Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.[F:38][C:39]1[CH:40]=[C:41]([CH:63]=[CH:64][C:65]=1[F:66])[CH2:42][N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([NH:51][CH2:52][C:53]2[CH:54]=[C:55](B(O)O)[CH:56]=[CH:57][CH:58]=2)=[O:50])[C:44]1=[O:62].[B].[Cl:68][C:69]1[CH:70]=[C:71]2[C:77](I)=[CH:76][NH:75][C:72]2=[N:73][CH:74]=1>>[Cl:68][C:69]1[CH:70]=[C:71]2[C:77]([C:55]3[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=3)[CH2:52][NH:51][C:49]([C:45]3[C:44](=[O:62])[N:43]([CH2:42][C:41]4[CH:63]=[CH:64][C:65]([F:66])=[C:39]([F:38])[CH:40]=4)[CH:48]=[CH:47][CH:46]=3)=[O:50])=[CH:76][NH:75][C:72]2=[N:73][CH:74]=1
Reactant: Clc1cnc2[nH]cc(I)c2c1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(Cl)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 5-Chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to yield the product. 1H NMR (300 MHz, CDCl3-MeOH-d4) d ppm 8.564 (dd, J=7.3, 2.2 Hz, 1H) 8.332 (d, J=2.0 Hz, 1H) 8.230 (d, J=2.1 Hz, 1H) 7.584 (s, 1H) 7.565 (s (br), 1H) 7.538 (dd, J=6.8, 2.1 Hz, 1H) 7.468-7.370 (m, 2H) 7.303 (d, J=6.9 Hz, 1H) 7.168-7.061 (m, 2H) 7.027-6.955 (m, 1H) 6.461 (t, J=6.9 Hz, 1H) 5.134 (s, 2H), 4.716-4.659 (m, 2); MS m/z=50.05 M+H.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[C:2]#[CH:3].Br[C:16]1[C:17]([NH:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:22]([C:19]1[N:20]=[CH:21][C:16]2[CH:3]=[C:2]([CH2:1][C:4]3[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[CH:6][CH:5]=3)[N:24]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=2[N:18]=1)#[N:23]
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#CCc1ccc(CS(N)(=O)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(Cc2ccc(CS(N)(=O)=O)cc2)cc2cnc(C#N)nc21
Temperature: 70 °C
Yield: 60.7 %

Procedure:
To a solution of N.-(4-prop-2-ynyl-phenyl)-methanesulfonamide (1.0 mmol) and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (0.5 mmol) in DMF (5 ml), triethylamine (1.5 mmol), dichlorobis-dichlorobis(triphenylphosphine)palladium (II) (0.05 mmol) and copper (I) iodide (0.1 mmol) is added. The reaction mixture is heated at 70° C. ca. for 2.5 h. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product, which is purified by silica gel column chromatography. Yield: 60.7%. Rf=0.55 (n-hexane:AcOEt=1:1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)CC)C.[CH3:24][OH:25].C1(N=C=NC2CCCCC2)CCCCC1>C(=S)=S>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:24]=[O:25])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:16]
Reactant: CO
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: S=C=S
Product: CCn1c2ccccc2c2cc(N=C=O)ccc21
Reaction time: 4 h

Procedure:
38.6 g of 3-amino-9-ethylcarbazole and 27.9 ml of triethylamine were added to 300 ml of methanol, and, while cooling with ice, 15.2 g of carbon disulfide was added dropwise thereto. After conducting reaction at room temperature for 3 hours, 41.3 g of dicyclohexylcarbodiimide was added thereto, followed by reacting at room temperature for 4 hours. Crystals thus precipitated were collected by filtration, heat-refluxed in 500 ml of ethyl acetate, and cooled to precipitate and then filter off solids. The filtrate was concentrated to obtain the desired product (29 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH2:18][CH3:19])[C:3]=1[C:20]#[N:21].N.[OH:23]O>C(O)C>[NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:5]=[C:4]([CH2:18][CH3:19])[C:3]=1[C:20]([NH2:21])=[O:23]
Reactant: CCc1nn(C(C)CCCc2ccccc2)c(N)c1C#N
Reactant: OO
Agent: N
Solvent: CCO
Product: CCc1nn(C(C)CCCc2ccccc2)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.08 g (18 mmol) of 5-amino-3-ethyl-1-(1-methyl-4-phenyl-butyl)-1-H-pyrazole-4-carbonitrile are dissolved in 100 ml of ethanol and, after 100 ml of concentrated NH3 solution (25% strength) and 50 ml of hydrogen peroxide solution (30% strength) have been added, the solution is stirred for 16 hours at room temperature. After the non-aqueous solvents have been removed, the pH is brought to 5 with 1N HCl. The aqueous phase is extracted three times with dichloromethane, and the organic phase is dried over sodium sulphate and evaporated on a rotary evaporator. This gives 3.58 g of a brown oil (66%).
Reaction SMILES: O[CH:2]([C:4]1([O:13]C)[C:8]([O:9][CH3:10])=[CH:7][CH:6]([O:11][CH3:12])[O:5]1)[CH3:3].C(O)=O.O>CO>[CH3:10][O:9][C:8]1[C:4](=[O:13])[CH:2]([CH3:3])[O:5][CH:6]([O:11][CH3:12])[CH:7]=1
Reactant: COC1=CC(OC)OC1(OC)C(C)O
Solvent: CO
Solvent: O
Solvent: O=CO
Product: COC1=CC(OC)OC(C)C1=O
Reaction time: 0.08 h

