Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:7]([CH3:8])[CH2:6]1)=[O:4].[N:22]#CBr>ClCCl.CO.ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH:20]=[C:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14]([NH:13][CH:12]=3)=[CH:15][CH:16]=[CH:17][C:18]=42)[N:7]([C:8]#[N:22])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: N#CBr
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C#N)C1

Procedure:
To a 50 ml round-bottom flask containing a solution of lysergic acid methyl ester (1.0 g, 3.54 mmol) in anhydrous dichloromethane (50 ml) is slowly added cyanogen bromide (2.02 g, 19.11 mmol) and the resulting black-coloured reaction mixture is stirred at room temperature for 4 hours by which time TLC in 10% methanol/dichloromethane showed partial conversion of starting material to give two faster-running products. The reaction mixture is left stirring over the weekend and monitored by TLC showing no change. The reaction mixture is then stirred at 50° C. for 4 hours and is then extracted between tartaric acid and dichloromethane. The aqueous phase is re-extracted with dichloromethane (100 ml) and the combined organic phases washed with brine (200 ml), dried over MgSO4, filtered and concentrated in vacuo to give a dark brown (tar-coloured) oil. Purification is carried out by Normal Phase Flash column chromatography (Biotage Flash 40, 90 g cartridge) using 40% ethyl acetate/hexane to achieve separation of the fast-running product which is isolated as a pale yellow solid. The product is crystallized from tert. Butyl methylether and slowly evaporated. The resulting crystallized material is filtered at the pump to give pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[NH:7][C:6]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2c1CC(=O)N2
Reactant: BrCc1ccccc1
Product: COc1cccc2c1C(Cc1ccccc1)C(=O)N2
Yield: 73 %

Procedure:
3-Benzyl-4-methoxy-1,3-dihydro-indol-2-one is prepared from 4-methoxyoxindole (4.8 mmol) and benzyl bromide (5.3 mmol) substantially as described above for Epoxide 4. The compound is purified by flash chromatography (SiO2, 25% ethyl acetate:hexane) to obtain the desired compound (36%). MS (ESI+) 254.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[C:5]3[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=3[C:9](=[O:10])[O:8][C:7]2=[O:11])=[CH:19][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of Compound 11 (5 g, 28 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added, and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 6.3 g (79%) of white solids. M.P. 153° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 5.24 (s, 2H), 7.14–7.17 (m, 3H), 7.44 (m, 2H), 7.54 (dd, J=1.7, 8.2 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H). Anal. (C16H12FNO3) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[CH3:38][O:39][C:40]([CH:42]1[CH2:46][CH2:45][NH:44][CH2:43]1)=[O:41].C(N(C(C)C)C(C)C)C>CN(C=O)C>[NH2:8][C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([N:44]2[CH2:45][CH2:46][CH:42]([C:40]([O:39][CH3:38])=[O:41])[CH2:43]2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: COC(=O)C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(c2cc(N)n3ncc(-c4cnc5ccccc5c4)c3n2)C1
Temperature: 180 °C

