Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][C:35]([OH:38])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (25.2 mL, 0.18 mol) in anhydrous THF (500 mL) is cooled to 0° C. and n-butyllithium (112.5 mL of a 1.6 M solution in THF, 0.18 mol) is added dropwise over 20 minutes to the cooled solution. The reaction mixture is stirred for an additional 15 minutes at 0° C. and then tri-n-butyltinhydride (48.4 mL, 0.18 mol) is added dropwise over 30 minutes. The reaction mixture is then stirred for one hour and then cooled to −78° C. N-(t-butoxycarbonyl)-3-pyrrolidone (0.15 mol) in THF (500 mL) is then added dropwise to the cooled solution over one hour. After addition is complete, the reaction is stirred for 2 hours at −78° C. and then quenched with buffer (pH 6). The mixture is extracted with ethyl acetate, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatrography (5% ethyl acetate/hexane to provide 1-(t-butoxycarbonyl)-3-hydroxy-3-tributylstannyl pyrrolidine.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)#[N:2].[CH:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH2:13].Cl[O-].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:13][CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:9][N:8]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCC(=O)O
Reactant: N#Cc1ccc(C=NO)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=NOC(CC(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a solution of 4-cyanobenzaldoxime (see Ex 43, Part A) (312 g, 2.13 mol) in tetrahydrofuran (3000 ml) at room temperature was added vinyl acetic acid (552 g, 6.41 mol). The yellow solution was cooled in an ice bath and sodium hypochlorite solution (5200 ml) was added in a dropwise fashion over 2h. After stirring overnight at room temperature the reaction was quenched with a 5% citric acid solution and diluted with 200 ml ether. The layers were separated and the aqueous acidified to pH 4 using citric acid. The acid layer was washed twice with 200 ml ether, the ether layers combined and extracted with saturated sodium bicarbonate solution. After acidifying the basic layer with citric acid, the product was extracted into 400 ml ether. The organic phase was washed three times with 150 ml water, once with brine, dried (MgSO4) and concentrated to give 220 g of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid as a white solid. Recrystallization from 25% water/ethanol yielded 165 g of analytically pure material. Anal. Calcd for C12H10N2O3 : C,62.61; H,4.38; N, 12.17. Found: C. 62.37; H 4.47; N, 11.71. 1H NMR(300 MHz, CDCl3): δ 7.77-7.76 (d, 2H, J=1.8 Hz); 7.72-7.71 (d, 2H, J=1.8 Hz); 5.22-5.14 (m, 1H); 3.63-3.54 (dd, 1H, J=10.6 Hz, 16.8 Hz); 3.19-3.11 (dd, 1H, J=7.3Hz, 16.8 Hz); 3.00-2.93 (dd, 1H, J=6.2 Hz, 16.5 Hz); 2.79-2.72 (dd, 1H, J=7.3 Hz, 16.5 Hz). IR(KBr pellet): 3202, 2244, 1736, 1610, 1432, 1416, 1194, 1152, 928, 840, 562 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16]I)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21](=[O:29])[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:29])[C:22]([CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]
Reactant: ICCc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Product: CCOC(=O)C(C)(CCc1cccc(OCc2ccccc2)c1)C(=O)OCC

Procedure:
2-(3-Benzyloxyphenyl)ethyl iodide and 2-Methylmalonic acid diethyl ester were used in the same manner as working example 52 (3) to give the subject compound.
Reaction SMILES: C.N[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]([O-])=O.[Na+]>O>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[CH2:3])=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: NC=Cc1ccccc1
Agent: C
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(N)cc1

