Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]\[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1.C1(C2C=CC=CC=2)C=CC(C(C2C=CC(C3C=CC=CC=3)=CC=2)=C/C=C/C(NCCCCC2C=NC=CC=2)=O)=CC=1>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]\[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(C(=C/C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reactant: NCCCCc1cccnc1
Agent: O=C(/C=C/C=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1)NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C\C(=O)NCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 39 %

Procedure:
As in Example 134, a solution of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.2 g) and 3-pyridinebutanamine (0.42 g) in tetrahydrofuran (7 mL) was stirred at room temperature for 1 hour. The crude amide that had been isolated in the usual way, was contaminated with a minor amount of the (E)-isomer. The mixture was separated by HPLC (ethyl acetate) and the desired product was crystallized from ether (2×) to yield 0.48 g of (Z)-5,5-bis(3-methoxyphenyl)-N-[4-(3-pyridinyl)-butyl]-2,4-pentadienamide mp 69°-73° C.
Reaction SMILES: CN(C)C=O.[CH:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([SH:16])[C:9]2=[CH:8][CH:7]=1.Br[C:18]1[O:22][CH:21]=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=1>O>[C:15]1([S:16][C:18]2[O:22][CH:21]=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=2)[C:9]2[C:10](=[CH:11][CH:6]=[CH:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Sc1cccc2ccccc12
Reactant: O=C(O)c1coc(Br)c1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2cccc3ccccc23)c1

Procedure:
Following the procedure of Example 9, except that a total volume of 90 ml. of dimethylformamide was used, 1-thionaphthol (5.02 g., 31.4 mmoles) was reacted with 5-bromofuran-3-carboxylic acid. Crude product was isolated as an oil according to Example 16. The oil was solidified by trituration with water (988 mg.). Recrystallization from hexane gave purified 5-(1-naphthylthio)furan-3-carboxylic acid (250 mg., m.p. 118°-120° C., m/e 270).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:2]1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>>[CH:18]([NH:21][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:20])[CH3:19]
Reactant: CC(C)N
Reactant: c1ccc(-c2ccccc2CCC2CO2)cc1
Product: CC(C)NCC(O)CCc1ccccc1-c1ccccc1

Procedure:
Following a precedure similar to that of Example 32, 1,2-epoxy-4-(1,1'-biphenyl-2-yl)butane was reacted with isopropylamine to provide N-isopropyl-2-hydroxy-4-(1,1'-biphenyl-2-yl)butylamine. The amine base so formed was reacted with hydrogen chloride to provide N-isopropyl-2-hydroxy-4-(1,1'-biphenyl-2-yl)butylaminium chloride. M.P. 153°-154° C.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[O:36])[NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[C:9]1=[O:37])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:37]=[C:9]1[N:10]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26](=[O:36])[NH:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:23][CH:24]=2)[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][C:6]([OH:38])=[O:5]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccc(CC(=O)NCCc3ccccc3)cc2)c(=O)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)n(-c2ccc(CC(=O)NCCc3ccccc3)cc2)c(=O)c2ccccc21
Reaction time: 18 h

Procedure:
A stirred solution of {2,4-dioxo-3-[4-(phenethylcarbamoyl-methyl)-phenyl]-3,4-dihydro-2H-quinazolin-1-yl}-acetic acid tert-butyl ester (Intermediate E) (470 mg, 0.916 mmol) and triethylsilane (0.37 ml, 2.9 mmol) in dry DCM (2.5 ml) under argon is treated dropwise with TFA (2.5 ml). After 18 hours, the reaction mixture is evaporated in vacuo and the residue is triturated with MeOH resulting in a white solid. The solid is filtered and dried under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([S:31]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1>>[C:35]([NH:34][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=3)[C:10]([CH3:11])=[C:2]2[CH3:1])=[CH:20][CH:21]=1)(=[O:33])=[O:32])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 6, Example 1, using the ethyl 2,3-dimethyl-1H-indole-5-carboxylate and 4′-(bromomethyl)-N-(tert-butyl)-[1,1′-biphenyl]-2-sulfonamide.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:32])([F:31])[C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:30][CH2:29][C:27]3[O:26][N:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:28]=3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nc(C(F)(F)F)no1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b) was reacted with C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methyl amine hydrochloride (CAS 944905-93-5) in the presence of TBTU and DIEA to give the title compound as white solid; MS (EI): m/e=434.5 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:10])[CH3:9])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[C:24]2[Cl:31].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([N:8]([CH3:9])[CH3:10])=[CH:6][C:5]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[C:24]3[Cl:31])=[CH:4][N:3]=1
Reactant: CN(C)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1Cl
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)c1cc(-c2ccc3nccc(Cl)c3c2)cnc1Cl
Temperature: 25 °C
Yield: 71.2 %

