C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of ethyl 1-benzyl-3-benzyloxy-1H-pyrazol-4-ylacetate (14.9 g), 5% palladium-carbon (15.0 g), tetrahydrofuran (150 ml) and ethanol (150 ml) was stirred for 2 hours under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated to obtain ethyl 1-benzyl-3-hydroxy-1H-pyrazol-4-ylacetate (9.76 g, yield 88%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 156–157° C.
Reaction SMILES: IC1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:18])([C:14]([F:17])([F:16])[F:15])[C:11]([O-])=O.[K+].O.CCOCC>CN(C=O)C.[Cu](I)I>[CH3:8][C:5]1[CH:6]=[CH:7][C:11]([C:10]([F:18])([F:9])[C:14]([F:17])([F:16])[F:15])=[CH:3][CH:4]=1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: Cc1ccc(I)cc1
Agent: I[Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Procedure adapted from Syn. Comm., (1988) 18(9):965-972. A mixture of copper iodide (129 g, 679 mmol), 1-iodo-4-methylbenzene (1) (74 g, 339 mmol) and potassium 2,2,3,3,3-pentafluoropropanoate (120 g, 594 mmol) were dissolved in DMF (500 mL) and heated to 120° C. for 30 minutes and then heated at 160° C. for 4 hours, after which the mixture was allowed to cool to room temperature. Water (200 mL) and ether (200 mL) were added and after stirring for 30 minutes the solids were filtered and washed with ether. The phases were separated and the organic layer was washed with brine/water (3×250 mL). The organic layer was dried and concentrated to yield 1-methyl-4-(perfluoroethyl)benzene (66 g, 92%) as a dark oil.
Reaction SMILES: [N:1]#[C:2]N.Cl[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17].Cl>O>[N:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:18][C:2]=1[NH:1][C:5]([O:7][CH3:8])=[O:6]
Reactant: N#CN
Reactant: COC(=O)Cl
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Nc1nc2ccccc2[nH]1
Temperature: 105 °C
Reaction time: 0.75 h

Procedure:
To a jacketed reactor equipped with feed ports stirrer, reflux condenser, and pH probe are added 32 parts of 50% cyanamide solution and 100 parts of water. Methyl chloroformate (41.1 parts) and 67 parts of 50% sodium hydroxide solution are changed concurrently so as to maintain the pH of the solution at 7 - 7.5 and the reacton temperature at 40° - 50° C. The solution is held at 50° C. for 45 minutes and then 36 parts of o-phenylenediamine is added. The pH of the solution is held at 3.9 to 4.1 by the gradual addition of 65 parts of 37% HCl. The solution is heated to 105° C. and held at this temperature for 30 minutes. During this hold time, the product starts to crystallize. The reaction mass is cooled to 25°-30° C. and the solid product is filtered, washed with water and acetone, and dried in the vacuum oven at 80° C. to give 59.6 parts of 2-benzimidazolecarbamic acid, methyl ester. This represents a product yield of 93.5% based on o-phenylenediamine.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCN1CCC(=O)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN1CC=C(N2CCCC2)CC1

Procedure:
A mixture of 1-butyl4-piperidone (10.5 g, 67.6 mmol), pyrrolidine (6.73 g, 94.7 mmol), amberlyst-15 (200 mg) and toluene (100 ml) was stirred at reflux overnight, with a Dean and Stark water collector connected. The crude mixture was co-evaporated with toluene twice (100 ml). The product was isolated as an oil in quantitative yield.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=C1.[CH3:8][N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(C1C=CC(B(O)O)=CC=1)(C)(C)C>>[CH3:8][N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([C@H:5]2[CH2:4][CH2:3][C:1](=[O:7])[CH2:6]2)=[CH:12][CH:11]=1
Reactant: O=C1C=CCCC1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: CC(C)(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc([C@H]2CCC(=O)C2)cc1

Procedure:
The title compound was prepared using the procedure as described in Example 28A, substituting 2-cyclopenten-1-one for cyclohexen-1-one, S-BINAP and 4-(dimethylamino)-phenylboronic acid for 4-(tertbutyl)-phenylboronic acid. The mixture was purified on SiO2 (hexane/ethyl acetate 4/1) to provide the title compound. [α]D=−22.31 c=1.0 (CH3OH). 1H NMR (CD3OD, 300 MHz); δ 1.85-2.01 (m, 1H), 2.21-2.40 (m, 4H), 2.42-2.50 (m, 1H), 2.88 (s, 6H), 3.29-3.39 (m, 1H), 6.78-6.81 (m, 2H), 7.11-7.21 (m, 2H). MS (DCI) m/z 204 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[C:11]([CH:25]=1)=[CH:12][CH:13]=[C:14]1[C:19]=2[O:18][CH2:17][C:16]2[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:15]1=2)(=O)=O.C([Sn](CCCC)(CCCC)[C:33]([O:35]CC)=[CH2:34])CCC.O.[Br:47]N1C(=O)CCC1=O>CN(C)C=O.ClCCl.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Br:47][CH2:35][C:33]([C:7]1[CH:8]=[CH:9][C:10]2[C:11]([CH:25]=1)=[CH:12][CH:13]=[C:14]1[C:19]=2[O:18][CH2:17][C:16]2[CH:20]=[C:21]([Br:24])[CH:22]=[CH:23][C:15]1=2)=[O:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=S(=O)(Oc1ccc2c3c(ccc2c1)-c1ccc(Br)cc1CO3)C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c3c(ccc2c1)-c1ccc(Br)cc1CO3
Temperature: 25 °C
Reaction time: 30 h
Yield: 70.5 %

