Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[NH:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C=O.C(O)(=O)C>CO>[CH3:1][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: [BH3-]C#N
Reactant: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1NC(=O)NN=C1c1ccc2c(c1)CCCN2C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Sodium cyanoborohydride (0.19 g) was added portionwise to a suspension of 6-(1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.74 g), 36% aqueous formaldehyde (0.34 ml), acetic acid (1 ml) and methanol (3 ml) at room temperature. After stirring for 0.5 hours at the same temperature, the resultant precipitates were collected by filtration, washed with methanol, dried, and recrystallized from 70% aqueous ethanol to give 0.66 g of 6-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=[O:17])[C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+]>CN(C)C=O.O>[C:19]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=[O:17])[C:7]=2[CH:18]=1)#[N:20]
Reactant: [C-]#N
Reactant: O=C1c2cc(CBr)ccc2COc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc2c(c1)C(=O)c1ccccc1OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 6.4 gm of the bromomethyl compound of Step C in 75 cc of dimethylformamide and add 2.95 gm of sodium cyanide. Stir the mixture at room temperature for 1.5 hours. Dilute with 600 cc of water and extract three times with ether. Wash the combined organics with water, dry and strip to a solid residue. Triturate in hexane and recover the solid by filtration.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:10][C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-n2cnc(C)c2)c(C#N)c1

Procedure:
In analogy to example 5a, 2-fluoro-5-methyl-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup the title compound was obtained as a white solid (yield: 48%). MS: m/e=198.4 [M+H]+.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][S:25][CH2:26][CH2:27][NH2:28]>>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][S:25][CH2:26][CH2:27][NH:28][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1
Reactant: NCCSCc1nccs1
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Product: COc1cccc(Cc2nnc(NCCSCc3nccs3)[nH]c2=O)c1
Yield: 50.4 %

Procedure:
3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.18 g) and 2-(2-thiazolylmethylthio)ethylamine (0.87 g) were heated together on an oil bath (160°-70° ) for 3/4 hour. The resulting oil, after chromatography and crystallisation from ethanol, gave the title compound as a colourless solid (0.88 g) m.p. 128°-29°.
Reaction SMILES: [H-].[Na+:2].[C:3]([C:11]1[C:15]2=[C:16]([C:21]([OH:23])=[O:22])[C:17]([OH:20])=[CH:18][CH:19]=[C:14]2[O:13][C:12]=1[C:24]([F:27])([F:26])[F:25])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32](S(C)(=O)=O)[N:31]=1.O>CN(C)C=O>[C:3]([C:11]1[C:15]2=[C:16]([C:21]([O-:23])=[O:22])[C:17]([O:20][C:32]3[N:33]=[C:34]([O:36][CH3:37])[CH:35]=[C:30]([O:29][CH3:28])[N:31]=3)=[CH:18][CH:19]=[C:14]2[O:13][C:12]=1[C:24]([F:27])([F:25])[F:26])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:2]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C(O)c1c(O)ccc2oc(C(F)(F)F)c(C(=O)c3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccc3oc(C(F)(F)F)c(C(=O)c4ccccc4)c3c2C(=O)[O-])n1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
While stirring 0.35 g of sodium hydride in 30 ml of N,N-dimethylformamide at room temperature, 1.73 g of 3-benzoyl-5-hydroxy-2-trifluoromethylbenzofuran-4-carboxylic acid was gradually added thereto. After completion of the addition, the mixture was further stirred for one hour. While stirring this mixture at room temperature, 1.08 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added thereto, and then the mixture was stirred at 70° C. for 3 hours. The mixture was returned to room temperature and poured into water. Precipitated crystals were separated by filtration and washed with water and acetone to obtain 1.02 g (yield: 40.5%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:16][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1[nH]nc(C(F)(F)F)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Dissolve 5-methyl-3-(trifluoromethyl)pyrazole (1.00 g, 6.66 mmol) in 60% aqueous acetic acid (13 mL). Add sodium acetate (0.819 g, 9.99 mmol) and cool to 0° C. Add bromine (1.17 g, 7.33 mmol) dropwise over 10 min. Stir at 0° C. for 3 hr, then at room temperature for 18 hr. Add ethyl acetate and saturated aqueous sodium sulfite solution. Separate organics and wash one time with saturated aqueous sodium bicarbonate solution followed by saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole (1.50 g, 100%). GC-MS: m/z=229 [M+].
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[OH-].[NH4+:10]>O1CCCC1>[C:5]([CH2:4][C:2](=[CH2:3])[C:1]([OH:7])=[O:8])(=[O:6])[NH2:10]
Reactant: C=C1CC(=O)OC1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(CC(N)=O)C(=O)O
Reaction time: 1 h
Yield: 40 %

