Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])c(F)c1
Yield: 58 %

Procedure:
A mixture of 1.1 g (4.2 mmol) of 4-methyl-4′-nitro-3′-fluorobenzophenone, 0.654 g of recrystallized N-bromosuccinimide, 60 mg benzoyl peroxide, and 20 mL CCl4 were refluxed under argon for 3 hours. The hot solution was filtered through a glass sintered filter and rinsed with 20 mL of hot CCl4, until the crystals became colorless. The crystals were washed with 6 mL of cold CCl4 and the solution was concentrated under reduced pressure. The crude product was recrystallized from hexane and dried under vacuum. The resultant yield was 58%. 1H-NMR CDCl3: δ8.18 (dd, aromatic, 2H), 7.78 (d, aromatic, 2H), 7.68 (m, aromatic, 1H), 7.56 (d, aromatic, 2H), 4.57 (s, methyl, 3H). 13C-NMR: δ 192.4 (carbonyl); 156.2, 154.0, 146.7, 144.5, 144.4, 143.7, 143.6, 135.0, 133.0 130.5, 126.5, 125.5, 119.7, 119.4 (aromatic); 31.7 (alkyl). 19F-NMR: δ −118.5 ppm.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[C:19]([F:21])[CH:20]=[C:15]3[C:14]([C:22]3[N:23]=[N:24][C:25]([C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=O)=[C:26](O)[N:27]=3)=[N:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH3:36]>C(#N)C>[CH:6]1([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[C:19]([F:21])[CH:20]=[C:15]3[C:14]([C:22]3[N:23]=[N:24][C:25]4[C:29]([CH3:34])([CH3:35])[C:30](=[O:32])[NH:36][C:26]=4[N:27]=3)=[N:13]2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(CC3CCCC3)c3ncc(F)cc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 ml (53.642 mmol) of phosphoryl chloride were added to 376 mg (0.863 mmol) of methyl 2-{3-[1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate, and the mixture was stirred at RT overnight. The reaction solution was diluted with 20 ml of dry acetonitrile and, with ice-cooling, slowly added dropwise to 83 ml of a 25% strength aqueous ammonia solution, and the mixture was stirred at RT overnight. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. The residue was triturated with DMF/methanol, filtered off with suction and dried under high vacuum. This gave 84 mg of the target compound (24% of theory).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1.[CH2:24]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH2:24]([N:28]([CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1)[CH2:29][CH:30]([CH3:32])[CH3:31])[CH:25]([CH3:27])[CH3:26]
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccccc2C1=O
Reactant: CC(C)CNCC(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1nnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1)CC(C)C
Yield: 77.2 %

Procedure:
1.64 g (5 mmol) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 1.62 g (12.5 mmol) of diisobutylamine and 20 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.63 g (77%) of 3-(5-diisobutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 138°-140°, which was converted into the hydrochloride of m.p. 177°-180°.
Reaction SMILES: ClN1[C:7](=[O:8])[N:6]([Cl:9])[C:5](=O)N(Cl)C1=O.[Cl:13][CH2:14][CH:15]1[O:19]C(=O)NC1>C(Cl)Cl>[Cl:9][N:6]1[CH2:5][CH:15]([CH2:14][Cl:13])[O:19][C:7]1=[O:8]
Reactant: O=C1NCC(CCl)O1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: O=C1OC(CCl)CN1Cl

Procedure:
8.4 grams (0.036 moles) trichloroisocyanuric acid were dissolved in dried methylene chloride. To this suspension were added 5 grams (0.036 moles) 5-Chloromethyl-2-oxazolidinone. The mixture was stirred for several hours before filtering to remove solids. The methylene chloride layer was rotovaped to recover the product, a yellow liquid Proton NMR Data: δ3.7 (m, 4 protons), 4.8(m, 1 proton). Elemental analysis Chlorine found 39.66 (theory 41.7).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].C([O:15][C:16]1[C:17](=[O:26])[C:18](=O)[C:19]=1[NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])CCC>O1CCCC1>[C:21]([NH:20][C:19]1[C:16](=[O:15])[C:17](=[O:26])[C:18]=1[NH:5][CH2:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[Cl:1])([CH3:24])([CH3:22])[CH3:23]
Reactant: NCc1cc(Cl)ccc1Cl
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2cc(Cl)ccc2Cl)c(=O)c1=O
Yield: 52.1 %

