Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10]Br>C(Cl)(Cl)Cl>[Br:10][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[S:1][CH:5]=1
Reactant: BrBr
Reactant: c1ccc2sccc2c1
Solvent: ClC(Cl)Cl
Product: Brc1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 6 g (0.044 mol) of Benzo[b]thiophene and 80 mL of CHCl3. is cooled by using an ice-water bath. A solution of 7.89 g (0.044 mol) of Br2 and 40 mL of CHCl3 is added slowly. After the addition is completed, the mixture is stirred for 1 h at room temperature and then hydrolysed with 150 mL of saturated aqueous Na2S2O6 solution. The aqueous phase is extracted two times with 150 mL of CHCl3. The combined organic phases are washed several times with water, dried over magnesium sulfate and then are concentrated under reduced pressure. The crude product is purified by distillation to give a colourless liquid (8.0 g, 84% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=1)=[O:17])C>>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([F:30])[C:25]=1[O:29][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:21][CH:19]1[CH2:20][CH:18]1[C:16]([OH:17])=[O:15]
Reactant: CCOC(=O)C1CC1Cc1cc(F)c(O)c(F)c1
Reactant: CCCSc1ncccc1CCl
Product: CCCSc1ncccc1COc1c(F)cc(CC2CC2C(=O)O)cc1F
Yield: 76.2 %

Procedure:
3-chloromethyl-2-propylsulfanyl-pyridine (0.016 g, 0.08 mmol) obtained in Step C of Preparation Example 14 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.02 g, 0.08 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.024 g, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[C:14](=O)[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:5]=[N:6][CH:7]=1.NN.S(NN)(C1C=CC(C)=CC=1)(=O)=O.C([BH3-])#N.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:5]=[N:6][CH:7]=1
Reactant: O=C1C2CCN(CC2)C1Cc1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: NN
Agent: [BH3-]C#N
Product: Brc1cncc(CC2CC3CCN2CC3)c1

Procedure:
The manner in which 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane and other analogous compounds possessing substituents at the C-5 position of the pyridine ring are synthesized can vary. In another example, 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane can be prepared starting with the aldol condensation of 5-bromo-3-pyridinecarboxaldehyde and 3-quinuclidinone hydrochloride (commercially available from Aldrich Chemical Company) which proceeds in 75% yield using potassium hydroxide in methanol. The carbon-carbon double bond of the resulting 2-((5-bromo-3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one can be selectively reduced with an appropriate reducing agent, such as lithium tri-sec-butylborohydride (L-Selectride®) or potassium tri-sec-butylborohydride (K-Selectride®) (available from Aldrich Chemical Company) in tetrahydrofuran at −78° C. using methodology described by J. M. Fortunato et al., J Org. Chem. 41 (12): 2194-2200 (1976) or with sodium borohydride modified with nickel(1) chloride hexahydrate in an ethanolic or aqueous solution to give 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one. The latter ketone can be reduced under Wolff-Kishner conditions with hydrazine and base (or under modified Wolff-Kishner conditions with tosylhydrazine and sodium cyanoborohydride) to yield 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:31].BrC1C(C)=CC(C)=CC=1C.OCC1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(N(CC)CC)C.CS(Cl)(=O)=O.ClCC1C=CC(C2C(C)=CC(C)=CC=2C)=CC=1>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C.C1COCC1>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([CH3:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=3[CH3:28])=[CH:20][CH:21]=2)=[CH:8][C:7]([CH3:31])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:32])=[O:2]
