Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[S:7][C:8]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:10]=1[NH2:11])=[O:5].[CH2:18]([O:25][CH:26]1[CH2:29][C:28](=O)[CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C:6]1[S:7][C:8]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:10]=1[NH:11][CH:28]1[CH2:29][CH:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:27]1)=[O:5]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: O=C1CC(OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.7 %

Procedure:
A mixture of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester, hydrochloride salt (750 mg, 2.74 mmol) and 3-benzyloxy-cyclobutanone (2.5 g, 14.3 mmol) in DCM (40 mL) was treated with sodium triacetoxyborohydride (3.34 g, 15.8 mmol) portionwise. The mixture was stirred at room temperature for 3 hours. The solution was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, water, and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% ethyl acetate:hexanes). This resulted in 1.26 g (quant. yield) of 3-(3-benzyloxy-cyclobutylamino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester as a mixture of cis- and trans-isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:16]([P:19](Cl)(Cl)=[O:20])([CH3:18])[CH3:17]>>[CH:16]([P:19]1(=[O:20])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9][N:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:18])[CH3:17]
Reactant: Clc1ccc(NCc2ccccc2)cc1
Reactant: CC(C)P(=O)(Cl)Cl
Product: CC(C)P1(=O)c2ccccc2CN1c1ccc(Cl)cc1
Yield: 16 %

Procedure:
The procedure of Example 1 was employed utilizing N-(4-chlorophenyl)-N-benzylamine and isopropyl phosphonic dichloride to yield 1-isopropyl-2-(4-chlorophenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.9 g, 16% yield) as a white solid having a melting point of 172°-174° C. and the following analysis:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:18]1([C:21]2[C:26]([C:27](O)=[O:28])=[CH:25][N:24]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[N:22]=2)[CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:27]([C:26]2[C:21]([CH:18]3[CH2:20][CH2:19]3)=[N:22][C:23]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=3)=[N:24][CH:25]=2)=[O:28])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[4-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([C:17]1[O:21][C:20]([C:22]([OH:24])=O)=[N:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@@H:30]([NH2:32])[CH3:31].C1CCN2C(=NCCC2)CC1>C1COCC1>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@@H:30]([NH:32][C:22]([C:20]1[O:21][C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:18][N:19]=1)=[O:24])[CH3:31]
Reactant: CC(C)(C)c1cnc(C(=O)O)o1
Reactant: C[C@H](N)c1cccs1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ncc(C(C)(C)C)o1)c1cccs1
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of carbonyl diimidazole (CDI) (2.42 g, 15 mmol) in THF (40 ml) is added to a stirred solution of 5-tert-butyl-oxazole-2-carboxylic acid (2.3 g, 13.6 mmol) in THF (40 ml). The mixture is stirred for 30 min, then (S)-(1-thiophen-2-yl-ethyl)-amine (2.59 g, 20.4 mmol) is added, followed 10 min later by a solution of DBU (2.24 ml, 15 mmol) in THF (20 ml). The mixture is refluxed for 16 h and the THF is then removed by distillation. The residue is dissolved in ethyl acetate and the organic solution is washed with 2N hydrochloric acid and then twice with water. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 7:3 v/v) to give (S)-5-tert-butyl-oxazole-2-carboxylic acid (1-thiophen-2-yl-ethyl)-amide (2.40 g, 63%) as an oil.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(OP([CH2:21][C:22]([O:24][CH3:25])=[O:23])(OCC)=O)C.C[O-].[Na+]>C1C=CC=CC=1.CO>[CH3:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CCCCCCCCCC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CCCCCCCCCC(C)=CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Undecanone (methyl nonyl ketone) (1′) (73.9 g, 434 mmols) and methyl (diethylphosphono)acetate (99.4 g, 433 mmols) were dissolved in dry benzene (300 ml). The solution was stirred at room temperature, and a 28% sodium methoxide solution (83.7 g) in methanol was slowly added. Stirring was continued overnight at room temperature. The reaction mixture was poured into ice water, and extracted with diethyl ether. The organic layer was washed (water and a saturated aqueous solution of sodium chloride), and dried (sodium sulfate), followed by removing the solvent in a vacuum to obtain methyl 3-methyl-2-dodecenoate (2′) as a geometric isomer mixture.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[Li]C(C)(C)C.CCCCC.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C:21]1([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]1)[C:20]2=[N:33][S:34]([CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])(=[O:36])=[O:35].C(OC=C[Li])C>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:23]([CH2:22][C:21]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:20]2([NH:33][S:34]([CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])(=[O:36])=[O:35])[C:1]([O:3][CH2:4][CH3:5])=[CH2:2])=[CH:24][CH:25]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)(=O)CC[Si](C)(C)C
Reactant: C=COCC
Agent: [Li]C(C)(C)C
Agent: [Li]C=COCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: C=C(OCC)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.17 h

