Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([OH:17])[C:15]#[CH:16]>C(COC)OC.[Pd].[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:16]#[C:15][CH2:14][OH:17])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCO
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: OCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
25.8 g of 3-bromopyridine, 3.47 g of 10% palladium-activated carbon (Pd—C), 3.41 g of triphenyl phosphine, 56.4 g of potassium carbonate and 1.24 g of copper iodide were dissolved in 250 ml of 50% aqueous dimethoxyethane solution, followed by stirring at room temperature for 30 minutes. Then, 22.9 g of propargyl alcohol was added thereto, followed by heating at 80° C. for 16 hours under stirring. After cooling, the insolubles were removed, the dimethoxyethane was distilled off in vacuo. Thereafter, the resultant mixture was acidified by adding hydrochloric acid and, after washing with toluene, the mixture was alkanized again with the addition of potassium carbonate, followed by extracting with ethyl acetate. The extract thus obtained was purified by column chromatography to obtain 19.6 g (90%) of 1-(3-pyridyl)-1-propyn-3-ol. Then, 19.6 g of the 1-(3-pyridyl)-1-propyn-3-ol obtained above and 72 mg of 4-dimethylamino pyridine were dissolved in 150 ml of tetrahydrofuran and 14.8 g of diketene was added thereto at 0° C., followed by stirring at room temperature for 2 hours. After the solvent was distilled off in vacuo, the resultant product was extracted with ethyl acetate to obtain 3-(3-pyridyl)-2-propynyl ester. Then, this compound was dissolved, without purification, in 500 ml of tetrahydrofuran, followed by blowing gaseous ammonia thereto at 0° C. for 4 hours. After allowing to stand at room temperature for 3 days, the solvent was distilled off in vacuo and the residue was purified with Florisil (magnesium silicate manufactured by Florisine to obtain the target compound in an amount of 22.2 g (73%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:12][C:13]2[CH:23]=[CH:22][C:16]3[N:17]=[C:18]([S:20][CH3:21])[S:19][C:15]=3[CH:14]=2)[CH:10]=O)=[C:5]([N+:24]([O-])=O)[CH:4]=1)#[N:2].IC1C=CC(N(CC2C=CC3N=C(SC)SC=3C=2)C=O)=C([N+]([O-])=O)C=1>>[CH3:21][S:20][C:18]1[S:19][C:15]2[CH:14]=[C:13]([CH2:12][N:9]3[C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[N:24]=[CH:10]3)[CH:23]=[CH:22][C:16]=2[N:17]=1
Reactant: CSc1nc2ccc(CN(C=O)c3ccc(C#N)cc3[N+](=O)[O-])cc2s1
Agent: CSc1nc2ccc(CN(C=O)c3ccc(I)cc3[N+](=O)[O-])cc2s1
Product: CSc1nc2ccc(Cn3cnc4cc(C#N)ccc43)cc2s1

Procedure:
1-((2-(Methylthio)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile was synthesized as a white solid (694 mg, 86%) using a procedure analogous to that described in Step 3 of Example 232, substituting N-(4-cyano-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide from the previous step for N-(4-iodo-2-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide used in Example 232. LCMS (ESI) m/z 337 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[O-:11][C:12]#[N:13].[K+].Cl>O>[C:5]1([C:3]2[NH:13][C:12](=[O:11])[NH:1][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#C[O-]
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]cc(-c2ccccc2)[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.8 %

Procedure:
2-Aminoacetophenone (5.6 g, 32.65 mmol) was dissolved in 200 ml of water in a three necked flask equipped with a thermometer and was heated up to 70° C. Potassium cyanate (2.9 g, 35.92 mmol) was added in several portions at 70° C. while the pH of the reaction solution was maintained in the range of 1 to 3 by the continuous addition of conc. HCl. After the addition of potassium cyanate was completed, the reaction mixture was stirred at 70° C. for 4 hours and left at room temperature overnight. The brownish precipitate thus formed was collected by filtration and dried to obtain 3.7 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:30]3[CH2:31][CH2:32][C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:29]3)=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ccccc3C2)no1
Temperature: 60 °C
Yield: 93.7 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with 1,2,3,4-tetrahydroisoquinoline (0.95 ml, 7.60 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 9 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (80:20). The residue was further purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (90:10) gradually changing to pentane:ethyl acetate (70:30) to afford the title compound (343 mg).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:40]([F:41])=[C:39]([O:42][CH3:43])[CH:38]=[C:37]([O:44][CH3:45])[C:36]=3[F:46])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1)=O.[CH3:47][NH2:48]>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:47][NH:48][CH2:15][C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:36]([F:46])=[C:37]([O:44][CH3:45])[CH:38]=[C:39]([O:42][CH3:43])[C:40]=3[F:41])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1F
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNCc1c[nH]c(NC(=O)c2ccc(-c3c(F)c(OC)cc(OC)c3F)c3nccnc23)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
Sodium triacetoxyborohydride (72.4 mg, 0.341 mmol, 1.5 equiv) was added to a suspension of 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-formyl-1H-imidazol-2-yl)-amide (100 mg, 0.228 mmol) (Example 185) and methylamine (40% wt in H2O, 40 μL, 0.455 mmol, 2 equiv) in DCM (4 mL) at rt, under an argon atmosphere. The reaction mixture was stirred for 4 h at rt. After further addition of sodium triacetoxyborohydride (72.4 mg, 0.341 mmol, 1.5 equiv), the reaction mixture was stirred for additional 16 h at rt. Then, methylamine (50 μL) and sodium triacetoxyborohydride (150 mg) were added. The reaction mixture was stirred for 4 h at rt, diluted with EtOAc/saturated aqueous solution of NaHCO3 and extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91.5:7.5:1) to afford 41 mg of the title compound as a yellow solid: ES-MS: 455 [M+H]+; tR=3.00 min (System 1); TLC: Rf=0.10 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12]C)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1>Br.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1CC(=O)O
Agent: Br
Solvent: O
Product: O=C(O)Cc1cc(Cl)ccc1O
Yield: 88.5 %