Procedure:
2(1-hydroxy ethyl)-2,3,5-trimethoxy-2,5-dihydrofuran (8.4 g, 0.45 moles) in 3 ml methanol was added to 25 ml of formic acid and 1.2 ml methanol. After stirring for 5 minutes, the reaction was poured into 75 ml of water and extracted with chloroform. Concentration of the chloroform layer yielded a brown oil which solidified overnight. Recrystallization from hexane-ether yielded 4,6-dimethoxy-2-methyl-2H-pyran-3(6H)-one as white needles, mp 73°-74.5° C., NMR (CDCl3,δ) 5.75 (1H, d, J=4Hz), 5.3 (1H, d, J=4Hz), 4.62 (1H, q, J=7Hz), 3.68 (3H, s), 3.52 (3H, S), 1.2 (3H, t, J=7Hz).
Reaction SMILES: [CH2:1]([O:3][Si:4]([CH2:11][CH2:12][CH2:13][Cl:14])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:17]>C(O)C>[Cl-:14].[CH3:15][N+:16]([CH3:17])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][CH2:12][CH2:11][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCN(C)C
Reactant: CCO[Si](CCCCl)(OCC)OCC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCC[Si](OCC)(OCC)OCC
Product: [Cl-]
Temperature: 135 °C
Yield: 150.4 %

Procedure:
Firstly, 41.5 g (0.17 moL) of triethoxysilylpropyl chloride (Tokyo Kasei Kogyo Co., Ltd.), 44.6 g (0.150 moL) of N,N-dimethyl octadecylamine (Tokyo Kasei Kogyo Co., Ltd.) and 40.5 g of ethanol are fed into a nitrogen-purged pressurized reactor and heated to 135° C. After the reaction for 20 hours, 121.4 g of dimethyloctadecyl[3-(triethoxysilyl)propyl]ammonium chloride (EtAC) in ethanol solution is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:42][CH2:41][CH2:40][CH2:39]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:39][CH:40]4[CH2:42][CH2:41]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (5 mL), piperidine (78 mg, 0.92 mmol, 3.0 equiv), and cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was diluted with 10 mL of dichloromethane, and the solution was washed with saturated aqueous ammonium chloride, water and brine. The organics were dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 36 mg (21%) of 2-[[(3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]carbonyl]-3-cyclopropylprop-2-enenitrile as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13](C)[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1C=C2N(C3C=CC=CC=3Cl)CC3(CCN(C)CC3)C2=CC=1.Cl[C:56]([O:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:57].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:9][C:10]3([CH2:15][CH2:14][N:13]([C:56]([O:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)=[O:57])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCC2(CC1)CN(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.8 g of 6-chloro-1(2-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine], free base of Example 28, and 0.5 g of phenyl chloroformate in 20 ml of methylene chloride is stirred at ambient temperature for 16 hours. Thereafter, the mixture is successively washed with 10% sodium hydroxide, washed with water, dried and concentrated under vacuum leaving a brownish oil. The oil is passed through an alumina column, ether eluant, providing a colorless gum of 6-chloro-1-(2-chlorophenyl)-1'-phenoxycarbonylspiro[indoline-3,4'-piperidine]. IR and NMR spectra confirm the assigned structure.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]([CH2:17][CH:18]=[CH2:19])[CH2:14][CH:15]=[CH2:16].[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]=[CH:15][CH2:14][CH:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[CH2:17][CH:18]=[CH2:19]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCC(CC=C)OCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCC(CC=C)OCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reaction time: 11 h
Yield: 76.8 %

Procedure:
15 g of the compound (4), 8.3 g of methyl 4-hydroxybenzoate and 23 g of potassium carbonate were dissolved in 100 ml of 2-butanone, and reflux was carried out for 11 hours in an atmosphere of argon. After the solid matter generated was filtered off, the solvent was evaporated, and the residue was purified by a chromatography using a column filled with alumina and silica gel, to obtain 14 g of the compound (5). (Yield: 77%)
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]1(=[O:12])[O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([NH:3][CH2:2][CH2:1][NH:4][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:12])=[O:11])=[O:12]
Reactant: O=C1CCCCCO1
Reactant: NCCN
Solvent: O
Product: O=C(CCCCCO)NCCNC(=O)CCCCCO
Temperature: 20 °C
Reaction time: 15 h