Procedure:
11.4 g of sodium nitrite, 28.0 g of sulfanilic acid and 1200 g of 0° C. water were fed into a reactor to form diazonium sulfanilate, to which was added 200 g of a carbon black pigment, Raven C. When the generation of nitrogen ceased, the reaction mixture was concentrated, and further reacted at an elevated temperature. The resulting mixture was extracted with ethanol for 12 hours in a Soxhlet's extractor to remove unreacted compounds and side products, and this was again dissolved in water and filtered to obtain a dispersion of about 20 wt. % sulfanilate-processed carbon black pigment. On the other hand, 3.6 g of aminostyrene, 2.1 g of sodium nitrite and 150 g of water were fed into a separate reactor to form a diazonium salt of 4-aminostyrene, and this was dissolved in 10 g of ethanol. The sulfanilate-processed carbon black pigment dispersion was added to the diazonium salt solution and reacted for 18 hours with stirring. Then, this was filtered and purified through Soxhlet extraction to obtain a dispersion of a carbon black pigment having 4-aminostyrene added to its surface. Next, 30 g of deionized water was degassed in a nitrogen atmosphere at 90° C. in a reactor, and a mixture of 28.13 g of the 4-aminostyrene-added carbon black pigment dispersion, 2.0 g of methyl methacrylate, 2.0 g of butyl acrylate, and 1.0 g of polyethylene glycol 2000 monomethyl ether acrylate dissolved in 3.0 g of deionized water was dropwise added thereto over a period of 20 minutes. 0.22 g of potassium persulfate was added thereto and reacted at 80° C. for 18 hours. The resulting product was concentrated under reduced pressure, and extracted with acetone in an Soxhlet's extractor to remove the non-added polymer. The process gave an intended dispersion of a pigment having a polymer group bonded to its surface.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([OH:23])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13]2)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=[O:26])C.N1C=CC=CC=1>ClCCl>[C:21]([OH:22])(=[O:26])[CH3:20].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[C:16]([OH:23])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Agent: O=C(Nc1ccc(Cl)cc1)Nn1cnc2c(O)cccc2c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O
Reaction time: 8 h

Procedure:
A mixture of 1-(p-chlorophenyl)-3-(3,4-dihydro-8-hydroxy-4-oxo-3-quinazolinyl)urea (0.66 g, 2.00 mmol) in dichloromethane is treated with acetyl chloride (0.155 mL, 2.11 mmol) and pyridine (0.165 mL, 2.04 mmol), stirred overnight, washed sequentially with 5% hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain a solid. The solid is washed with dichloromethane and dried to give the title product as a white solid, 0.30 g, mp 216°-218° C., which is identified by 1HNMR spectral analysis.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH:8]=1
Reactant: Oc1cccnc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccnc2)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 27.1 %

Procedure:
To an N,N-dimethylformamide (30.0 mL) solution of 3-hydroxypyridine (3.00 g, 31.5 mmol) and 4-fluorobenzaldehyde (5.08 g, 41.0 mmol) was added potassium carbonate (8.71 g, 63.0 mmol) under nitrogen atmosphere, which was stirred for 17 hours at 70° C. The reaction mixture was then cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1→3:1) to obtain the title compound (1.70 g, 27.1%).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[CH3:22].B(Br)(Br)Br.COC1C=C2C(=CC=1)N(CC1C=CC=CC=1)C(C)=C2CC(O)=O.Cl>C(Cl)Cl.CCO>[OH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]([CH3:22])=[C:5]2[CH2:4][C:3]([OH:23])=[O:2]
Reactant: COC(=O)Cc1c(C)n(Cc2ccccc2)c2ccc(O)cc12
Agent: BrB(Br)Br
Agent: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(CC(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Reaction time: 17 h
Yield: 100 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester. Three mL (30 mmol) of BBr3 was added to 3.1 g (10 mmol) of 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid in 250 mL of CH2Cl2 and the mixture stirred for 17 hours. After stirring with 1N HCl, some EtOH was added, the organic layer separated, washed with a saturated NaCl solution, dried and concentrated at reduced pressure to give 2.95 g (100% yield) of crude 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid. A methanol solution of 1.7 g of he material was treated with sulfuric acid as described in Part A to give after silica gel chromatography (30% ether/hexane→60% ether/hexane) 1.5 g of 5-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester.
Reaction SMILES: OS(O)(=O)=O.[OH:6][CH2:7][C:8]([CH2:13][OH:14])([CH3:12])[C:9]([OH:11])=[O:10].[CH3:15]O>>[CH3:15][O:10][C:9](=[O:11])[C:8]([CH2:13][OH:14])([CH3:12])[CH2:7][OH:6]
Reactant: CO
Reactant: CC(CO)(CO)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(CO)CO
Temperature: 25 °C
Reaction time: 70 h