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-pyrazolo-[1,5-a]pyrimidin-7-amine (55 mg, 0.10 mmoL), methylpyrrolidine-3-carboxylate (52 mg, 0.30 mmoL) and EtN(iPr)2 (86 uL, 0.50 mmoL) in DMF (1.0 mL) was heated at 180° C. under microwave condition for 45 min. The mixture was purified by prep-LC to afford the title compound. LC/MS RT=3.30 min. Mass calculated for, M+H 389.17, observed 389.17.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH:14]([OH:17])([CH3:16])[CH3:15].CC([O-])(C)C.[K+]>C1COCC1>[CH:14]([O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11])([CH3:16])[CH3:15]
Reactant: CC(C)O
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 1.5 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (154 g, 814 mmol) in THF (1.5 L) was added isopropanol (73.4 g, 1.22 mol). The reaction flask was purged with N2 and cooled in an ice bath (1.5° C. internal temperature). t-BuOK (1.0 M in THF, 847 mL, 847 mmol) was added slowly over 10 minutes via addition funnel (slight exotherm to 31° C. was observed) and let stir at that temperature for 30 min (temp decreased to 18° C. during this time). The ice bath was removed and allowed to stir at room temperature until starting material was consumed as observed by LC/MS (˜20 min). The resulting mixture was quenched with water (500 mL) and the layers were separated. The organic layer was concentrated and the aqueous layer was extracted with MTBE (1 L). The organics were combined and washed with H2O (750 mL) and brine (750 mL). Dried organics over MgSO4, filtered, and concentrated to give 4-isopropoxy-3-(trifluoromethyl)benzonitrile (183 g, 798 mmol, 98% yield) as a yellow solid. Exact mass calculated for C11H10F3N0: 229.1, found: LCMS m/z=230.2, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (d, J=6.1 Hz, 6 H), 4.73 (sep, J=6.1 Hz, 1 H), 7.06 (d, J=8.7 Hz, 1 H), 7.75 (dd, J1=8.7, J2=2.1 Hz, 1 H), 7.85 (d, J=1.9 Hz, 1 H).
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]1([N:16]2[CH:20]=[C:19]([B:21]3[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]3)[CH:18]=[N:17]2)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)#[N:3]>O1CCOCC1.C(Cl)Cl>[ClH:1].[CH3:28][C:23]1([CH3:29])[C:24]([CH3:26])([CH3:27])[O:25][B:21]([C:19]2[CH:18]=[N:17][N:16]([C:5]3([CH2:4][C:2]#[N:3])[CH2:6][NH:7][CH2:8]3)[CH:20]=2)[O:22]1.[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)OB(c2cnn(C3(CC#N)CNC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.0 N HCl in 1,4-dioxane (2.0 mL) was added to solution of tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (1.68 g, 4.33 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated under reduced pressure to afford the desired product as HCl salt which was directly used in the next step reaction without further purification. LCMS cacld. for C14H22BN4O2 (M+1)+: m/z=289.2. Found: 289.1.
Reaction SMILES: ClC(C[C@@H](O)C)C[C@@H:4]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[K+].[CH2:33]([OH:35])[CH3:34]>>[CH2:19]([O:18][C:17]([NH:16][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=1)[C@@H:34]1[O:35][CH2:33]1)=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCO
Reactant: C[C@H](O)CC(Cl)C[C@H](Cc1ccc2ccccc2c1)NC(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)[C@H]1CO1)OCc1ccccc1