Procedure:
To a mixture of 3 g (0.027 mol) of itaconic anhydride in 30 ml of tetrahydrofuran, 3 ml of 28% ammonium hydroxide was added. After 1 hr. the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 15 ml of water, then acidified to pH 2 with concentrated hydrochloric acid and allowed to stay overnight at 4°. The precipitate formed was filtered off, washed with a small portion of cold water and dried to give 1.4 g (40% yield) of the title compound melting at 153-154° C.; NMR (DMSO-d6): 3.11 (s, 2H, CH2); 5.67,6.13 (s, s, 1H, 1H, CH); 6.7, 7.9 (broad s, s 1H, 1H, NH); 12.15 (broad s, 1H, OH).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][CH:23]([C:25]([O:27]C)=O)[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:44]>>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][C@@H:23]([C:25]([NH2:44])=[O:27])[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: N
Reactant: COC(=O)C1CC[C@@]2(CCN(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](C(N)=O)N2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 87 %

Procedure:
In a sealed tube a solution of methyl (5S,7R)-8-{[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 22, 63 mg, 0.107 mmol) in 7 N ammonia solution in MeOH (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated to dryness and the crude was purified by flash-chromatography [Si cartridge (5 g), from 1:0 to 95:5 DCM/MeOH] to give the title compound (53.5 mg, 0.093 mmol, 87% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.95 (s, 1H) 7.61 (s, 2H) 7.24-7.32 (m, 1H) 7.15-7.24 (m, 1H) 6.98-7.05 (m, 1H) 6.92 (d, 1H) 6.79 (t, 1H) 4.65 (d, 1H) 4.36 (d, 1H) 4.15 (d, 1H) 3.44-3.59 (m, 1H) 3.38 (d, 1H) 2.93 (s, 3H) 2.75 (t, 1H) 2.65 (br. s., 1 H) 2.33 (s, 3H) 1.99-2.21 (m, 1H) 1.51-1.93 (m, 6H) 1.45 (t, 1H); HPLC: Rt 4.88 mins; MS: m/z=575 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21](O)[CH2:22][CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:19][CH2:18][C:17]4([O:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Clc1cccc(C#CC2=NOC3(CCC4(CC3)OCCCO4)C2)c1
Yield: 75.3 %

Procedure:
A solution of the compound of Example 32 (0.41 g, 1.42 mmol), 1,3-propandiol (0.15 g, 1.95 mmol) and p-toluensulfonic acid. H2O (7.5 mg, 0.04 mmol) in 30 mL of benzene was stirred at reflux for 10.5 h, removing water with a Dean-Stark Apparatus. Dilution with water, washing with aq. 5% NaHCO3, drying the organic layer over Na2SO4 afforded the title compound as dense yellow oil. This was further purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 9:1 to 7:3) giving a white solid. Yield: 75.3%.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][OH:14])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][OH:14])[C:6]=4[N:5]=[C:4]3[CH2:1][CH2:2][CH3:3])[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CCCc1nc2c(CO)cccc2[nH]1
Product: CCCc1nc2c(CO)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 90.7 %

Procedure:
[step 2] Using (2-propyl-1H-benzo[d]imidazol-4-yl)methanol (47 mg, 0.25 mmol) obtained in step 1 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (92 mg, 0.26 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (106 mg, 92%) was obtained.
Reaction SMILES: CS([O:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=O)=O.[OH-].[Li+].Cl>C1COCC1.O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1COc1ccc(CCCOc2ccc(O)cc2)cc1
Yield: 20.6 %

Procedure:
Methyl 2-{[4-(3-{4-[(methylsulfonyl)oxy]phenoxy}propyl)phenoxy]methyl}benzoate (0.38 g, 0.81 mmol) was dissolved in a mixture of THF/water (7/1, 4 ml) and lithium hydroxide (9.3 mg, 0.39 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 63 mg of 2-({4-[3-(4-hydroxyphenoxy)propyl]phenoxy}methyl)benzoic acid (yield 20.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:56][C:57]1[NH:58][C:59]2[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=2[N:61]=1>C(Cl)Cl>[NH:58]1[C:59]2[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=2[N:61]=[C:57]1[NH:56][C:13](=[O:15])[CH:12]([C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Br:1])[CH:3]=1)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1Br
Yield: 52.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.266 mmol), triethylamine (110 μL, 0.80 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (187 mg, 0.42 mmol), and 2-aminobenzimidazole (56 mg, 0.42 mmol) in methylene chloride (10 mL) was stirred at 25° C. for 1.5 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 chloroform/methanol) afforded N-(1H-benzimidazol-2-yl)-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (69 mg, 53%) as a white solid: mp>220° C.; EI-HRMS m/e calcd for C22H24BrN3N3OS(M+) 489.722, found 489.727.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:20]1(Br)[CH2:22][CH2:21]1>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:20]2[CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: BrC1CC1
Reactant: Oc1cnc(Cl)c2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(OC3CC3)cnc(Cl)c2c1
Temperature: 145 °C
Yield: 20 %

Procedure:
To a solution of 1-chloro-7-fluoroisoquinolin-4-ol (1 g, 5.06 mmol) in DMF (5 mL) was added Cs2CO3 (4.95 g, 15.18 mmol) followed by cyclopropyl bromide (1.2 mL, 15.18 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.24 g, 20%) as a yellow solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.C(O)(=O)C>ClCCCl>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)=[CH:23][CH:24]=2)[N:19]=[C:18]([CH3:28])[CH:17]=1
Reactant: Cc1cc(Cl)c2ccc(C=O)cc2n1
Reactant: N#Cc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(Cl)c2ccc(CNc3ccc(C#N)cc3)cc2n1
Yield: 65 %