Procedure:
Add H2SO4 (4.5 g) to a suspension of 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid (100 g) in MeOH (1 L, HPLC grade solvent) and stir at room temperature through the week-end (ca. 70 h). Remove the solvent and partition the residue between EtOAc (1 L) and H2O (100 mL). Re-extract the aqueous layer with EtOAc, and dry the combined organic layers over MgSO4. Filter and concentrate under reduced pressure to yield 3-hydroxy-2-hydroxymethyl-2-methyl-propionic acid methyl ester. 1H NMR (CDCl3, 300 MHz): δ ppm 3.9 (d, 2H, J=11.1. Hz), 3.76 (s, 3H), 3.71 (d, 2H, J=1-1. Hz), 2.8 (bs, 2H), 1.1 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[C:28]2[CH:29]=[C:30]3[O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][C:31]3=[CH:32][C:33]=2[N:34]=[CH:35][N:36]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:27]4[C:28]5[CH:29]=[C:30]6[O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][C:31]6=[CH:32][C:33]=5[N:34]=[CH:35][N:36]=4)=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cc3c(cc12)OCCOCCOCCO3
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)cn2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(Oc3ncnc4cc5c(cc34)OCCOCCOCCO5)cn2)c1=O
Temperature: 25 °C
Yield: 93.6 %

Procedure:
2-(4-Fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 4-Chloro-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]-naphthalene (2.08 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude title compound and further purification to yield product (3.68 g, 90%). 1HNMR (400 MHz, DMSO): 9.18 (s, 1H), 8.60 (m, 3H), 8.45 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H), 7.21 (m, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+587.6. found 587.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(#N)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cccc(Cl)n1
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCNCC2)n1
Yield: 81.4 %

Procedure:
54.4 g of 2-chloro-6-trifluoromethyl pyridine are dissolved into a mixture of 350 ml of acetonitrile and 77.4 g of anhydrous piperazine. The mixture is filtered and washed with acetonitrile. The solvent is evaporated. The residue is taken up with dichloromethane and washed with water. The solution is dried over magnesium sulfate. The solvent is evaporated and the residue distilled, to obtain 56.4 g of 1-[6-(trifluoromethyl)-2-pyridinyl]piperazine (81.4% yield), having a boiling point of 103° C. at 0.05 mm Hg.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29](O)=[O:30].[NH2:49][CH2:50][C:51]1[CH:56]=[N:55][C:54]([CH3:57])=[CH:53][N:52]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([NH:49][CH2:50][C:51]1[CH:56]=[N:55][C:54]([CH3:57])=[CH:53][N:52]=1)=[O:30]
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cnc(CN)cn1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)cn1
Yield: 42 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 2-(aminomethyl)-5-methylpyrazine, the title compound was obtained as a white powder in 42% yield: mp 172-173° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.36 (s, 1H), 7.63 (d, J=7.8 Hz, 2H), 7.42 (d, J=7.8 Hz, 2H), 6.77 (t, J=4.8 Hz, 1H), 4.68 (d, J=4.8 Hz, 2H), 4.59 (s, 2H), 4.11-4.05 (m, 2H), 3.49-3.43 (m, 2H), 2.59 (s, 3H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 157.5, 155.5, 153.0, 152.6, 148.7, 143.4, 142.7, 139.7, 130.6, 130.2, 128.5, 125.9, 125.8, 122.1, 117.7, 47.6, 42.3, 42.0, 41.9, 21.2, 17.3; MS (ES+) m/z 491.2 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16]>>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(C)=CCCl
Product: CC(C)=CCn1ccc2c(C=O)cccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 1-chloro-3-methyl-2-butene instead of the benzyl bromide used in Example 1 to give 554 mg of 1-(3-methyl-2-butenyl)indole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 52%.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH2:41][C:42]23[C:48]([F:50])([F:49])[CH:47]2[CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH2:41][C:42]34[C:48]([F:50])([F:49])[CH:47]3[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3(F)F)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-4-(((1RS,6SR)-7,7- difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoate (stereochemistry arbitrarily assigned), the title compound was obtained as a yellow oil (0.23 g, 81%): MS (ES+) m/z 341.0 (M−55).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:15])[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].C([O-])([O-])=[O:30].[Na+].[Na+].OO>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([NH2:15])=[O:30])[C:8]=2[N:7]=[C:6]1[C:16]1[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (1.10 g, 2.88 mmol) dissolved in ethanol (100 mL) and 3 M Na2CO3 (10 mL) was added 30% hydrogen peroxide (10 mL). After stirring overnight at room temperature, the reaction was concentrated. The residue was then redissolved in EtOAc, and washed with NaHSO4(10% soln), NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from methanol, yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylic acid amide (0.83 g, 2.08 mmol, 72% yield). M.p. 260-261° C. 1H-NMR (200 MHz, CD2Cl2): δ 8.10 (dd, J=1.1, 7.7 Hz, 1H, H5), 7.71 (br d, J=8.1 Hz, 1H, H7), 7.59 (m, 1H, H4′), 7.43 (dd, J=7.7, 8.1 Hz, 1H, H6), 7.28 (m, 1H, H4″), 7.13 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.43 (s, 2H, CH2PhF2), 1.92 (s, 2H, NH2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[C:15](Cl)=[CH:14][C:13]([NH2:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:9][C:10]1[C:15]([S:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)=[CH:14][C:13]([NH2:17])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Cc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Sc2cc(N)c([N+](=O)[O-])cc2Cl)c1
Temperature: 90 °C
Yield: 80.8 %