Procedure:
1.02 g of benzyl [3-chloro-2(S)-hydroxypropyl-1(S)-[(2-naphthyl)methyl]propyl]carbamate were stirred in 40 ml of ethanol with 4 ml of 0.7M potassium hydroxide solution in ethanol for 0.75 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was dried over anhydrous sodium sulphate and evaporated to give a white solid which was recrystallized from ethyl acetate/n-hexane. There was obtained 0.879 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-(2-naphthyl)butane as a white solid of melting point 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([Cl:1])=[N:3][CH:4]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn2ncnc(Cl)c12
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnn2ccc(CBr)c12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
A mixture of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (2.0 g, 11.93 mmol, WO 03/042172) and AKIN (195 mg, 1.19 mmol) in CCl4 (80 mL) under N2 was heated to 100° C. for 5 min, NBS (2.55 g, 14.3 mmol) was added. The reaction mixture was stirred for 10 min, then cooled to rt, filtered. The CCl4 layer was washed with dilute NaHCO3 aqueous solution, dried (MgSO4), filtered and concentrated to give the desired product (2.70 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([OH:17])=O)[N:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][C:15](=[O:17])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]4=[O:33])=[CH:23][C:22]=3[F:34])[N:10]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(O)Cn1ccc(NC(=O)c2ccc(Cl)cc2)n1
Product: O=C(Cn1ccc(NC(=O)c2ccc(Cl)cc2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
59.3 According to general method B, [3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 4-chloro-N-(1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-pyrazol-3-yl)-benzamide. White solid. MS 466.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=3)[CH:39]=[CH:40][C:41]=2[OH:42])=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:42][C:41]2[CH:40]=[CH:39][C:38]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:50])([F:51])[F:52])[CH:44]=3)=[CH:37][C:36]=2[C:33]2[CH:34]=[CH:35][N:30]=[N:31][CH:32]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4cccc(C(F)(F)F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 219 mg, 0.474 mmol) and 3-pyridazin-4-yl-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 3, 150 mg, 0.474 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (196 mg, 1.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with a 1M aqueous solution of sodium hydroxide whereupon a precipitate formed. The solid was collected by filtration, washed with water and freeze dried to afford the title compound as a solid (266 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH2:5][CH:6]1[CH2:8][O:7]1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH2:19][CH2:18]1.O>CN(C)C=O>[OH:7][CH:6]([CH2:5][C:4]1[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]([OH:12])=[C:2]([CH3:1])[CH:3]=1)[CH2:8][N:21]1[C:17](=[O:23])[CH2:18][CH2:19][C:20]1=[O:22]
Reactant: Cc1cc(CC2CO2)cc(C(C)(C)C)c1O
Reactant: O=C1CCC(=O)N1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CC(O)CN2C(=O)CCC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A solution of 6.6 g (0.03 mol) of 3-methyl-5-tert.-butyl-4-hydroxybenzyl-oxirane and 3 g (0.03 mol) of succinimide in 30 ml of dimethylformamide is stirred for 18 hours at a temperature of 150°-55° C whilst passing a slight stream of nitrogen through the mixture. After cooling to room temperature, the reaction mixture is poured into 150 ml of water and the oily reaction product which precipitates is dissolved in toluene. Successive extraction of the toluene phase with dilute hydrochloric acid, 5% strength aqueous sodium bicarbonate solution and water, drying over sodium sulphate and evaporation of the solvent gives the crude product. After recrystallisation from methylcellosolve, 6.5 g (68% of theory) of N-[2-hydroxy-3-(3-methyl-5-tert.-butyl-4-hydroxyphenyl)-propyl]-succinimide of melting point 217.5°-218° C are obtained in the form of colourless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:25](=[O:37])[NH:26][C:27]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:29][CH:28]1[CH:30]=[CH2:31])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:35]([O:34][C:32]([C:27]1([NH:26][C:25]([CH:9]2[NH:8][CH2:12][CH:11]([O:13][C:14](=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)[CH2:10]2)=[O:37])[CH2:29][CH:28]1[CH:30]=[CH2:31])=[O:33])[CH3:36]
Reactant: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1)C(=O)OCC
Yield: 98 %

Procedure:
Compound 21b (11.84 g, 22.9 mmol) was deprotected in TFA (30 ml) dissolved in DCM (100 ml) and then worked up by methods known in the chemical art to give the title compound (9.37 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][NH:11][C:12]3[N:20]=[CH:19][N:18]=[C:17]4[C:13]=3[N:14]=[CH:15][N:16]4C3CCCCO3)[N:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][NH:11][C:12]3[N:20]=[CH:19][N:18]=[C:17]4[C:13]=3[N:14]=[CH:15][NH:16]4)[N:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1
Reactant: Fc1ccc2nc(CNc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1ccc2nc(CNc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1
Yield: 85.5 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-ylmethyl)[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (0.125 g, 0.28 mmol) in MeOH (2 mL) was treated with 4M HCl in dioxane (0.35 mL). After 15 min at 20° C. the reaction was poured onto a 10 g SCX cartridge which was eluted first with methanol then with 1:1 MeOH/2M NH3 in isopropanol. Product containing fractions were evaporated to a white solid. This was triturated with diethyl ether and dried to give 443 as a white solid, (86 mg, 85%). LCMS (Method C): RT 3.16 min [M+H]+ 360.02. NMR δ (ppm) (DMSO-d6): 12.9 (1H, s), 8.11 (2H, s), 7.92 (1H, s), 7.66-7.60 (6H, m), 7.09 (1H, td, J=9.31, 2.45 Hz), 6.93 (1H, dd, J=8.96, 2.50 Hz), 4.8 (2H, bs)
Reaction SMILES: [CH2:1]([S-:4])[CH2:2][CH3:3].[Na+].Cl[C:7]1[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=[C:9]([CH3:21])[CH:8]=1>CO>[CH3:21][C:9]1[CH:8]=[C:7]([S:4][CH2:1][CH2:2][CH3:3])[C:20]2[C:11](=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[N:13]3)[N:10]=1
Reactant: CCC[S-]
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Agent: [Na+]
Solvent: CO
Product: CCCSc1cc(C)nc2c1ccc1cccnc12
Yield: 76.1 %