Procedure:
C2C monomer is prepared by reacting 1.2 kg ethylene diamine (EDA) with 4.56 kg of ε-caprolactone under a nitrogen blanket in a stainless steel reactor equipped with an agitator and a cooling water jacket. An exothermic condensation reaction between the ε-caprolactone and the EDA occurs which causes the temperature to rise gradually to 80 degrees Celsius (° C.). A white deposit forms and the reactor contents solidify, at which point the stirring is stopped. The reactor contents are then cooled to 20° C. and are then allowed to rest for 15 hours. The reactor contents are then heated to 140° C. at which temperature the solidified reactor contents melt. The liquid product is then discharged from the reactor into a collecting tray. A nuclear magnetic resonance study of the resulting product shows that the molar concentration of C2C in the product exceeds 80 percent. The melting point of the C2C product is determined to be 140° C.
Reaction SMILES: [CH3:1][N:2]([CH3:39])[C:3]1[CH:38]=[CH:37][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([C:21]3[C:29]4[C:24](=[CH:25][C:26]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[CH:27][CH:28]=4)[NH:23][CH:22]=3)[CH2:17][N+:18]([O-])=O)[C:11]=2[F:36])=[O:8])=[CH:5][CH:4]=1.[H][H]>CO.[Ni]>[NH2:18][CH2:17][CH:16]([C:12]1[C:11]([F:36])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:39])=[CH:38][CH:37]=2)[CH:15]=[CH:14][CH:13]=1)[C:21]1[C:29]2[C:24](=[CH:25][C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=2)[NH:23][CH:22]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(C(C[N+](=O)[O-])c3c[nH]c4cc(N5CCOCC5)ccc34)c2F)cc1
Agent: [Ni]
Solvent: CO
Product: CN(C)c1ccc(C(=O)Nc2cccc(C(CN)c3c[nH]c4cc(N5CCOCC5)ccc34)c2F)cc1
Yield: 82.1 %

Procedure:
A mixture of 4-(dimethylamino)-N-(2-fluoro-3-(1-(6-morpholino-1H-indol-3-yl)-2-nitroethyl)phenyl)benzamide (0.388 g, 0.730 mmol) and Raney Ni (a small amount) in MeOH (35 mL) was treated with hydrogen at 55 psi a Parr shaker apparatus for 3 hr. The catalyst was removed by suction filtration. The filtrate was concentrated under vacuum, diluted with CH2Cl2 (100 mL), washed with brine (25 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.321 g, 0.599 mmol, 82% yield) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17].[Cl-].[NH4+]>C(OCC)C.O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
2,5-Dibromopyridine (5.4 g) was stirred in diethyl ether (100 ml) under a nitrogen atmosphere, the solution was cooled at −78° C., then n-butyllithium (2.66M solution in hexane) (8.5 ml) was added dropwise thereto followed by stirring for 20 minutes, then N,N-dimethylformamide (4.0 ml) was added dropwise thereto followed by stirring for 10 minutes. A saturated aqueous solution of ammonium chloride and water were sequentially added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.2 g).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]=[C:26]1[C:31](C(Cl)=O)=[CH:30][CH:29]=[C:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:27]1.[Cl:40][C:41]1[CH:42]=[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH:44]=[CH:45][C:46]=1[Cl:47]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:11][C@@H:12]([C:22]([N:51]2[CH2:50][CH2:49][N:48]([C:43]3[CH:44]=[CH:45][C:46]([Cl:47])=[C:41]([Cl:40])[CH:42]=3)[CH2:53][CH2:52]2)=[O:24])[N:13]([C:15]([C:31]2[C:26](=[O:25])[O:27][C:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:30]=2)=[O:17])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Product: CCCCCc1ccc(C(=O)N2CC(=NOCc3ccccc3)C[C@H]2C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 1-(3,4-dichlorophenyl)piperazine the title compound was obtained in 47% purity by LC/MS. MS(ESI+): m/z=639.8.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Cl:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][CH3:13])[C:9]=2[CH:14]=1
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1CNCCc2cc(OC)c(Cl)cc21
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.421 g, 1.25 mmol) in methanol (30 mL) was treated with 15% aqueous NaOH (30 mL), and stirred overnight at 20 C. The product mixture was diluted with brine (100 mL), extracted twice with EtOAc (200 mL), dried with MgSO4, and concentrated to give 0.241 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.05 (s, 1H), 6.79 (s, 1H), 3.84 (s, 3H), 3.03 (m, 3H), 2.91 (s, 1H), 2.86-2.76 (m, 3H), 2.64 (m, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 0.93 (dd, J=8, 8 Hz, 3H). MS calculated for C13H18clNO+H: 240, observed: 240.
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH2:10][CH2:11][C:12]([O:14]C)=O)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2].[H-].[Na+].CO>C1(C)C=CC=CC=1>[C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:4][CH:5]([C:6]([O:8][CH3:9])=[O:7])[C:12](=[O:14])[CH2:11][CH2:10]1)#[N:2]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CC(C#N)(c2ccccc2F)CCC1=O
Yield: 92.8 %