Procedure:
To a solution of ethyl vinyl ether (7 mL, 73 mmol) in THF (10 mL) was added dropwise a solution of 1.7 M t-BuLi in pentane (26 mL, 44 mmol) at −78° C. under nitrogen. After 10 min, the reaction mixture was cooled in an ice bath and stirred for 45 min. To a solution of N-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-(trimethylsilyl)ethanesulfonamide (2) (1.3508 g, 2.86 mmol) in THF (20 mL) was added a solution of -ethoxyvinyllithium, obtained as described above, at −78° C. under nitrogen via a cannula. After 2 h, LC-MS indicated the disappearance of starting material. The reaction mixture was quenched with saturated NaHCO3 (5 mL) and saturated brine (20 mL) and then vigorously stirred at room temperature for 1 h. The mixture was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product 9 (1.7654 g) was directly used in the next step without further purification. LC-MS tR=2.43 min in 3 min chromatography, m/z 544, 546 (MH+), 480, 482.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=O)=[CH:23][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C=O)=CC=1)(=O)C1C=CC=CC=1.[NH2:43]C1C=C(C=CC=1N)C(O)=O>>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([NH2:43])=[O:26])=[CH:23][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccc(C(=O)c4ccccc4)cc3)nc2c1
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: O=Cc1ccc(C(=O)c2ccccc2)cc1
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C(=O)c4ccccc4)cc3)nc2c1

Procedure:
2-(4-Benzoyl-phenyl)-1H-benzoimidazole-5-carboxylic acid. This compound was prepared as described in Example 1 using 4-benzoyl-benzaldehyde (100 mg, 0.47 mmol) and 3,4-diamino-benzoic acid (72 mg, 0.47 mmol) in Step C. The title compound was obtained as a tan solid (135 mg, 85%). MS (ESI): mass calculated for C21H14N2O3, 342.1; m/z found, 342.9 [M+H]+. HPLC (Method A): Rt=7.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)cc1

Procedure:
2-(4-chloro-phenyl)-2-(4-iodo-phenyl)-morpholine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst to give the title compound. LCMS (PS-A3) Rt 6.88 min [M+H]+ 340. 1H NMR (Me-d3-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m), 3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d), 7.92 (2H, br. s).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH:19]2[CH2:21][CH2:20]2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=1[F:30])=[O:9])=[CH2:2].COC(C1N(C2CC2)C2C=CN=CC=2C=1NC1C=C[C:51]([S:54]C)=CC=1F)=O>>[CH:1]([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH:19]2[CH2:21][CH2:20]2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:54][CH3:51])=[CH:25][C:24]=1[F:30])=[O:9])=[CH2:2]
Reactant: COC(=O)c1c(Nc2ccc(SC)cc2F)c2cnccc2n1C1CC1
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Product: C=COCCONC(=O)c1c(Nc2ccc(SC)cc2F)c2cnccc2n1C1CC1

Procedure:
This compound was prepared in an analogous fashion to 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]-pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide, using 1-cyclopropyl-3-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester as the starting material. 1H-NMR (500 MHz, CDCl3) δ ppm 9.50 (br s, 1H), 8.60 (d, J=0.88 Hz, 1H), 8.38 (d, J=5.97 Hz, 1H), 7.46 (dd, J=5.98 Hz, 1H), 7.10 (dd, J=11.45 Hz, 1H), 6.89 (dd, J=8.41 Hz, 1H), 6.66 (t, J=8.67 Hz, 1H), 6.42 (dd, J=14.33 Hz, 1H), 6.33 (br s, 1H), 4.29-4.22 (m, 2H), 4.18 (dd, J=14.33 Hz, 1H), 4.04 (dd, J=6.82 Hz, 1H), 3.98-3.90 (m, 2H), 3.61-3.53 (m, 1H), 2.44 (s, 3H), 1.33-1.20 (m, 2H), 1.01-0.96 (m, 2H); LC-MS (method D): [M+H]+=443.3, RT=2.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)(O)[O-].[Na+].Br[CH2:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][CH:12]=3)[CH2:28][C:29]([OH:34])([C:30]([F:33])([F:32])[F:31])[N:21]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 25 %