Procedure:
Solid sodium 1-propanethiolate (2.35 g, 24.0 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (1.10 g, 4.8 mmol) in methanol (50 mL). The reaction mixture was refluxed for 18 hours and allowed to reach room temperature. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid residue was treated with ethyl ether, filtered, and dried yielding 0.98 g of a dark orange solid (76%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9](O)[CH3:10]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCO
Reactant: CCc1ccccc1
Product: CCc1ccccc1CC

Procedure:
Argon gas is then flowed over the coked zeolite catalyst, and a reaction mixture of ethylbenzene and ethanol is injected into the reaction chamber to produce diethylbenzene, which is then removed from within the reaction chamber. The reaction temperature is preferably between approximately 250° C. and approximately 400° C. at a gas pressure between approximately 1.0 atmospheres and approximately 5.0 atmospheres. The ethylbenzene and ethanol are preferably provided in a molar ratio of between 1 to 1 and 1 to 6.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Cl:12][C:13]([F:21])([F:20])[C:14]([Cl:19])([F:18])[CH2:15][CH2:16]I.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:19][C:14]([F:18])([C:13]([Cl:12])([F:21])[F:20])[CH2:15][CH2:16][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: FC(F)(Cl)C(F)(Cl)CCI
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCC(F)(F)F)CCC(F)(Cl)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.4 %

Procedure:
1.6 g of 2-(3,3,3-trifluoropropyl)malononitrile and 3.1 g of 1,2-dichloro-4-iodo-1,1,2-trifluorobutane were dissolved in 5 ml of dimethyl sulfoxide, 1.4 g of potassium carbonate was added, and the mixture was stirred at room temperature for 6 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.9 g of 2-(3,4-dichloro-3,4,4-trifluorobutyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (54)).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[N:18][C:17]([CH3:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:22].[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([CH3:21])[N:18]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCNCC2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-chloro-3,5-dimethylpyrazine (2.8 g), 1-Boc-piperazine (3.7 g), palladium (II) acetate (225 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (953 mg) and sodium tert-butoxide (2.7 g) was added toluene (40 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 3′,5′-dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (5 g). 3′,5′-Dimethyl-2,3,5,6-tetrahydro[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (5 g) was dissolved in chloroform (15 mL), 4N hydrogen chloride/ethyl acetate (15 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (3.3 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCc1nc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: Nc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(Nc2ccc(CO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 75 °C
Yield: 16 %

Procedure:
2-Chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.140 g, 0.55 mmol) and 4-aminobenzyl alcohol (0.135 g, 1.1 mmol) were suspended in acetic acid (5 mL). The mixture was heated to 75° C. for 1 h. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethyl acetate) and then triturated with hexanes to afford the title compound (0.030 g, 16%) as a yellow solid. MW=340.81. 1H NMR (DMSO-d6, 500 MHz) δ 10.24 (s, 1H), 8.42-8.31 (m, 2H), 7.75-7.68 (m, 3H), 7.61 (t, J=7.5 Hz, 1H), 7.36-7.28 (m, 2H), 5.11 (t, J=5.5 Hz, 1H), 4.48 (d, J=5.5 Hz, 2H), 2.78 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 341 [M+H]+.
Reaction SMILES: CO.[C:3]1([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[O:23])[C:18](OCC)=[O:19])[N:16]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>O1CCCC1>[OH:23][CH:17]([C:15]1[N:16]=[C:12]([NH:11][C:10]([NH:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:24])[S:13][CH:14]=1)[CH2:18][OH:19]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)Nc1nc(C(O)CO)cs1
Temperature: 25 °C

Procedure:
7 ml of methanol were added dropwise, over a period of one hour, to a mixture comprising 1 g of ethyl 2-(3-phenylureido)thiazol-4-ylglyoxylate, 0.6 g of sodium borohydride and 20 ml of tetrahydrofuran kept heated under reflux. The resulting mixture was cooled to room temperature and acidified with 3N hydrochloric acid. The solvent was evaporated off under reduced pressure, and the residue was washed with water, giving the desired compound as a white powder.