Procedure:
Employing the procedure of Example 2, Step 4, and a reaction period of 23 hours, 2,5-dichlorobenzylamine (0.88 g, 5 mmol) and 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1. 13 g, 5 mmol) in tetrahydrofuran (15 mL ) were converted to 1.52 g of a cream-colored solid. Recrystallization of this material from acetonitrile (twice) and from methanol provided 0.853 g of the tide compound as a white solid: mp 236° C. (softens 216° C.). MS (m/z) 326/328/330 (M+).
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH:22]([OH:24])[CH3:23])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[OH:24][CH:22]([CH3:23])[CH2:21][O:20][C:7]1[C:8]2[C:9](=[O:19])[CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:12][C:13]=2[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C=CCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(OCC(C)O)c2c(=O)cc(C(=O)OCC)oc12

Procedure:
To a suspension of ethyl 8-allyl-5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate (1.2 g) in ethanol (50 ml) was added 5% palladium on charcoal (0.2 g). The resulting suspension was then hydrogenated at a pressure of 4 atmospheres. After 30 minutes hydrogen uptake had ceased. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residual solid was crystallised from ethanol giving ethyl 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate identical in all respects with authentic material.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.N1C=C[CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:24]([O:5][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH2:9][CH:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:23]#[CH:22]
Reactant: CCCCCC(C)CC=CC(C)=CC(=O)O
Reactant: c1ccncc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: C#CCOC(=O)C=C(C)C=CCC(C)CCCCC
Temperature: 22 °C
Reaction time: 1 h