Procedure:
A solution of 8-bromo-6H-dibenzo[c,h]chromen-2-yl trifluoromethanesulfonate (780 mg, 1.7 mmol) and tributyl(1-ethoxyvinyl)stannane (0.86 mL, 2.6 mmol) in dimethylformamide was degassed with a stream of argon for 15 minutes. PdCl2(dppe) (50 mg, 0.086 mmol) was added and the reaction was stirred at room temperature. After 30 hours, water (1 mL) and N-bromosuccinimide (756 mg, 4.2 mmol) were sequentially added to the reaction. After stirring for 2.5 hours at room temperature the reaction was diluted with dichloromethane. The organics were washed with 5% aqueous LiCl solution, saturated aqueous NaHCO3 solution, and brine. After the organic layer was dried (Na2SO4) and concentrated, the crude material was recrystallized from dichloromethane and hexanes to yield 2-bromo-1-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)ethanone (518 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(N(CC)CC)C.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(Cl)c(Br)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 3-bromo-4-chloroaniline (200 mg, 0.969 mmol) in dichloromethane (5 mL) was added triethylamine (0.374 mL, 2.91 mmol). The solution was cooled to 0° C. and benzenesulfonyl chloride (188 mg, 1.066 mmol) was added dropwise. After stirring at room temperature for 12 hours, the mixture was extracted with dichloromethane and the organic layer washed with water and brine (25 mL each). Drying over sodium sulfate, filtration and concentration afforded the title compound. LCMS: 346.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].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>[F:9][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Ic1ccccc1
Reactant: Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 9.21 g of 4-bromo-2-fluorotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to −78° C. in a nitrogen atmosphere, and the mixture was then stirred at −78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at −78° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a solution of 6.63 g of iodobenzene and 0.52 g of tetrakis(triphenylphosphine)palladium (0) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.00 g of oily 3-fluoro-4-methylbiphenyl.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>ClCCl.FC(F)(F)C(O)=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.5 %

Procedure:
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(dimethylamino)-5-oxopentanoate (Compound SP447) (15.2 g, crude product) was dissolved in a mixture of dichloromethane (200 ml) and trifluoroacetic acid (200 ml), followed by stirring at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure, and the resulting solid was washed with a mixed solution of hexane and tert-butyl methyl ether and then dried in vacuo to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(dimethylamino)-5-oxopentanoic acid (Compound SP448) (9.12 g, 85%, two steps).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[N:21][C:22]#[N:23])SC)[N:11]=1.[NH2:27][CH2:28][CH2:29][NH2:30]>C(O)C>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]=[C:5]([NH2:24])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:21][C:22]#[N:23])=[N:27][CH2:28][CH2:29][NH2:30])[N:11]=1
Reactant: NCCN
Reactant: CSC(=NC#N)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: N#CNC(=NCCN)NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)-guanidino]-4-[5-(3-cyano-2-methylisothioureido)pentyl]-thiazole (0.5 g.) and 1,2-diaminoethane (1.5 ml.) in ethanol (1 ml.) was allowed to stand at room temperature overnight. The mixture was then evaporated to dryness and the residue purified by preparative medium pressure liquid chromatography on silica gel using methanol/chloroform 1:4 v/v as solvent to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[5-(3-cyano-2-[2-aminoethyl]guanidino)pentyl]thiazole as a straw coloured gum. A sample of the salt prepared with maleic acid included the following n.m.r. resonances when examined in d6 dimethylsulphoxide containing tetramethylsilane as an internal standard (δ=0) (δ):-1.5 (multiplet, 6H); 3.0 (multiplet, 4H); 3.3 (multiplet, 2H); 4.1 (multiplet, 2H); 6.5 (singlet, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[NH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][CH2:31][CH2:32]2>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[C:33]4[C:29]=2[CH2:30][CH2:31][CH2:32]4)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: Nc1cccc2c1CCC2
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=S(=O)(Nc1cccc2nc(Nc3cccc4c3CCC4)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=452.0 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 4-aminoindane.