Procedure:
Dimethyl 4-cyano4-(2-fluorophenyl)heptanedioate (D1, 35.86 g, 0.12 mol) was stirred under Ar in toluene (500 ml) as sodium hydride (80% in mineral oil, 3.5 g, 0.12 mol) was added. Methanol (10 ml) was added dropwise, and the mixture was then stirred at reflux for 16 h, partitioned between ethyl acetate and dilute HCl, and separated. The organic portion was washed with brine, dried (Na2SO4) and evaporated to an oil. This was dissolved in dichloromethane (500 ml), filtered, and evaporated to give the title compound (30.66 g, 95%) as a cream solid.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10]OC)=[CH:5][N:4]=1)[CH3:2].[CH3:13][C:14]1[N:15]=[CH:16][CH:17]=[C:18]2[CH:22]=[CH:21][S:20][C:19]=12.[ClH:23].N1C=CC=NC=1>C1(C)C(C)=CC=CC=1>[ClH:23].[Cl-:23].[NH2:9][C:7]1[C:6]([CH2:10][N+:15]2[C:14]([CH3:13])=[C:19]3[S:20][CH:21]=[CH:22][C:18]3=[CH:17][CH:16]=2)=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[N:8]=1
Reactant: Cc1nccc2ccsc12
Reactant: CCc1ncc(COC)c(N)n1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: c1cncnc1
Product: CCc1ncc(C[n+]2ccc3ccsc3c2C)c(N)n1
Product: [Cl-]
Temperature: 65 °C
Reaction time: 12 h

Procedure:
50 G. of 2-ethyl-4-amino-5-methoxymethyl pyrimidine, 50 g. of 7-methylthieno[2,3-c]pyridine and 500 ml. of xylene are placed in a 2-liter flask equipped with reflux condenser, stirrer, thermometer and gas inlet tube. Hydrogen chloride gas is added to this mixture over 30 minutes at a rate sufficient to add an amount equivalent to 0.2 moles, that of the pyrimidine. The temperature rises to about 67° C. The gas inlet tube is replaced with a distillation unit and the mixture heated at reflux (138° C.) for two hours during which fresh xylene is added to replace the volume of liquid that distills. An additional 25 g. of 7-methylthieno[2,3-c]pyridine are added and the mixture refluxed for 40 minutes. At the end of the reflux period, the reaction mixture is cooled to 65° C., the xylene decanted, and 50 ml. of acetonitrile added to the residue. The resulting mixture is stirred at room temperature for about 12 hours, filtered, and the solid 6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno-[2,3-c]pyridinium chloride hydrochloride thus obtained washed. The product has a m.p. of 249°-250° C., dec.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([N:12]3[CH2:15][C:14]([F:17])([F:16])[CH2:13]3)=[CH:10][N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:21][CH:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([NH2:25])=[O:24].Cl>>[NH2:25][C:23](=[O:24])[CH:22]([NH:21][C:18]([C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:11]([N:12]2[CH2:13][C:14]([F:16])([F:17])[CH2:15]2)=[CH:10][N:9]=1)=[O:20])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Reactant: CC(C)(C)C(N)C(N)=O
Agent: Cl
Product: CC(C)(C)C(NC(=O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 4-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (example 53e) and 2-Amino-3,3-dimethyl-butyramide; hydrochloride (CAN 113582-42-6) as starting materials and isolated (58 mg, 83%); MS (ESI, m/z): 397.3 (M+H+).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15](Cl)=[O:16].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][N:38]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>>[CH2:29]([NH:28][C:26](=[O:27])[C:25]1[CH:36]=[CH:37][N:38]=[C:23]([NH:22][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([F:11])[CH:20]=[C:19]([F:21])[CH:18]=2)[CH:24]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cc(F)cc(F)c2)c1
Yield: 68 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 3,5-difluorobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3,5-difluorobenzamido)isonicotinamide was obtained as a colorless solid in 68% yield: mp 185-187° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 11.16 (s, 1H), 9.35 (t, J=6.0 Hz, 1H), 8.54-8.50 (m, 2H), 7.75-7.71 (m, 2H), 7.58-7.47 (m, 2H), 7.31-7.21 (m, 5H), 4.46 (d, J=5.9 Hz, 2H); MS (ES+) m/z 368.5 (M+1).