Procedure:
1.6 g of 3,7-dimethyl-2,4-dodecadienoic acid is dissolved in 20 ml of absolute diethyl ether and 0.55 ml of pyridine. The resulting mixture is added dropwise over a period of about 10 minutes to 0.57 ml of thionyl chloride at a temperature between 0°C. and +10°C. Subsequently the mixture is stirred for 1 hour at room temperature (22°C.), then decanted off, and the residue is washed with absolute diethyl ether. The solution is evaporated to dryness under anhydrous conditions. The residue is dissolved in 10 ml of absolute diethyl ether. The ethereal solution is added dropwise at a temperature between 0°C. and +10°C., over a period of about 20 minutes, to a solution consisting of 0.56 ml of propargyl alcohol and 0.55 ml of pyridine in 10 ml of absolute ether. After stirring overnight (16 hours) at room temperature (22°C.) the mixture is diluted with diethyl ether, washed with 1-N hydrochloric acid, saturated aqueous sodium bicarbonate solution and finally with aqueous sodium chloride solution. After drying, the ethereal phase is evaporated. The crude product is chromatographed on a 30-fold amount of Kieselgel, using hexane/diethyl ether (19:1 parts by volume) as the eluant. There is obtained 3,7-dimethyl-2,4-dodecadienoic acid propargyl ester as a colorless oil; boiling point 105°C/0.05 mmHg (bulb tube); n25 25= 1.4951.
Reaction SMILES: [Cl:1][C:2]([C:11]#[N:12])=[CH:3][S:4][C:5]([Cl:10])=[C:6]([Cl:9])[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].S(Cl)([Cl:22])(=O)=O>C(Cl)Cl.ClC(Cl)C>[Cl:10][C:5]([S:4][C:3]([Cl:22])=[C:2]([Cl:1])[C:11]#[N:12])=[C:6]([Cl:9])[C:7]#[N:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: N#CC(Cl)=CSC(Cl)=C(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: N#CC(Cl)=C(Cl)SC(Cl)=C(Cl)C#N
Temperature: 70 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
3.3 g of 1,2-dichloro-2-cyano-vinyl 2-chloro-2-cyano-vinyl sulphide were dissolved in 20 ml of methylene chloride, 2 g of potassium carbonate were added, and 2.15 g of sulphuryl chloride in 10 ml of dichloroethane were added dropwise at room temperature. The mixture was stirred at 70° C. for 12 hours and filtered, the filtrate was washed with water and concentrated and the resulting oil was chromatographed. 1.7 g of bis-(1,2-dichloro-2-cyano-vinyl) sulphide were obtained as an oil, which was identical to the product from Example 8.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:13]#[N:14]
Reactant: N#CC(Br)c1ccccn1
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(Sc1nc2ccccc2[nH]1)c1ccccn1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
A mixture of 2-mercaptobenzimidazole (0.30 g, 3.0 mmole), bromo(2-pyridyl)acetonitrile (0.59 g, 3.0 mmole) and potassium carbonate (0.37 g 3.0 mmole) in 50 ml of dry N,N-dimethylformamide was heated at 60° C. for 6 h. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with water and then saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and evaporated to give a solid. The crude product was further purified by column chromatography on silica gel (100% ethyl acetate) to give 66 mg (10%) of the title compound as a solid; mp 166-167° C.; 1H NMR (DMSO-d6)δ 9.3 (m, 1H), 8.65 (m, 2H), 8.32 (m, 1H), 7.78 (br s, 4H), 4.81 (br s, 2H) ppm; IR ν 2206, 1512, 1465, 1432, 1357, 1179, 740 cm-1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrCC1C=CC=CC=1[S:39][C:40]([F:43])([F:42])[F:41]>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:39][C:40]([F:43])([F:42])[F:41])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)Sc1ccccc1CBr
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1ccccc1SC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 1-bromomethyl-2-trifluoromethylsulfanyl-benzene (available from Fluorochem Ltd.) as starting material and making non-critical variations, to yield the title compound. 1H NMR (300 MHz, CDCl3) δ: 2.05-2.33 (m, 3H), 2.49-2.65 (m, 1H), 3.10-3.35 (m, 2H), 3.43-3.55 (m, 1H), 3.67-3.89 (m, 2H), 3.91-4.08 (m, 2H), 4.09-4.22 (m, 1H), 6.91-7.05 (m, 1H), 7.10-7.42 (m, 12H), 7.50-7.63 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.C(OO)(=[O:18])C.S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O.C(Cl)Cl>[F:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:13]([OH:18])=[N:12][CH:11]=[N:10][CH:9]=1
Reactant: N#Cc1nccc(-c2cncnc2)c1F
Reactant: CC(=O)OO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: N#Cc1nccc(-c2cncnc2O)c1F
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a vial charged with 3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.400 g, 1.998 mmol) in acetone (Volume: 11.89 ml) were added peroxyacetic acid (0.841 ml, 4.00 mmol) and sulfuric acid (0.222 ml, 4.00 mmol). The reaction mixture was refluxed for 1 h, and then allowed to cool to room temperature. The reaction mixture was neutralized with 4 M NaOH and extracted with CH2Cl2 (5×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 0-25% MeOH in CH2Cl2 over 25 min, tr=16 min) gave the title compound (263 mg, 1.204 mmol, 60.3% yield) as a yellow solid. ESI MS (M+H)+=217.1.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:7][C:6]=12.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:31]#[C:32][C:2]2[CH:3]=[N:4][N:5]3[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:7][C:6]=23)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#Cc1ccccc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccccc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-Iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1, method 2, step 2) (340 mg, 1.0 mmol) and phenylacetylene (267 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (250 mg, 58%). MS (ISP) 432.3[(M+H)+]; mp 144-145° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)[CH:5]=[CH:4][C:3]=1/[CH:34]=[CH:35]/[O:36][CH2:37][CH3:38].[F:39][C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[CH:42]=[C:43](B1OC(C)(C)C(C)(C)O1)[NH:44]2>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:37]([O:36]/[CH:35]=[CH:34]/[C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:30])=[O:31])=[CH:10][C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[C:13]([C:23]([NH:25][CH3:26])=[O:24])[C:12]=3[CH:27]=2)=[N:7][C:2]=1[C:43]1[NH:44][C:45]2[C:41]([CH:42]=1)=[C:40]([F:39])[CH:48]=[CH:47][CH:46]=2)[CH3:38]
Reactant: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
To a degassed solution of (E)-5-(6-chloro-5-(2-ethoxyvinyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.36 mmol) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (140 mg, 0.54 mmol) in 1,4-dioxane (3 mL) and water (200 μl) was added CS2CO3 (234 mg, 0.72 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (24 mg, 0.04 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred at this temperature for 3 hours. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with 0-30% acetone/hexane) provided (E)-5-(5-(2-ethoxyvinyl)-6-(4-fluoro-1H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (65 mg, yield: 28%) MS (M+H)+: 657.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:20]=2[N+:31]([O-:33])=[O:32])[N:16]=[CH:15][N:14]=1>CN(C=O)C.Cl>[N+:31]([C:20]1[CH:21]=[CH:22][C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:24][C:19]=1[C:17]1[N:16]=[CH:15][N:14]=[C:13]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[CH:18]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 90 °C
Yield: 74.5 %

Procedure:
A solution of 15 mg of 3-(trifluoromethyl)aniline and 27 mg intermediate 3.1b in 1 mL of DMF was treated with 1 drop of concentrated hydrochloric acid and heated to 90° C. for 1 h. The solution was cooled and partitioned between ethyl acetate and water. The organic extracts were washed with brine and dried over Na2SO4. The solvent was evaporated at reduced pressure to give 28 mg of product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH:26]=[CH2:27])[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][CH:26]=[CH2:27])[CH:22]=[C:21]([C:28]#[N:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 83.1 %