Reactant: COC(=O)COc1cc(OC)c(SCc2ccc(-c3c(C)cc(C)cc3C)cc2)cc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2c(C)cc(C)cc2C)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Preparation of [5-Methoxy-2-methyl-4-(2′,4′,6′-trimethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 5A) 2-Bromo-1,3,5-trimethyl-benzene (396 mg, 2mmol), 4-hydroxymethylphenylboronic acid (334 mg, 2.2 mmol), cesium carbonate (1.3 g, 4 mmol), and PdCl2(dppf) (82 mg, 0.1 mmol) were added to 5 ml of a 1:1 solution of DMF/THF. The reaction was flushed with nitrogen and heated to 90° C. for 1 h. The reaction was cooled, poured into diethyl ether and washed with water (2×10 ml), brine (1×10 ml) and dried over anhydrous sodium sulfate. The organic solution was filtered through silica gel, eluted with diethyl ether, and concentrated. The crude product was dissolved in 10 ml dichloromethane. Added to this solution were triethylamine (202 mg, 2 mmol) then methanesulfonyl chloride (184 mg, 1.6 mmol) and allowed to stir at ambient temperature for 18 h. The reaction was poured into water and extracted with methylene chloride. The organic solution was dried over anhydrous sodium sulfate, decanted and concentrated to provide the crude alkyl chloride. The product from Example 1D (387 mg, 1.6 mmol), the crude 4′-chloromethyl-2,4,6-trimethyl-biphenyl, and cesium carbonate (1 g, 3.06 mmol) were stirred in 10 ml acetonitrile for 3 h, filtered, concentrated, and purified by normal phase chromatography to afford the title product. MS m/z 451 (M+1). Step 2. Preparation of [5-Methoxy-2-methyl-4-(2′,4′,6′-trimethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid The title compound was prepared in the manner analogous to Example 1 using 5A. mp 141° C.; 400 MHz 1H NMR (DMSO-d6) δ 12.81 (br(s), 1H), 7.04 (d, 2H, J=8.4 Hz), 6.77 (m, 3H), 6.69 (s, 2H), 6.36 (s, 1H), 4.43 (s, 2H), 3.82 (s, 2H), 3.58 (s, 3H), 2.03 (s, 3H), 1.82 (s, 3H), 1.67 (s, 6H). MS m/z 437 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:28]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:15]3[CH:7]=[C:8]([CH3:28])[S:9][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2ncnc(NCCc3ccc4c(c3)OCO4)c2c1Cl
Reactant: c1c[nH]cn1
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 5-chloro-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:15]1([CH2:20][CH2:21][CH2:22]O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH2:21][CH2:20][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: OCCCN1CCCC1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a suspension of 4-chloro-6-cyano-7-hydroxyquinoline (10.22 g, 50 mmol), (prepared as described for the starting material in Example 1), 3-(pyrrolidin-1-yl)propan-1-ol (8.1 ml, 60 mmol) and triphenylphosphine (26.2 g, 100 mmol) in methylene chloride (200 ml) was added diethyl azodicarboxylate (16.4 ml, 100 mmol) in portions. After stirring the reaction mixture for 2 hours at ambient temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene choride (1/4/5 followed by 1/0/9) followed by methanol saturated with ammonia/methylene chloride (1/9 followed by 2/8). The fractions containing the expected product were combined and the volatiles were removed under vacuum. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (14.3 g, 90%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([OH:8])[CH:6]([OH:9])[CH:5]([CH2:10][O:11][P:12]([OH:15])([OH:14])=[O:13])[O:4][CH:3]1[CH2:16][CH2:17][CH2:18][O:19]C(=O)CCCCC.[OH-].[Na+:28].C([O-])(=O)C.[Na+]>O.C(O)C.C(OCC)C>[Na+:28].[OH:9][CH:6]1[CH:7]([OH:8])[CH:2]([OH:1])[CH:3]([CH2:16][CH2:17][CH2:18][OH:19])[O:4][CH:5]1[CH2:10][O:11][P:12](=[O:13])([OH:14])[O-:15]
Reactant: CCCCCC(=O)OCCCC1OC(COP(=O)(O)O)C(O)C(O)C1O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: O=P([O-])(O)OCC1OC(CCCO)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