Procedure:
(Some starting materials may be obtained from ECA International, Palatine, Ill.) To a microwave vial (5 mL), 2-chloro-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (0.110 g, 0.390 mmol), 6-bromo-4-chloroquinoline (0.102 g, 0.419 mmol), PdCl2 (dppf)-CH2Cl2 adduct (0.0183 g, 0.0224 mmol) and potassium carbonate (0.500 mL, 1.00 mmol) were added into 1,4-dioxane (3 mL). The mixture was degassed by bubbling nitrogen through for 10 min. The tube was irradiated with microwave at 100° C. for 10 min. The reaction was cooled to RT then partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (eluent: acetone in hexanes 0% -30%) to afford the title compound as a white solid (0.0884 g). m/z: calc'd for C16H13Cl2N3; 317.0, found: 318.1 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.97 (s, 6 H), 7.55-7.63 (m, 2 H), 7.98 (dd, J=8.8, 2.0 Hz, 1 H), 8.25 (d, J=8.8 Hz, 1 H), 8.38 (dd, J=5.3, 2.0 Hz, 2 H), 8.84 (d, J=4.7 Hz, 1 H).
Reaction SMILES: [NH2:1][CH:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>C1COCC1>[C:26]([NH:1][CH:2]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(N)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(C)=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-amino-2-ethoxy-2-oxoethyl)benzoic acid, as described in Example 1, Step B, (0.94 g, 2.79 mmol) and DIPEA (1.509 mL, 8.64 mmol) were suspended in THF (4 mL) and acetic anhydride (0.289 mL, 3.07 mmol) was added. The mixture was stirred at room temperature overnight. 2N HCl was added and the products extracted into EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as a white powder. 1H NMR (DMSO-d6, 600 MHz) δ 13.00 (br s, 1H), 8.77 (d, J=7.2 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 5.45 (d, J=7.2 Hz, 1H), 4.07 (m, 2H), 1.88 (s, 3H), 1.09 (t, J=7.2 Hz, 3H). MS: cal'd 266 (MH+), exp 266 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>CN(C=O)C>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[O:1][C:17]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)CCl
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1oc2ccccc2c1N
Temperature: 120 °C
Yield: 63.9 %

Procedure:
To a solution of 2-hydroxy-benzonitrile (1000 mmol) in DMF (dimethylformamide, 80 mL) was added K2CO3 (207 g, 1.5 mol) portionwise under stirring, followed by 1-chloro-propan-2-one (139 g, 1.5 mol). After addition, the mixture was heated to 120° C. and stirred at that temperature for 2 hours. TLC showed the reaction was completed. The reaction mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was washed with dichloromethane, filtered and dried to give 112 g of 1-(3-amino-benzofuran-2-yl)-ethanone (1A).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.ClC1C=CC(C[CH:16]2[C:21](=[O:22])[O:20][C:19]([CH3:24])([CH3:23])[O:18][C:17]2=[O:25])=CC=1.ClC1C=CC(CC(C(O)=O)C(O)=O)=CC=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH:16]2[C:21](=[O:22])[O:20][C:19]([CH3:24])([CH3:23])[O:18][C:17]2=[O:25])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C(O)C(Cc1ccc(Cl)cc1)C(=O)O
Product: CC1(C)OC(=O)C(Cc2ccc(F)cc2)C(=O)O1

Procedure:
The title compound was prepared using 4-fluorobenzaldehyde in place of 4-chlorobenzaldehyde using the procedure described for the preparation of 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a).
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3CCOCC3)=O)C)=CN=2)=CC=1.[NH2:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29].[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](O)=[O:51]>>[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50]([NH:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29])=[O:51]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccc(OC)c3)nn2)cc1
Yield: 26.4 %