Procedure:
4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.034 g, 0.059 mmol) dissolved in DCM (2.5 mL) was treated with TFA (2.5 mL) at 25° C. for 3 days with stirring. The reaction mixture was concentrated to dryness and the residue was purified by mass-directed HPLC on a SunFire prep C-18 column eluted with 30 to 85% CH3CN/H2O (0.1% formic acid buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(2-propen-1-yl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (0.022 g, 0.049 mmol, 84% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br. s., 1H), 8.28 (br. s., 1H), 7.78 (s, 1H), 7.50 (d, J=8.52 Hz, 1H), 7.44 (s, 1H), 7.35 (t, J=7.62 Hz, 1H), 7.25 (br. s., 1H), 7.15 (br. s., 1H), 5.85-6.03 (m, 1H), 5.09 (d, J=6.46 Hz, 1H), 5.06 (s, 1H), 4.53 (d, J=4.39 Hz, 2H), 3.41 (d, J=6.46 Hz, 2H). LC-MS (ES−) m/z 443.10, 445.17 [M−1]. LC-MS (ES+) m/z 445.05, 447.08 [M+H].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C1C(=O)N([Br:26])C(=O)C1>C(#N)C>[Br:26][C:14]1[C:13]([OH:16])=[CH:12][C:9]2[CH2:10][CH2:11][N:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])[CH2:6][CH2:7][C:8]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Solvent: CC#N
Product: O=C(N1CCc2cc(O)c(Br)cc2CC1)C(F)(F)F
Temperature: 80 °C
Yield: 68.4 %

Procedure:
Into a 100 ml flask, the product of step (d) (1.65 g, 6.37 mmol) dissolved in acetonitrile (25 ml) was added. To this stirred solution, NBS (1.07 g, 6.05 mmol) was added. The reaction mixture was heated to 80° C. for 15 minutes and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexanes) gave the sub-title compound as a yellow solid (1.4 g). MS: ESI (positive): 338, 340 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:17]([C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)([CH3:19])[CH3:18].[BH4-].[Na+].[N+](C1C=C[C:35]([O:38]C(=O)OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O>C1C=CC=CC=1.CO>[CH:17]([C:20]1[S:21][CH:22]=[C:23]([CH2:25][N:1]2[CH2:2][CH2:3][N:4]([C@@H:5]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[C:35]2=[O:38])[N:24]=1)([CH3:18])[CH3:19]
Reactant: CC[C@H](C)[C@H](NCCN)C(=O)OC(C)(C)C
Reactant: CC(C)c1nc(C=O)cs1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2csc(C(C)C)n2)C1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution containing the product from Example 3G (1.304 g, 5.66 mmol) in a mixture of benzene (15 mL) and methanol (15 mL) was treated with the product from Example 97A (1.05 g, 6.79 mmol), was heated at 50° C. for 3 hours, cooled to 0° C., treated with sodium borohydride (0.428 g, 11.32 mmol), stirred at 25° C. for 16 hours, quenched with sodium bicarbonate solution, and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the concentrate (5.66 mmol) in toluene (30 mL) was treated with bis(4-nitrophenyl)carbonate (2.066 g, 6.79 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% ethyl acetate in dichloromethane to give the title compound (1.68 g, 75% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccc2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, benzyl alcohol and DBU in DME. ES-MS m/e (%): 313 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH2:21])[CH3:14]>C1(C)C(C)=CC=CC=1>[CH2:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][NH:21][C:9](=[O:11])[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[N:6][CH:7]=1)[CH3:14].[C:8]1([CH2:9][OH:11])[CH:3]=[CH:4][CH:5]=[CH:13][CH:7]=1
Reactant: COC(=O)c1cnccc1OC
Reactant: CCN1CCCC1CN
Solvent: Cc1ccccc1C
Product: CCN1CCCC1CNC(=O)c1cnccc1OC
Product: OCc1ccccc1

Procedure:
6.7 g (0.04 mole) of methyl 4-methoxynicotinate (m.p. 82°-83° C, W. C. J. Ross, J. Chem. Soc. 1966, 1816) and 7.18 g (0.06 mole) of 1-ethyl-2-(aminomethyl)-pyrrolidine are dissolved in 50 ml of xylene and the solution is heated for 6 hours so that a slow distillation takes place. Approx. 15 ml of distillate with a boiling point of 60°-80° C are collected. The mixture is then completely concentrated in a high vacuum at 50°-60° C and the oily residue obtained is chromatographed through a column of 200 g of basic silica gel. Pure N-[(1-ethyl-2-pyrrolidinyl)-methyl]-4-methoxynicotinamide is obtained as an oil with benzene-methanol (99:1) as eluant.