Hexanoic acid 3-(3,4,5-trihydroxy-6-phosphonooxymethyl-tetrahydro-pyran-2-yl)-propyl ester (2.1 g, 5.25 mmol) (prepared in Example 8) was dissolved in water (50 ml) and aqueous sodium hydroxide (1M, 4 eq, 12 ml) was added and stirred for 40 minutes at room temperature after which the solution was acidified (pH˜2) with Dowex 50W X8 H+ form. The solution was washed with dichloromethane (2×100 ml) and the solvent was removed. The residue was then dissolved in a minimum of water and added dropwise to a solution of sodium acetate (1.2 eq, 0.34 g) in ethanol (150 ml) and diethyl ether (50 ml). The resulting precipitate was centrifuged and the ethanol decanted off, the residue was washed with diethyl ether (2×100 ml) and dried to give phosphoric acid mono-[3,4,5-trihydroxy-6-(3-hydroxy-propyl)-tetrahydro-pyran-2-ylmethyl] ester monosodium salt (1.01 g, 63%). 1Hnmr (500 MHz, D2O): δ 1.35-1.46 (m, 2H), 1.46-1.58 (m, 1H), 1.62-1.72 (m, 1H), 3.41-3.50 (m, 3H) 3.56 (t, J=9.0 Hz, 1H), 3.65-3.70 (m, 1H), 3.71-3.79 (m, 2H), 3.83-3.96 (m, 2H); ESMS (−ve) 301 (M−H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:38])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:34](=[CH:35][CH:36]=1)[O:33][C:12]1([CH2:16][CH2:15][N:14](C(=O)[C@H](C3C=CC4C(=CC=C(OC)C=4)C=3)C)[CH2:13]1)[CH2:11][C:10]2=[O:37]>CC(O)=O>[CH3:2][O:3][C:4](=[O:38])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:34](=[CH:35][CH:36]=1)[O:33][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:37]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)[C@@H](C)c3ccc4cc(OC)ccc4c3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Yield: 34.8 %

Procedure:
HCl 20% aq. (5 ml) was added to a suspension of (−)-(E)-3-[1′-[(S)-2-(6-methoxynaphthalen-2-yl)propanoyl]-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (600 mg, 1.20 mmol) in glacial AcOH (5 ml). The mixture was treated following the procedure used for Example 3, Step B to give (−)-(E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (120 mg) as a white solid (free base).
Reaction SMILES: [Br:1]Br.[OH:3][CH:4]([CH2:18][OH:19])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:17])[CH:8]=1>C(O)(=O)C>[Br:1][C:8]1[C:9]([CH3:17])=[N:10][C:11]2[C:16]([C:7]=1[NH:6][CH2:5][CH:4]([OH:3])[CH2:18][OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: BrBr
Reactant: Cc1cc(NCC(O)CO)c2ccccc2n1
Solvent: CC(=O)O
Product: Cc1nc2ccccc2c(NCC(O)CO)c1Br
Reaction time: 2 h

Procedure:
Bromine (33.7 g) was added dropwise to a solution of 49 g of N-(2,3-dihydroxypropyl)-2-methyl-4-quinolinamine in 600 ml of acetic acid. After two hours of stirring, the resultant oil was separated by decantation, dissolved in 500 ml of water and the mixture made alkaline (pH=10) with potassium carbonate. The resultant free base solid was filtered and recrystallized from ethanol. The yield was 33 g, mp 140°-141° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH:23]3[CH2:28][CH2:27][CH:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:18]=2)[CH:13]=1)[C:8]([F:11])([F:10])[F:9].C(O)C.[OH-].[Na+].O.Cl>>[C:29]([CH:26]1[CH2:27][CH2:28][CH:23]([O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([CH:7]([NH:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])[C:8]([F:11])([F:9])[F:10])[CH:21]=[CH:20]3)[CH2:24][CH2:25]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)CCNC(c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1CCC(Oc2ccc3cc(C(NCCC(=O)O)C(F)(F)F)ccc3c2)CC1
Reaction time: 1 h

Procedure:
3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionic acid methyl ester (164 mg, 0.352 mmol) was dissolved in Ethanol (2 mL, 40 mmol) then treated with 1 M of sodium hydroxide in Water (2 mL, 2 mmol). The mixture was stirred vigorously for 1 hour. pH was adjust to 3-4 with 6 N HCl and reaction was then extracted three times with EtOAc. Organics were combined then dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Ethyl ether was then added and a white ppt formed. The ppt. was removed via filtration to give a white solid that 99% pure by NMR and HPLC-traces of ethanol remain. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.83 (s, 9H) 0.93-1.10 (m, 1H) 1.11-1.27 (m, 2H) 1.27-1.42 (m, 2H) 1.73-1.89 (m, 2H) 2.19 (d, J=10.29 Hz, 2H) 2.67 (t, J=6.53 Hz, 2H) 3.03-3.18 (m, 2H) 4.22-4.37 (m, 1H) 5.33-5.51 (m, 1H) 7.13 (dd, J=8.91, 2.38 Hz, 1H) 7.21-7.29 (m, 1H) 7.46 (d, J=8.78 Hz, 1H) 7.76 (d, J=9.04 Hz, 1H) 7.85 (d, J=8.78 Hz, 1H) 7.93 (s, 1H).