Procedure:
A solution of (5-chloro-2-methoxy-phenyl)-acetic acid (15.5 g, 77.5 mmol) in 48% aqueous hydrogen bromide was heated to reflux for 20 hours. The solution was cooled, diluted with water and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by trituration in 2:1 methylene chloride:hexanes to give (5-chloro-2-hydroxy-phenyl)-acetic acid (12.8 g). This was dissolved in a solution of ethanol saturated with hydrochloric acid and stirred 12 hours. The reaction was concentrated in vacuo, then the crude product was dissolved in diethyl ether and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (12.7 g)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C=O.[BH3-][C:37]#N.[Na+]>CO.CC(O)=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([CH3:37])[CH2:27][CH2:26]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCNCC4)n3)cc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCC4CCN(C)CC4)n3)cc2)CC1
Reaction time: 20 h
Yield: 77.9 %

Procedure:
To a solution of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide (25 mg, 0.055 mmol) and 37% aq. CH2O (0.020 mL, 0.27 mmol) in MeOH (1 mL) and CH3CO2H (0.1 mL) at room temperature, NaBH3CN (23 mg, 0.36 mmol) was added. The solution was stirred for 20 h. The mixture was then purified by HPLC to give the titled compound (20 mg). MS 467.46 (M+H).
Reaction SMILES: C(OC1C=CC(C)=C2C=1C=NN2)C1C=CC=CC=1.[CH2:19]([O:26][C:27]1[CH:35]=[C:34]([CH2:36]C)[CH:33]=[C:32]2[C:28]=1[CH:29]=[N:30][NH:31]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]2[C:28]=1[CH:29]=[N:30][NH:31]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCc1cc(OCc2ccccc2)c2cn[nH]c2c1
Agent: Cc1ccc(OCc2ccccc2)c2cn[nH]c12
Product: Cc1cc(OCc2ccccc2)c2cn[nH]c2c1

Procedure:
In an analogous manner, there are obtained 4-benzyloxy-5-methyl-indazole (m.p. 94°-95° C.); 4-benzyloxy-7-methyl-indazole (m.p. 175°-177° C.), and 4-benzyloxy-6-ethyl-indazole.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][C:20]=1[C:27]([F:30])([F:29])[F:28].[I-].[K+]>CN(C)C=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:8]2[C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[NH:5][C:4]3=[CH:3][S:2][CH:1]=[C:10]3[C:9]2=[O:11])=[CH:21][C:20]=1[C:27]([F:28])([F:29])[F:30]
Reactant: FC(F)(F)c1cc(CCl)ccc1Cl
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cscc2Nc2ccccc2N1Cc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a solution of 8.64 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of dimethylformamide is added 2.1 g. of 50% sodium hydride in mineral oil. The mixture is stirred for one hour and 10.0 g. of 4-chloro-3-trifluoromethyl benzyl chloride and 10 mg of potassium iodide are added. The mixture is stirred for a prolonged period and the solvent is removed in vacuo. The residual gum is dissolved in methylene chloride, dried over magnesium sulfate and filtered through magnesol. The filtrate is evaporated to give tan crystals which are recrystallized from ethanol giving the desired product as off-white crystals, mp. 181°-183° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:7]1[C:2]2[NH:1][C:13](=[O:14])[CH2:12][O:10][C:3]=2[CH:4]=[CH:5][C:6]=1[F:9]
Reactant: Nc1c(O)ccc(F)c1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2ccc(F)c(F)c2N1
Yield: 14.6 %