Procedure:
In a similar manner as described for Intermediate 50, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 3-methoxybenzoic acid (68 mg, 0.45 mmol) to give 3-(methyloxy)-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (41 mg) as a yellow solid. MS m/z 380 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14][CH:15]2[CH2:20][NH:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH:8]1([CH2:14][CH:15]2[CH2:20][N:19]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CNCC(CC2CCCCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(CC2CCCCC2)CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (340 mL, 2.4 mmol) was added to a solution of ethyl 5-(cyclohexylmethyl)piperidine-3-carboxylate (155 mg, 0.60 mmol) and methanesulfonyl chloride (75 mL, 0.90 mmol) in CH2Cl2 (6 mL) cooled to 0° C. The reaction was maintained at this temperature for 15 min at which point the whole was allowed to warm to RT and stir for an additional 3 h. The reaction was diluted with CH2Cl2 (20 mL) and poured into HCl (1N, 20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were sequentially washed with H2O (10 mL) and brine before being dried over Na2SO4. Concentration under reduced pressure provided the title compound. MS m/z: 332.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]1[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:16]=[CH:17][N:18]=1>CCOC(C)=O.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][CH2:13][C:14]2[N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH:16]=[CH:17][N:18]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1ccnc1CCCc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccnc1CCCc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution of compound 123 (150 mg, 0.43 mmol) in EtOAc (10 mL) was added Pd/C (25 mg, 10%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at room temperature for 2 h. The suspension was filtered and the solid was washed by EtOAc. The filtrates were concentrated to dryness to give compound 124 (100 mg, 64%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ7.28-7.32 (m, 1H), 6.93-6.98 (m, 1H), 6.82-6.86 (m, 1H), 6.30-6.40 (m, 2H), 3.02 (t, 2H, J=7.6 Hz), 2.63 (t, 2H, J=7.6 Hz), 1.97-2.09 (m, 2H), 1.62 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:15]([O:16][CH3:17])=[C:9]2[N:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:14][C:12]1[CH:11]=[N:10][C:9]2=[C:15]([O:16][CH3:17])[N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[CH:13]=1
Reactant: COc1c2ncc(Cl)cc2nn1CC(C)(N)C#N
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: COc1c2ncc(Cl)cc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, 2-amino-3-(6-chloro-3-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (15 mg, described in Example 146) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (20 mg, 67%). MS (ES): M/Z [M+H]=470. 1H NMR: (400 MHz, CHLOROFORM-d): 1.92 (s, 3H), 4.53 (d, J=14.2 Hz, 1H), 4.67 (s, 3H), 4.86 (d, J=14.2 Hz, 1H), 7.77-7.82 (m, 3H), 7.93 (d, J=8.2 Hz, 2H), 8.31 (d, J=1.9 Hz, 1H) and 8.82 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]2[N:10]([CH3:26])[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[O:16])[C:13](=[O:14])[C:8]=2[S:7][CH:6]=1)=[N+:2]=[N-:3].[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.Cl.C1C[O:46][CH2:45]C1>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C=O)C>[N:1]([CH2:4][C:5]1[C:9]2[N:10]([CH3:26])[CH:11]=[C:12]([C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[O:16])[C:13](=[O:14])[C:8]=2[S:7][C:6]=1[CH:45]=[O:46])=[N+:2]=[N-:3]
Reactant: C1CCOC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2scc(CN=[N+]=[N-])c21
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C=O)c(CN=[N+]=[N-])c21
Temperature: -78 °C

Procedure:
Into a cold (−78° C.), stirred mixture of 2.54 g of 3-(azidomethyl)-N-(4-chlorobenzyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 100 mL of dry THF is added via cannula a solution of LDA in THF, prepared from 3.7 mL of diisopropylamine and 8.0 mL of 2.5 M (hexanes) butyllithium in 50 mL of THF. The mixture is stirred at −78° C. for 90 min, then 2.5 mL of dry DMF is added and the mixture is allowed to warm to 0° C. Aqueous workup (CHCl3/dil. HCl) followed by flash chromatography on silica using 2% MeOH in CH2Cl2 affords 1.61 g of the title compound as an amber foam.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][N:29]=[C:28]3[N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=3)[C:44](O)=[O:45])[CH2:37][CH2:36]2)[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:50]1[CH:54]=[CH:53][N:52]=[C:51]1[NH2:55].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>ClCCl>[S:50]1[CH:54]=[CH:53][N:52]=[C:51]1[NH:55][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[C:41]([N:38]2[CH2:37][CH2:36][N:35]([C:28]3[C:27]4[C:32](=[CH:33][CH:34]=[C:25]([C:23]5[CH:22]=[N:21][N:20]([C:1]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)([C:8]6[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=6)[C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)[CH:24]=5)[CH:26]=4)[N:31]=[CH:30][N:29]=3)[CH2:40][CH2:39]2)[CH:42]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1cccc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)c1cccc(N2CCN(c3ncnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Reaction time: 12 h
Yield: 115.1 %