Reaction SMILES: [C:1]([CH:4]1[C:13]2([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[O:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].[NH2:27][N:28](C)[C:29](=O)OC(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:49]>C(O)C>[ClH:49].[ClH:49].[CH3:29][N:28]1[C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][C:13]3([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:4]=2[C:1]([CH3:2])=[N:27]1
Reactant: CC(=O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(C)c2c1C1(CCNCC1)Oc1ccccc1-2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (250 mg, 0.70 mmol), tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) and p-toluene sulfonic acid monohydrate (27 mg, 0.14 mmol) in ethanol (8 mL) was heated at 80° C. overnight. Additional tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixture was heated at 80° C. for 6.5 h, then another portion of tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixture was heated at 80° C. for 2 h. HCl (0.87 mL of 4.0 M in dioxane, 3.5 mmol) was added and the mixture was stirred at 80° C. for 1 h. After cooling, the precipitate was collected via filtration and washed with cold EtOH to provide 1,3-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride (295 mg, >100%, may contain some methyl hydrazine HCl salt) as a solid. ESI-MS m/z calc. 269.2, found 270.5 (M+1)+; Retention time: 1.11 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.71 (dd, J=7.8, 1.3 Hz, 1H), 7.33-7.27 (m, 1H), 7.17-7.14 (m, 1H), 7.11-7.05 (m, 1H), 4.02 (s, 3H), 3.28-3.15 (m, 4H), 2.40-2.30 (m, 2H), 2.23 (s, 3H), 2.07-1.97 (m 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH2:13][OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.C(Cl)Cl>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[CH2:13][O:14][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1-c1ccccc1
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cc(COCc2ccccc2-c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a solution of 1.53 g (6.26 mmol) (3,5-bis-trifluoromethyl-phenyl)-methanol in 15 ml N,N-dimethylformamide 0.30 g (7.52 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture was stirred for 1 hr. After the addition of 1.27 g (6.26 mmol) 2-chloromethyl-biphenyl in 5 ml N, N-dimethylformamide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate 40:1) to give 1.25 g (47%) 2-(3,5-bis-trifluoromethyl-benzyloxymethyl)-biphenyl as a colorless oil, MS (EI):410 (M+).
Reaction SMILES: [Na].[CH3:2][SH:3].[CH3:4][CH2:5][NH:6][C:7]1[N:12]=[C:11](Cl)[N:10]=[C:9]([NH:14][CH:15]([CH3:17])[CH3:16])[N:8]=1>CO>[CH3:2][S:3][C:11]1[N:10]=[C:9]([NH:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([NH:6][CH2:5][CH3:4])[N:12]=1
Reactant: CCNc1nc(Cl)nc(NC(C)C)n1
Reactant: CS
Agent: [Na]
Solvent: CO
Product: CCNc1nc(NC(C)C)nc(SC)n1
Temperature: 25 °C

Procedure:
1 g of sodium was added to 100 ml of dry methanol. The solution was allowed to cool to room temperature, 12 g of methanethiol was added, then 4.5 g atrazine, and the mixture was refluxed for 2 hours. The solvent was evaporated, the residue was dissolved in water, and the solution was extracted with ether. The extract phase was dried (MgSO4) and the solvent was evaporated. The residue was dissolved in a minimum amount of boiling hexane. The solution was cooled and the solid product was collected and dried to give 2-(methylthio)-4-(1-methylethylamino)-6-(ethylamino)-1,3,5-triazine (15A) (Ametryne).
