Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].[I-:36].[Na+]>C(C(C)=O)C>[I:36][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:34][CH3:35])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)OC
Yield: 85.5 %

Procedure:
To a solution of 972 mg (1.8 mM) of 3-(3-chloropropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane III a1 in 10 ml of methyl ethyl ketone is added 500 mg (3.38 mM) of sodium iodide and the mixture is refluxed for 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane - ethyl acetate (1:1) mixture as an eluent. The product is recrystallized from chloroform-n-hexane to give 972 mg (1.54 mM) of 3-(3-iodopropylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane II a1 in 86% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:8]([CH:11](Br)Br)=[CH:9][CH:10]=1)=[O:4].[OH2:24]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:8]([CH:11]=[O:24])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(Br)Br)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1ccc(C=O)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 1 h

Procedure:
The compound of step 2 (2.1 g, 4.65 mmol) was dissolved in acetonitrile (25 ml). Silver nitrate (1.97 g, 11.6 mmol) was dissolved in water (3 ml) and this solution was added to the acetonitrile solution. This mixture was stirred for 1 h in reflux. Acetonitrile was evaporated in vacuo, the remainder was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium chloride, filtered over a small plug of silica and evaporated to dryness. A crystalline crop was yielded on addition of methanol and filtration. The mother liquor was evaporated to dryness and purified by silica gel chromatography with a heptane/ethyl acetate gradient to yield a second crop. Both were combined to yield the title compound (1.0 g).
Reaction SMILES: CS([C:4]1[N:19]=[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[C:11]([NH2:12])[N:6]2[N:5]=1)=O.[N:20]12[CH2:30][CH2:29]C[N:27]=[C:26]1[CH2:25]CCCC2>CC1NC=CN=1>[CH3:25][C:26]1[N:20]([C:4]2[N:19]=[C:7]3[CH:8]=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[CH:10]=[C:11]([NH2:12])[N:6]3[N:5]=2)[CH:30]=[CH:29][N:27]=1
Reactant: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc2cc(-c3ccccn3)cc(N)n2n1

Procedure:
The title compound, MS m/e (%):292 (M+H+,100), was prepared in accordance with the method of example 339b) from 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 1,8-diazabicyclo[5.4.0]undec-7-en in 2-methylimidazole at 170° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1>N1C=CC=CC=1>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccncc1
Yield: 76.1 %