Procedure:
118 mg 3-{4-[6-(1-trityl-1H-4-pyrazolyl)-4-quinazolinyl]piperazin-1-yl}benzoic acid (compound in Example 828), 18 mg 1,3-thiazol-2-amine, 20 mg triethylamine and 89 mg benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate were dissolved in dichloromethane and stirred for 12 hours. The reaction solution was concentrated and purified by silica gel column chromatography, to give 150 mg of the title compound.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].B(F)(F)F.CCOCC.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[Cl-].[Na+]>>[CH2:18]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Oc1ccccc1O
Reactant: C=CCCCCCCC
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCc1cccc(O)c1O
Temperature: 104 °C

Procedure:
Into a 500ml, 3-neck reaction vessel was placed 64.8g (0.3125 moles) of catechol, after which time it was heated to 104° C. under a nitrogen flow. After the catechol was completely melted, 3.25g (5% based on the wt. of the catechol) of borontrifluoride-etherate was added dropwise, with stirring. After adding all of the catalyst, 63.2 g (0.25 moles) of 1-nonene was added dropwise to the reaction mixture, the rate of addition being adjusted so as to maintain a temperature of 130° C. After all of the 1-nonene was added, the resultant mixture was allowed to react for 3 hours, after which time 100 ml of a 10% sodium chloride solution was added to the reaction mixture. The resultant mixture was then stirred for 15 minutes at 95° to 100° C., after which time the bottom layer was separated. The mixture was again stirred at 95° to 100° C. for 15 minutes, after which time the bottom layer was again separated. The organic layer was then isolated to obtain a viscous, brown oil of the formula ##STR7##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]#[N:16])[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[NH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: N#CNc1ccccc1-c1cccc(F)c1
Solvent: COCCOC
Product: CN1CCN(C(=N)Nc2ccccc2-c2cccc(F)c2)CC1

Procedure:
A mixture of 3'-fluoro-2-biphenylylcyanamide (4.1 g) and N-methylpiperazine (1.9 g) in 1,2-dimethoxyethane (30 ml) was heated at 90°-95° C. for 4 hours to yield N-(3'-fluoro-2-biphenylyl)-4-methylpiperazine-1-carboxamidine (m.p. 117°-118° C.) which was recrystallised from hexane.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>>[CH3:1][N:2]([CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CC(C)NC
Product: CCOC(=O)CCN(C)C(C)CC(=O)OCC
Temperature: 110 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
A mixture of 54.4 gm (0.374 mole) ethyl 3-(N-methylamino)butanoate and 100 gm (0.999 mole) ethyl acrylate was heated at 110° C. with stirring for 18 hours. The reaction mixture was cooled to room temperature and then distilled under reduced pressure to provide 61.7 gm (67.1%) of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[N:13]1([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[N:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Clc1cncc(-c2ccsc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1cc(-c2cncc(N3CCNCC3)n2)cs1
Temperature: 85 °C

Procedure:
A mixture of the product from step 1 above (1.04 g, 5.29 mmol), piperazine (1.32 g, 15.3 mmol), and K2CO3 (0.81 g, 5.82 mmol) in acetonitrile (6 mL) was heated in a sealed pyrex flask at 85° C. for 8.5 h. The reaction mixture was diluted with dichloromethane, filtered, and concentated in vacuo. The semi-solid residue was purified by column chromatography on silica gel (18×5 cm) using CHCl3/MeOH (9:1)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1
Reactant: N#Cc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(CO)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a 0° C. solution of 5-formylpicolinonitrile (490 mg, 3.71 mmol) in 15 mL of MeOH was added NaBH4 (140 mg, 3.71 mmol). The reaction mixture was stirred at 0° C. for 1 h and quenched with 5% citric acid. After most MeOH was removed by concentration, the residue was partitioned between DCM and sat. NaHCO3 (aq.). The aqueous layer was extracted with DCM (10×). The organic layer was washed with brine and dried (Na2SO4). The product 5-(hydroxymethyl)picolinonitrile (431 mg) was obtained by concentration under vacuum.