Procedure:
To a mixture of 3-chloro-4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (2.35 g, 7.3 mmol) and sodium bicarbonate (1.23 g, 14.6 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating to reflux the reaction mixture for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.3 g) was chromatographed (silica gel, toluene/ethyl acetate, 1/1) to give 2-(3-chloro-4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.79 g, 25%) as a white solid: mp 201° C. Anal. Calc'd. for C18H16N2SO3F3Cl.0.5 PhCH3 : C, 53.92, H, 4.21, N, 5.81. Found: C, 54.20, H, 4.19, N, 5.67.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[NH:8][C:9]2=[O:13])=[CH:4][C:3]=1[Br:17].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>CC#N.CN(C=O)C>[Br:17][C:3]1[C:2]2[N:1]=[C:23]([C:22]3[CH:25]=[CH:26][C:19]([CH3:18])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=3)[NH:12][C:11]=2[C:10]2[C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]([CH3:15])([CH3:16])[C:5]=2[CH:4]=1
Reactant: CC1(C)C(=O)NC(=O)c2c1cc(Br)c(N)c2N
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3c(Br)cc4c(c3[nH]2)C(=O)NC(=O)C4(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 7,8-diamino-6-bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (1.40 g, 4.70 mmol) in MeCN (47 mL) and DMF (3 mL) was added 4-methyl-3-nitro-benzaldehyde (814.2 mg, 4.93 mmol) and p-chloranil (1.21 g, 4.93 mmol). The reaction mixture was stirred at 60° C. for 8 h. The cooled mixture was diluted with MeCN (50 mL) and the suspension was filtered. The solid was dried to give the title compound (1.65 g, 79% yield).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18].Cl[CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[CH2:17]([O:19][C:20]([C:22]1([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: ClCOCc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a pre-cooled THF solution under an argon atmosphere was added at −5° C. LDA (2 M, in THF/hepatane/ethylbenzene, 17.5 ml) and then dropwise a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (5 g) in THF, keeping the temperature at about −7° C. The mixture was stirred 2 hours between −10 and −5° C. then treated slowly and dropwise with benzyl chlormethyl ether (5.47 g) at −5° C. The mixture was stirred 1 hour at 0° C. and 48 h at RT. The solvent was evaporated off, the residue partitioned between AcOEt and water. The layers were separated, the organic layer washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 5%) to give the desired 4-Benzyloxymethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (5.79 g) as a light brown oil. MS (ESI): 378.4 (MH+).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(#N)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:21][CH:18]([CH3:20])[CH3:19])#[N:2]
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=NC#N)NC1CCCc2ccccc21
Reaction time: 154 h

Procedure:
A solution of 30.0 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-napthyl)-S-methylisothiourea and 40 ml of isopropylamine in 300 ml of acetonitrile was heated at reflux with stirring for 154 hours. The solvent and excess isopropylamine were removed by evaporation in vacuo, leaving the crude product as a tacky, white solid. Crystallization from isopropyl acetate followed by a recrystallization from a mixture of isopropyl acetate and 2-propanol gave 5.13 g of N"-cyano-N-isopropyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 170.5°-172.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN(CC)CC.[C:31]([O:35][C:36](=[O:43])[N:37]([CH2:39][CH2:40][CH2:41][NH2:42])[CH3:38])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:42][CH2:41][CH2:40][CH2:39][N:37]([CH3:38])[C:36](=[O:43])[O:35][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (200 mg, 0.65 mmol) HATU (372 mg, 0.98 mmol), and Et3N (198 mg, 1.96 mmol) in DMF (3.0 mL). The mixture was stirred at room temperature for 0.5 hour, then tert-butyl(3-aminopropyl)(methyl)carbamate (147.39 mg, 0.79 mmol) was added. The mixture was stirred overnight at room temperature. The reaction mixture was purified by preparative HPLC to give tert-butyl (3-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinamido)propyl)(methyl)carbamate (150 mg, 48%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:21]([CH2:22][C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][N:21]1[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=[C:17]1[NH:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:11][CH2:12]1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1coc(Cn2c(NC3CCN(CCNc4nccs4)CC3)nc3ccccc32)c1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A mixture of 2.7 parts of 2-bromothiazole, 5.1 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-furanylmethyl)-1H-benzimidazol-2-amine, 5 parts of sodium carbonate, 0.1 parts of sodium iodide and 9 parts of N,N-dimethylacetamide was stirred for 3 hours at about 140° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3 parts of 1-(2-furanylmethyl)-N-[1-[2-(2-thiazolylamino)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 153.1° C. (compound 48).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH:7]([N:10]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[C:14]([O:20][CH3:21])[CH:13]=1)([CH3:9])[CH3:8].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O.O>[CH:23]1([N:10]([CH:7]([CH3:9])[CH3:8])[C:11](=[O:22])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cccc(O)c1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(OCc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2OC)c1

Procedure:
A slurry of K2CO3 (0.75 g, 5.43 mmol) in a solution of 4-bromomethyl-3-methoxybenzoic acid N-isopropyl-N-cyclohexyl amide (1.0 g, 2.7 mmol) and 3-methoxy phenol (0.35 g, 2.74 mmol) in dimethylformamide (DMF) (15 ml) was stirred overnight at room temperature. The reaction mixture was diluted with water (50 ml), extracted twice with ethyl acetate and dried (Na2SO4) The drying agent was filtered and the filtrate concentrated in vacuo to give the crude product as a dark oil. This material was purified by chromatography on silica gel using mixtures of ethyl acetate, CH2Cl2 and hexane as eluents to give the title compound as a glass.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16]>>[NH:21]1[C:22]2[C:18](=[C:17]([NH:14][C:15]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=3)=[O:16])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C=Nc1cccc2[nH]ccc12
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1cccc2[nH]ccc12
Yield: 65.8 %

Procedure:
4-(Trifluoromethoxy)benzylamine (0.21 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound (0.23 g). mp 177° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.36 (d, 2H), 6.52 (m, 1H), 6.95 (m, 3H), 7.24 (t, 1H), 7.36 (d, 2H), 7.48 (d, 2H), 7.63 (dd, 1H), 8.32 (1H), 11.06 (s, 1H); MS (DCI+) m/z 349.9 (M+H)+; Anal. Calcd. For C17H14N3F3O2: C, 58.63, H, 4.34, N, 12.07. Found: C, 58.51, H, 3.98, N, 12.03.