Procedure:
Sodium triacetoxyborohydride (74 mg, 0.34 mmol) was added to a solution of 4-chloro-2-methyl-quinoline-7-carbaldehyde (example 13a, 50 mg, 0.24 mmol), 4-aminobenzonitrile (29 mg, 0.24 mmol), and acetic acid (88 mg, 1.5 mmol) in 1,2-dichloroethane (0.5 mL), then after 16 h the reaction mixture was partitioned between ethyl acetate and 2 M aq. sodium hydroxide solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate 1:1) afforded the title compound (48 mg, 64%); White solid, ISP-MS: m/e=308.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5]Br.[CH2:23]([O:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29])[CH3:24]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5][P:26](=[O:30])([O:27][CH2:28][CH3:29])[O:25][CH2:23][CH3:24]
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(Oc2c(Cl)cc(CBr)cc2Cl)cc1C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1)OCC
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide (0.61 g, 1.51 mmol) and triethylphosphite (0.61 g, 3.56 mmol) in DMF (2.0 mL) was heated under reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and brine. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with acetone-hexanes (3:7) to afford diethyl 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)benzylphosphonate as an oil (0.59 g, 85%): 1H NMR (300 MHz, DMSO-d6): δ 7.55 (s, 2 H), 6.88 (d, J=9.0 Hz, 1 H), 6.75 (d, J=3.0 Hz, 1 H), 6.43 (m, 1 H), 4.01 (m, 4 H), 3.75 (s, 3 H), 3.41 (m, 2 H), 3.22 (m, 1 H), 1.20 (m, 6 H), 1.12 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (4:1); Rf=0.22.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:18][CH:17]=1>>[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[C:26]=2[C:1](=[O:10])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: BrCCOc1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)c2c(-c3ccc(OCCBr)cc3)oc3ccccc23)cc1

Procedure:
When p-anisoyl chloride and 2-[4'-(2-bromoethoxy)phenyl]benzofuran are reacted by the procedure described in Example 11 and the 2-[4'-(2-bromoethoxy)phenyl]-3-p-anisoylbenzofuran thus obtained is treated with piperidine as described in Example 11, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:7]=1
Reactant: Fc1ccc(I)cc1C(F)(F)F
Reactant: C#Cc1cncc(Cl)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 87.6 %

Procedure:
Sequentially add 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (300 mg, 2.2 mmol), (bis(triphenylphosphine)palladium (II) dichloride (69 mg, 0.10 mmol), and copper (I) iodide (38 mg, 0.198 mmol) to a solution of 1-fluoro-4-iodo-2-trifluoromethylbenzene (575 mg, 1.98 mmol) in triethylamine (4 mL) under nitrogen. Heat at 70° C. for 2.5 h and concentrate. Purify the residue by silica gel chromatography, eluting from 0:100 to 20:80 using ethyl acetate:hexanes, to give the title compound as a white solid (520 mg, 88%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>CN(C=O)C.O>[F:24][C:23]([F:26])([F:25])[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxyl benzaldehyde (1.1 g, 8.7 mmol) and Cs2CO3 (4.3 g, 13.1 mmol) in DMF (16 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 mL, 10.5 mmol). The reaction mixture was stirred at rt for 1 h and then diluted with H2O, followed by extraction with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The NMR of the crude product obtained (1.8 g, 100%) was clean. 1H NMR (CDCl3, 400 MHz) δ 9.93 (s, 1H), 7.91-7.87 (m, 2H), 7.09-7.05 (m, 2H), 4.45 (q, J=8.0 Hz, 2H).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>COC(C)(C)C>[CH3:9][S:10]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: C#CC(O)(CF)CF
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: C#CC(CF)(CF)OS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and methanesulfonyl chloride (0.85 ml) were dissolved in tert-butyl methyl ether (15 ml); to the solution under cooling with ice, triethylamine (1.5 ml) was added dropwise in a nitrogen atmosphere. After the end of the dropwise addition, the solution was stirred for 1.5 hours under cooling with ice. To the reaction mixture, tert-butyl methyl ether was added, followed by washing with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (1.9 g).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6]1([CH2:12][CH2:13][CH:14]([NH2:16])[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(C)C>[C:6]1([CH2:12][CH2:13][CH:14]([NH:16][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCC1CO1
Reactant: CC(N)CCc1ccccc1
Solvent: CC(C)O
Product: CC(CCc1ccccc1)NCC(O)CO
Temperature: 70 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of glycidol (11.5 g, 0.155 mol) in isopropanol (25 ml) was added dropwise under N2 at 40° C. to a solution of 1-phenyl-3-butylamine in isopropanol (50 ml). After 1 hour, the solution was heated to 70° C. for 1.5 hours and then at room temperature overnight. The isopropanol was removed under reduced pressure and the residue distilled to yield 24 g (70%) of 94; b.p.0.2 140°-5° C.