Procedure:
A mixture of 3-methyl-benzenethiol (2.30 mL, 19.3 mmol), 4,5-dichloro-2-nitro-phenylamine (2.00 g, 9.66 mmol), potassium carbonate (2.67 g, 19.3 mmol), and DMF (48 mL) was heated at 90° C. for 16 h. The reaction mixture was cooled to 23° C. EtOAc was added and the organic layer was washed with saturated aqueous NaHCO3 (2×80 mL) and brine (1×80 mL). The aqueous layers were extracted with EtOAc (3×80 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-100% EtOAc/hexanes) to yield the titled compound (2.30 g, 81%). 1H NMR (400 MHz, CDCl3): 8.12 (s, 1H), 7.41-7.36 (m, 3H), 7.34-7.30 (m, 1H), 5.95 (s, 1H), 5.88 (br s, 2H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:22]([CH3:24])([CH3:23])[CH:21]2[OH:25])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(Cl)ccc1N=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.5 %

Procedure:
To a mixture of 2-{[1-(3-bromo-phenyl)-methylidene]-amino}-5-chloro-benzoic acid methyl ester (5.3 g, 15 mmol) and ytterbium(III) triflate hydrate (0.93 g, 1.5 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (1.08 g, 15 mmol) and water (0.27 mL, 15 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (6.4 g, 100%) as a light yellow oil: LC/MS m/e calcd for C19H19BrClNO3 M+: 424.7, observed: 408.0.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=1[NH2:6].C1COCC1.Br[C:18]1[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=[C:22]([Cl:24])[CH:23]=1>CN(C=O)C>[Cl:24][C:22]1[CH:23]=[C:18]([NH:6][C:5]2[C:4]([F:3])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=1
Reactant: Nc1c(F)cccc1F
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1Nc1cc(Cl)nn2ccnc12
Temperature: 50 °C

Procedure:
To 60% NaH (22.5 mg, 0.563 mmol) in DMF (400 μl) was added 2,6-difluoroaniline (24 mg, 0.186 mmol). After stirring at RT for 5 minutes THF (1000 μl) was added followed by 8-bromo-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.186 mmol, prepared as described in Example 1, step (1b). The reaction was heated at 50° C. for 3 hours. The reaction was quenched with a few drops of water and methanol. The solution was then concentrated in vacuo to give crude 6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:16][OH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C:13]([CH2:14][O:15][S:35]([CH3:34])(=[O:37])=[O:36])([CH2:16][O:17][S:35]([CH3:34])(=[O:37])=[O:36])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[O:27][S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cn([C@@H]2OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H](OCc3ccccc3)[C@H]2OS(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a solution of nucleoside 5 (1100 mg, 2.91 mmol) in anhydrous tetrahydrofuran (20 cm3) was added anhydrous pyridine (5 cm3) followed by methanesulfonyl chloride (1.2 ml, 15.5 mmol). The mixture was stirred under a nitrogen atmosphere for 18 h at room temperature. The reaction mixture was evaporated to dryness under reduced pressure and dissolved in ethyl acetate. The organic phase was washed with saturated aqueous solution of sodium hydrogen carbonate (3×10 cm3) and dried (Na2SO4). The organic phase was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (2% methanol, v/v) as elutxnt to afford nucleoside 11 (908 mg, 51%). δC (CDCl3) 163.3, 150.6, 135.6, 134.6, 128.7, 128.3, 112.2, 87.9, 85.0, 83.1, 80.9, 77.2, 76.9, 76.6, 73.3, 66.6, 66.2, 38.6, 37.6, 37.6, 12.2.