Procedure:
4-Pyridinecarboxaldehyde (18.96 g, 0.177 mol) and malonic acid (55.3 g, 0.53 mol) were placed in 200 ml of pyridine. Piperidine (5.25 ml, 0.053 mol) was added and the reaction was refluxed for 6 hours. The reaction mixture was cooled in an ice bath and then the white solid was filtered off and rinsed with ether and dried to afford 20.1 g of the subtitle compound. Concentration of the filtrate and then filtration and rinsing with ether resulted in recovery of another 2.2 g of product (84% total yield).
Reaction SMILES: I[C:2]1[N:3]([CH3:13])[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.[CH3:14][C:15]1([CH3:31])[C:27]2[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2.C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=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>[CH3:14][C:15]1([CH3:31])[C:16]2[CH:17]=[C:18]([C:2]3[N:3]([CH3:13])[CH:4]=[C:5]([C:7]4[S:8][C:9]([CH3:12])=[CH:10][CH:11]=4)[N:6]=3)[CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: Cc1ccc(-c2cn(C)c(I)n2)s1
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(C)c(-c3ccc4c(c3)C(C)(C)c3ccccc3-4)n2)s1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 2-iodo-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 6 (1.26 g, 4.16 mmol), (9,9-dimethyl-9H-fluoren-2-yl)boronic acid (1.19 g, 5.00 mmol), Na2CO3 (2.20 g, 20.8 mmol) in H2O (10 mL) and DMF (40 mL) was degassed (N2 bubbling). Pd(PPh3)4 (120 mg, 0.10 mmol) was added and the mixture was heated to reflux for 2 h. The mixture was allowed to cool to room temperature and concentrated. The mixture was filtered through Celite washing with CH2Cl2 and the combined filtrate and washings were concentrated. The residue was taken up in CH2Cl2 and H2O and the organic phase was separated. The aqueous phase was re-extracted (CH2Cl2) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 5:95 then 10:90 then 12:88) to give 2-(9,9-dimethyl-9H-fluoren-2-yl)-1-methyl-4-(5-methylthiophen-2-yl)-1H-imidazole 9 (1.19 g, 76%) as a colourless solid. A portion of this material was further purified by, firstly, recrystallisation (EtOAc/hexanes) and, secondly, by sublimation (180° C., 10−6 mBar): m.p. 188-191° C. (DSC)1H NMR (CDCl3, 400 MHz) δ1.53 (s, 6H), 2.50 (d, J=0.6 Hz, 3H), 3.76 (s, 3H), 6.68-6.71 (m, 1H), 7.11 (s, 1H), 7.13-7.19 (m, 1H), 7.32-7.40 (m, 2H), 7.43-7.49 (m, 1H), 7.58 (dd, J 1.4, 8.0 Hz, 1H), 7.73-7.81 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ15.3, 27.1, 34.6, 47.0, 117.1, 119.8, 120.3, 122.1, 122.7, 123.6, 125.6, 127.0, 127.7, 137.8, 138.5, 139.9, 148.3, 153.9, 154.0; HRMS (EI) m/z 370.1490 C24H22N2S [M]+. requires 370.1498.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][CH:15]([C:17]1[S:18][CH2:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=1)[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][CH:15]([C:17]2[S:18][CH2:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=2)[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)[C@H]1CSC(C(C)N)=N1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: CCOC(=O)[C@H]1CSC(C(C)NC(=O)Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure A above and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-4-ethoxycarbonyl-2-thiazoline hydrochloride (Example G), the title compound was prepared as a semisolid. The reaction was monitored by tlc (Rf=0.2 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])=[CH:34][CH:33]=1>O1CCCC1.C(OCC)(=O)C.CCCCCC>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([NH:41][C:42](=[O:43])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][N:19]([CH:22]5[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:29][CH:30]=2)=[O:40])=[CH:36][CH:37]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)CC1
Reaction time: 3.5 h
Yield: 49 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (834 mg) in tetrahydrofuran (45 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (0.25 M, 15 ml) at room temperature, followed by stirring for 3.5 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (8 ml) and hexane (16 ml). The crystals were filtered off and dried under aeration to provide the titled compound (546 mg, 49%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:25]1[O:28][CH:26]1[CH3:27].B(F)(F)F.CCOCC.[OH-].[NH4+]>CCCCCC.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[CH2:25][CH:26]([CH3:27])[O:28][C:7]3([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CC1CO1
Agent: FB(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1CN2CC(=O)N(C)c3ccc(Cl)cc3C2(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 10.0 g. (35 mmole) of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 6.7 g. of aluminum chloride, 300 ml. of benzene and 30 ml. of hexane was chilled in an ice-bath and was treated with 10 ml. of propylene oxide. The reaction mixture was warmed to room temperature and was stirred overnight. Work-up as in Method A, Example 5, yielded a mixture of the epimers of 10-chloro-2,7-dimethyl-2,3,5,11b-tetrahydro-11b-phenyloxazole[3,2-d][1,4]benzodiazepin-6(7H)-one. A solution of 1.0 g. of this mixture was stirred overnight at 80° in 25 ml. of boron trifluoride etherate. The reaction mixture was poured carefully into ice water and made basic with ammonium hydroxide. The mixture was extracted with chloroform, water washed, dried and concentrated to a solid residue. Three recrystallizations from methylene chloride-hexane gave the above-titled isomer, m.. 142°-143°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:6]2=[O:24].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:7]2[C:6](=[O:24])[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH:2]=[O:1])[CH:4]=3)[N:9]([CH3:13])[CH:8]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(COc2cn(C)c3ccc(CO)cc3c2=O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(COc2cn(C)c3ccc(C=O)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a suspension of 6-(hydroxymethyl)-3-((4-methoxybenzyl)oxy)-1-methylquinolin-4(1H)-one (1.5 g, 4.61 mmol) in dichloromethane (DCM) (80 mL) at room temperature was added Dess-Martin periodinane (2.347 g, 5.53 mmol). The reaction mixture soon turned into a clear brown solution and was stirred at room temperature for 1 h. Saturated sodium bicarbonate solution was then added, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by automatic silica gel column chromatography (Combiflash RF) eluting with ethyl acetate/hexanes (0-100%) to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-6-carbaldehyde (1.1 g, 3.40 mmol, 73.8% yield) as a yellow solid. LCMS: (M+H)+: 324.0
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[C:3]1=[O:9]>CC(C)=O>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[C:3]1=[O:9]
Reactant: CN1CCCC(O)C1=O
Solvent: CC(C)=O
Product: CN1CCCC(=O)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
To a solution of 3-hydroxy-1-methylpiperidin-2-one (1 g, 7.59 mmol) in acetone (50 mL) was added Jones-reagent (2 mL) dropwise at room temperature. The resulting solution was stirred for 10 min at room temperature. The solid material was removed by filtration. The filtrate was concentrated in vacuo at 30-40° C. The residue was dissolved in DCM (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (220 mg, 11%) which was used in next step immediately without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[O:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)OC(=O)Nc1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 65 °C
Yield: 30 %