Reaction SMILES: [CH:1]([Mg])=[CH2:2].Cl[CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:17].Cl.[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O1CCCC1>[CH:1]([C:7]12[O:17][CH:6]1[CH2:5][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH2:2]
Reactant: O=C1CCCCCCCCCCC1Cl
Reactant: C=C[Mg]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC12CCCCCCCCCCC1O2
Temperature: 95 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A four-neck flask equipped with a thermometer, stirrer and condenser tube was charged with a tetrahydrofuran solution of vinylmagnesium (24 mmol), and to the solution, toluene (16 ml) was added. At 0° C., a toluene solution of 2-chlorocyclododecanone (2.94 g, 13.5 mol) was added dropwise for reaction for 1 hour. After completion of reaction, 16% hydrochloric acid (5 g) was added for hydrolysis, and the solution was separated to take out the organic layer. The organic layer was washed with 2% sodium hydroxide aqueous solution (10 ml). To the obtained toluene solution, added were 30% sodium hydroxide aqueous solution (6.8 g, 51.0 mmol) and tetrabutylammonium chloride (0.0417 g, 0.150 mmol), and the mixture was stirred for reaction at 95° C. for 2 hours. After completion of reaction, the solution was separated to take out the organic layer, and the organic layer was washed with 10% sulfuric acid (5 ml), saturated sodium hydrogencarbonate aqueous solution (10 ml) and a saline solution (10 ml). The solvent was distilled away under reduced pressure, and the residue was distilled for purification under reduced pressure, to obtain 1-vinyl-13-oxabicyclo[10.1.0]tridecane (2.42 g, 11.5 mmol, chemical purity 99%, cis form:trans form=86:14). The yield was 85%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12](=O)[CH2:13][C:14]#[N:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.[NH2:18][NH2:19].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(O)C.O>[CH3:1][C:2]1[C:3]([C:12]2[CH:13]=[C:14]([NH2:15])[NH:19][N:18]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NN
Reactant: Cc1nc2ccccc2nc1C(=O)CC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2ccccc2nc1-c1cc(N)[nH]n1
Temperature: 25 °C

Procedure:
A suspension of 3-(3-methylquinoxalin-2-yl)-3-oxopropanenitrile (45.8 g, 217 mmol) and hydrazine monohydrate (15.8 mL, 325 mmol) in acetic acid (109 mL) and ethanol (1083 mL) was refluxed for 17 h. After being cooled to ambient temperature, the reaction mixture was diluted with water (360 mL) and basified to pH 8 with sodium bicarbonate. The resulting precipitate was collected and washed with diisopropyl ether. The crude was diluted with methanol (1077 mL) and potassium carbonate (29.9 g), and then heated at 60° C. for 2 h. The precipitate was collected and washed with diisopropyl ether to give 3-(3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine. MS (APCI): m/z 226 (M+H).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:27])[C:5]([N:7]([CH3:26])[CH:8]1[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][N:10]2[C:16](=[O:25])[C:17]([OH:24])=[C:18]([C:20]([O:22]C)=O)[N:19]=[C:9]12)=[O:6])[CH3:3].C(N(CC)CC)C.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CO>[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:20]([C:18]2[N:19]=[C:9]3[CH:8]([N:7]([CH3:26])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:27])[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][N:10]3[C:16](=[O:25])[C:17]=2[OH:24])=[O:22])=[CH:38][CH:37]=1
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C)CC2N(C)C(=O)C(=O)N(C)C
Reactant: NCc1ccc(F)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Temperature: 25 °C

Procedure:
Methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-3-hydroxy-8-methyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate prepared as described in Step 2 was dissolved in methanol and treated with 1.2 eq. of triethylamine and 1.2 eq. of 4-fluorobenzylamine. The reaction mixture was refluxed overnight, then cooled to room temperature and purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound (trifluoroacetic salt) as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.4 (bs, 1H), 10.01 (bs, 1H), 7.63 (dd, J=8.6 Hz, J=5.7 Hz, 2H), 7.29 (t, J=8.6 Hz, 2H), 5.53-5.30 (m, 2H), 4.82-4.68 (m, 2H), 4.25-4.13 (m, 3H), 3.95 (bs, 1H), 3.48-3.42 (m, 1H), 3.25 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H), 3.13 (s, 3H); MS (ES) C22H27FN6O5 requires 474. Found: 475 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2cccnc2)cc1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4cccnc4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(pyridin-3-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(pyridin-3-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (50% EtOAc/hexanes) gave the product as an off white solid (0.126 g, 35% yield). MS: m/z 508.2 [M+H]+.