Procedure:
A crude of 2-amino-3,4-diflourophenol (0.68 g, 4.7 mmol), 2-chloroacetyl chloride (0.58 g, 5.2 mmol) and K2CO3 (1.36 g, 9.9 mmol) were mixed according to GP1. Purified by prep RP-HPLC to give the title compound (0.127 g, 14.5%). Rf=0.63 (heptanes/EtOAc 1:1). 1H NMR (CDCl3) d 6.69-6.57 (m, 2H), 4.47 (s, 2H); 13C NMR (CDCl3) d 165.0, 146.2 (dd, J=241.8 Hz, J=10.4 Hz), 140.3 (t, J=2.32 Hz), 138.7 (dd, J=247.2 Hz, J=17.3 Hz), 67.1 (t, J=2.7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][NH:15][C@H:14]([CH3:18])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:25]3[CH:26]=[C:21]([Cl:20])[N:22]=[CH:23][N:24]=3)[C@H:14]([CH3:18])[CH2:13]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOC(=O)c1cnc(N2CCN[C@H](C)C2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(N2CCN(c3cc(Cl)ncn3)[C@H](C)C2)c(Cl)c1

Procedure:
Heat a solution of 5-chloro-6-(3-(R)-methyl-piperazin-1-yl)-nicotinic acid ethyl ester (338 mg, 1.2 mmol), 4,6-dichloropyrimidine (179 mg, 1.2 mmol) and potassium carbonate (328 mg, 2.4 mmol) in DMA at 80° C. for 16 h. Partition between EtOAc and brine then separate layers and wash the organic layer with 10% NaOH (3×) followed by brine. Dry (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[Mg+2].[Br-].[Br-].[Cl:19][C:20]1[C:21]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[N:22][CH:23]=[C:24]([CH:26]=O)[CH:25]=1.Cl>C1COCC1.CCOC(C)=O.CCN(CC)CC>[Cl:19][C:20]1[C:21]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[N:22][CH:23]=[C:24](/[CH:26]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: Cl
Agent: [Br-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
The mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (2.51 mL), MgBr2 (2.73 g), Et3N (1.89 mL) in THF (45 mL) was stirred at 3-5° C. for 1 hr and to the mixture was dropwise added a solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate (3.0 g) in THF (21 mL) at 3-5° C. The reaction mixture was stirred at same temperature for 2.5 hrs. The reaction mixture was poured into a mixture of AcOEt and ice-water and the mixture was adjusted to pH 3.5 with 1N-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of AcOEt and hexane (1:2 v/v) as an eluant. The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.38 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.C(=O)([O-])[O-].[K+].[K+].[CH3:16][CH:17]([N:19]([CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:21][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:23]#[N:24])[CH3:18].[H-].[K+].N1C=CC=CC=1CCl>O.C1(C)C=CC=CC=1>[CH3:33][CH:31]([N:19]([CH:17]([CH3:18])[CH3:16])[CH2:20][CH2:21][C:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[C:23]#[N:24])[CH3:32]
Reactant: ClCc1ccccn1
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)(Cc1ccccn1)c1ccccc1)C(C)C
Yield: 46.8 %

Procedure:
To a solution of 26 g (159 mmole) of 2-picolyl chloride hydrochloride in 50 ml of water was added in portions 22 g (159 mmoles) of potassium carbonate. The solution was extracted into diethyl ether, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to oily 2-picolyl chloride. A mixture of 29.0 g (119 mmol) of α-[2-[bis(1-methylethyl)amino]ethyl]-phenylacetonitrile and 17.5 g (ca. 153 mmole) of potassium hydride (as a 30% dispersion in mineral oil) was heated for thirty minutes at 65°-70° in 550 ml of toluene. To this mixture was added a solution of the previously prepared 2-picolyl chloride dissolved in 400 ml of toluene. After the reaction mixture was stirred for thirty minutes at 70°, 400 ml of water was added. The toluene layer was separated and extracted with 10% hydrochloric acid. The acidic aqueous layer was separated and made basic with aqueous sodium hydroxide, then extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel afforded 18.7 g of the title compound as an oil. nmr (CDCl3): δ(ppm) 3.4 (pseudo-d, pyridyl-CH2 (non-equivalent H's)); 6.9-7.7 (m's, aromatic CH's); 8.4-8.6 (m, pyridine 6H).
Reaction SMILES: CN(C[N:5]=[CH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:11][CH2:12]1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: CN(C)CN=CC1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NCC1CCN(CCOc2ccc(F)cc2)CC1