Procedure:
To a solution of tert-butyl 4-hydroxypyridin-2-ylcarbamate (4.12 g, 19.6 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (3.34 g, 21.6 mmol) in DMF (40 mL) was added K2CO3 (4.06 g, 29.04 mmol). After heating to 65° C. for 64 hours, the mixture was cooled to room temperature and poured into ice water (200 mL). The reaction mixture was extracted several times with ethyl acetate. The combined organics were concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product (2.03 g, 30%).
Reaction SMILES: BrC1C=CC=C2C=1C=CN2.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCCCC.Br[CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1>>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[N:17]2[CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1
Reactant: COc1cccc2c1C(=O)C(=O)N2
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: COc1cccc2c1C(=O)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations to replace 4-bromoindole with 4-methoxy-1H-indole-2,3-dione, and 1-bromopentane with 2-(bromomethyl)-5-(trifloromethyl)furan, the title compound was obtained (26%): MS (ES+) m/z 348.2 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]2[C:14](=[O:17])[N:12]3[N:13]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)=[CH:10][C:11]3=[N:16]2)=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (18 mg, 0.05 mmol) and 4-trifluoromethyl benzylbromide (18 mg, 0.075 mmol) in anhydrous DMF (0.5 mL)) at 70° C. was added solid K2CO3 (13.8 mg, 0.1 mmol). After addition, the reaction mixture was stirred at 70° C. for 30 min. Analysis by HPLC/MS indicated the starting material had been consumed. After cooling to room temperature, the reaction was diluted with water, and extracted with EtOAc (5 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The obtained residue was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5 μ C18 21.2×100 mm; Eluted with 70% to 100% B, 8 min gradient, hold at 100% B for 6 min (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 mL/min, UV detection at 220 nm) to afford 18 mg (70%) of the title compound as a yellow powder. LC/MS (method A): retention time=4.05 min, (M+H)+=515. 1H NMR (CDCl3, 400 MHz): δ 7.57-7.70 (m, 4H), 7.42-7.48 (m, 1H), 7.41 (s, 1H), 7.30-7.38 (m, 2H), 7.17-7.25 (m, 3H), 7.02 (d,J=8.0 Hz, 2H), 5.30 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C@@H:3]([OH:5])[CH3:4].CC(C)([O-])C.[Na+].[Cl:14][C:15]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=1[S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(N(C)C)=O.[Cl-].[Na+].O.C(O)C.O>[Cl:14][C:15]1[CH:20]=[C:19]([O:5][C@@H:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])[CH:18]=[CH:17][C:16]=1[S:22][C:23]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Fc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reactant: C[C@H](O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@H](Oc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1)C(F)(F)F
Temperature: 2 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
(S)-1,1,1-Trifluoro-propan-2-ol (100 g, 877 mmol) was dissolved in dimethylacetamide (600 mL) and the solution was cooled to 2° C. (ice bath). A solution of sodium tert-butoxide (77.5 g, 790 mmol) in dimethylacetamide (100 mL) was added at 2° C. and the mixture was stirred for 15 min. This solution was treated with a solution of 2-chloro-4-fluoro-1-tritylsulfanyl-benzene (200 g, 494 mmol) in dimethylacetamide (100 mL) at room temperature and subsequently stirred for 3 h at 50° C. It was then poured into a mixture of brine (200 mL), ice (1.2 kg) and water (2.0 L), and extracted with tert-butyl-methylether (2×1000 mL). The combined organic extracts were washed with brine/water 1:1 (v/v, 300 mL) and concentrated in vacuo to give the crude product as a yellow viscous oil. The oil was dissolved in ethanol (1.6 L), before water (240 mL) was slowly added at room temperature. The resulting suspension was stirred for 14 h, cooled to 2° C. (ice bath) and stirred for another 2 h, before it was filtered. The solid was washed with ethanol/water 4:1 (v/v, 500 mL) and dried in vacuo to afford the title compound as a white crystalline solid (238 g, 97%). 1H NMR (CDCl3, 400 MHz): δ 1.43 (d, J=6.5 Hz, 3H), 4.50 (qq, J=6.2 Hz, 6.2 Hz, 1H), 6.44 (dd, J=2.8 Hz, 8.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 7.18-7.27 (m, 9H), 7.33-7.39 (m, 6H).
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13]1>>[CH2:1]([NH:11][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCCO1
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNC(=O)CCCO