Procedure:
In a similar manner to Example 3, a mixture of 4-(dimethylaminomethyliminomethyl)piperidine (6.42 g), 2-bromoethyl 4-fluorophenyl ether (8.3 g), triethylamine (5.3 ml) and toluene (20 ml) was heated on a steam bath for 16 hours to give 4-aminomethyl-1-[2-(4-fluorophenoxy)ethyl]piperidine as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[C:33]([Cl:35])[N:32]=[CH:31]3)=[C:26]([O:36][CH3:37])[CH:25]=2)[N:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[Cl:35][C:33]1[N:32]=[CH:31][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:20]3[N:19]=[C:18]4[CH:6]([C:7]5[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:9][CH:8]=5)[CH2:5][CH2:4][CH2:3][CH2:2][N:22]4[N:21]=3)=[CH:25][C:26]=2[O:36][CH3:37])[CH:34]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)F)cc3)n2)ccc1-n1cnc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(OCC(F)F)cc2)ccc1-n1cnc(Cl)c1
Yield: 20 %

Procedure:
A solution of 5-(5-chloro-1-(4-(2,2-difluoroethoxy)phenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (1.44 g, 2.61 mmol, sodium iodide (1.96 g, 13.1 mmol), and diisoproplylethylamine (2.28 mL, 13.1 mmol) in acetone (30 mL) was heated in a sealed vessel at 100° C. for 16 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform). The purified product was recrystallized from EtOAc/hexane to afford 279 mg (20% yield) of the titled compound as an off-white crystalline white solid. LC-MS (M+H)+ 515.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.51 (d, J=1.5 Hz, 1 H), 7.42 (d, J=2.4 Hz, 1 H), 7.12 (d, J=8.9 Hz, 2 H), 7.09 (d, J=8.5 Hz, 1 H), 7.02 (d, J=1.5 Hz, 1 H), 6.92 (d, J=8.5 Hz, 2 H), 6.84 (dd, J=8.4, 2.3 Hz, 1 H), 6.67 (s, 1 H), 6.10 (tt, J=55.1, 4.1 Hz, 1 H), 4.26 (d, J=8.5 Hz, 1 H), 4.15-4.25 (m, 4 H), 3.80 (s, 3 H), 2.16-2.30 (m, 1 H), 2.05-2.13 (m, 1 H), 1.83-2.02 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2F)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[O:9][C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[CH:11]=[N:10][C:4]=2[CH:3]=1
Reactant: Oc1cc(F)c(Br)cc1N=Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)Oc1cc(F)c(Br)cc1N=C2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-[(2,4-difluorobenzylidene)amino]-5-fluorophenol (15 g, 45.4 mmol) in 60 mL of DMF, Cs2CO3 (22 g, 67.5 mmol) was added. The resulting mixture was stirred at 50° C. for 3 h and then allowed to cool to ambient temperature. Water was added and the product was collected by filtration, washed with water, and dried under reduced pressure to yield the title compound which was used without further purification (14.1 g, 100%). 1H-NMR (400 MHz, CDCl3) 6.82-6.99 (m, 3H), 7.33 (m, 1H), 7.55 (d, J=7.8, 1H), 8.38 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([C:8]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:10])[CH:3]=1
Reactant: COc1ccccc1
Reactant: Cc1sc(Br)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)sc2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of acid 8 (10 g, 45.2 mmol) in CH2Cl2 (200 mL) were added oxalyl chloride (4.8 mL, 54.3 mmol) and catalytic amounts of DMF at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude acid chloride was dissolved with CH2Cl2 (200 mL) and cooled to 0° C. To the mixture was added anisole (5.0 mL, 45.2 mmol) at 0° C. and stirred at 0° C. for 5 min. To the reaction mixture was added AlCl3 (6.0 g, 45.2 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 2 hours, warmed up to room temperature and stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with CH2Cl2 (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was tritulated with MeOH (100 mL) and stirred at 0° C. for 1 hour. The precipitated solid was filtered and washed with MeOH (50 mL). The solid was dried under high vacuum and used without further purification (11.7 g, 83%).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:30](=[O:40])[NH:31][C:32]3[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=3[F:39])[CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[NH2:17][C@@H:18]([CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[C:30]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=1[F:39])=[O:40]
Reactant: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)Nc1ccc(I)cc1F)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N[C@@H](Cc1ccc2ccccc2c1)C(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of [(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-2-naphthalen-2-yl-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (1.05 g, 1.60 mmol) in dichloromethane (24 mL) was added piperidine (6 mL) and the mixture stirred at room temperature for 1 hour. After removal of the solvent, the residue was purified by chromatography over silica gel gradient eluted from 100% hexane up to 40% ethyl acetate/60% hexane in 30 minutes. Concentration of the product containing fractions gave (S)-2-amino-N-(2-fluoro-4-iodo-phenyl)-3-naphthalen-2-yl-propionamide as a yellow solid (390 mg, 56%).