Procedure:
In a glass reaction vessel, 157.3 grams of decylamine was mixed with 86.1 grams butyrolactone, whereupon the temperature rose to about 150° C. Reaction was spontaneous, and greater than 95% conversion of the butyrolactone to product was achieved. Titration of the product indicated that only 0.4 weight percent free amine remained unreacted. The liquid product was cooled by pouring on a glass surface at room temperature, whereupon the product froze to a hard white, waxy solid. Titration of the remaining reaction mixture indicated that only 0.4 weight percent free amine remained after removal of product. IR=6.11 mu.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C(N(CC)CC)C.N[CH2:25][C:26]([NH2:29])([CH3:28])[CH3:27]>CCO>[CH3:25][C:26]1([CH3:28])[CH2:27][NH:16]/[C:13](=[N:12]/[C:10]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=2)=[O:11])/[NH:29]1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(N)CN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)CN/C(=N/C(=O)c2nc(Cl)c(N)nc2N)N1

Procedure:
A suspension of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (0.2 g, 0.517 mmol) in EtOH (2 ml) is treated with triethylamine (0.029 ml, 0.258 mmol) followed by 1,2-diamino-2-methylpropane (0.07 ml, 0.672 mmol) and stirred at reflux overnight. The resulting suspension is filtered under vacuum to afford the title compound as a pale yellow solid; [M+H]+ 284
Reaction SMILES: [C:1]1(C([O-])=O)[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7].[K+].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][C:19]=1Cl.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC.O>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:18][C:19]=1[O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cccc(O)c1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
73 parts by weight of potassium 3-cresolate, 107 parts by weight of 3,4-dichlorobenzotrifluoride and 6.9 parts by weight of potassium carbonate in 500 parts by volume of dimethylsulfoxide were stirred at 140° C. for 8 hours. The reaction mixture was cooled to room temperature and was poured into 2,000 parts by volume of water. The oily residue was taken up in ether, and the organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. Fractional distillation gave 120 parts by weight (84% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-toluene of boiling point 91°-96° C./0.1 bar and refractive index nD25 : 1.5268.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:20](=[O:29])[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=2)=[CH:10][CH:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[C:20](=[O:29])[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nc(-c3cc4ccccc4[nH]c3=O)cs2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2nc(-c3cc4ccccc4[nH]c3=O)cs2)cc1

Procedure:
A solution of {4-[4-(2-oxo-1,2-dihydro-quinolin-3-yl)-thiazol-2-yl]-phenyl}-carbamic acid tert-butyl ester (Example 97, 70 mg, 0.17 mmol) in 0.8 mL of CH2Cl2 and 0.8 mL of TFA was stirred at RT for 1 h. Solvents were removed under vacuum and the residue was azeotroped twice with toluene. To the flask, 4.0 mL of aqueous HCl (1 M) was added and solids formed. The solvent was removed again and the solid was azeotroped with toluene twice. The solid was dried under vacuum overnight to afford the title compound as a light yellow solid. MS m/z: 320.2 (M+1). Anal. Calc'd for C18H13N3OS.0.8H2O.1.6HBr: C, 55.13; H, 4.16; N, 10.72; O, 7.34; S, 8.18. Found: C, 55.24; H, 4.15; N, 10.66; O, 7.45; S, 8.21.