Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([N:24]1[CH2:25][CH2:26][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:22][CH2:23]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(C(=O)C(C)(C)NC(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A suspension of 2-benzyloxycarbonylamino-2-methyl-propionic acid (2.37 g), 1-isopropylpiperazine (1.54 g), 1-hydroxybenzotriazole (1.49 g), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (2.88 g) and triethylamine (2.79 mL) in N,N-dimethylformamide (20 mL) was stirred at 50° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous ammonium chloride solution, water, 0.5 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was washed with a mixed solvent of n-hexane and ethyl acetate (2/1), and dried under reduced pressure to give 1-(2-benzyloxycarbonylamino-2-methylpropionyl)-4-isopropyl-piperazine (1.83 g). This material was dissolved in methanol (20 mL). To the solution was added 10% palladium-carbon powder (0.60 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was crystallized from a mixed solvent of n-hexane and ethyl acetate, and the crystals were collected by filtration. The crystals were washed with n-hexane, and dried under reduced pressure to give the title compound (0.76 g).
Reaction SMILES: [C:1]1([C@:11]23[CH2:16][CH:15]2[CH2:14][O:13][C:12]3=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClCCl>O1CCCC1>[C:1]1([C@:11]2([CH2:12][OH:17])[CH2:16][CH:15]2[CH2:14][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCC2C[C@]12c1cccc2ccccc12
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC1C[C@@]1(CO)c1cccc2ccccc12
Yield: 98.6 %

Procedure:
BMS (0.2 mL, 0.8 mmol) was added to (1S)-1-(1-naphthyl)-3-oxabicyclo[3.1.0]hexan-2-one (90 mg, 0.4 mmol) in dry tetrahydrofuran (1 mL), under nitrogen atmosphere. The reaction mass was refluxed for 5 hours and monitored by TLC (dichloromethane (100%)). The reaction mass was quenched with 10% potassium carbonate solution. The aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 90 mg (98.5%) of desired product. 1H NMR δ(300 MHz,CDCl3): 1.09-1.43 (3H,m), 1.67-1.69 (2H,m,) 1.83-1.90 (1H,m), 3.5-3.7 (2H,m), 4.25-4.27 (2H,m), 7.4-7.65 (4H,m), (1H,m) 7.77-7.89 (2H,m), 8.25 (1H,brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1>CC(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[O:8][C:7](=[O:9])[CH2:6][CH:5]2[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1C=CC(=O)O
Reactant: Oc1ccc(Cl)cc1
Solvent: CC(C)=O
Product: COc1ccccc1C1CC(=O)Oc2ccc(Cl)cc21
Yield: 49 %

Procedure:
6-Chloro-4-(2-methoxyphenyl)-3,4-dihydrocoumarin (CVII) was prepared in a similar way in 49% yield from 2-methoxycinnamic acid and p-chlorophenol, the reaction temperature being 130° in this case. M.p. 172°-173° (acetone).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6](O)[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[Cl:17].S(Cl)([Cl:20])=O>>[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([Cl:20])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[Cl:17]
Reactant: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: CC(C)(C)NCC(Cl)c1cc(Cl)c(N)c(Cl)c1

Procedure:
Under N2 atmosphere, 27.72 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol is added to 200 ml of thionyl chloride stirred at 0°-5° C. After addition is completed, the reaction mixture is stirred at ambient temperature for 3 hours. Subsequently, the mixture is evaporated to dryness in vacuo to afford 37.34 g of yellow solid, which is used as is.
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1.C(OC1C2C(=CC(OC)=CC=2)C(C2C=CC=C([F:49])C=2)=C(C#N)N=1)C=C>>[OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([F:49])[CH:22]=2)=[C:7]([C:23]#[N:24])[N:6]=1
Reactant: COc1ccc2c(OCC(O)CO)nc(C#N)c(-c3ccccc3)c2c1
Reactant: C=CCOc1nc(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc12
Product: COc1ccc2c(OCC(O)CO)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
Following the procedure for 1-(2,3-dihydroxypropoxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using 1-(allyloxy)-6-methoxy-4-(3-fluorophenyl)isoquinoline-3-carbonitrile in place of 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, the title compound was synthesized.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][N:5]([CH3:9])[N:4]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH3:9][N:5]1[CH:6]=[C:7]([CH3:8])[C:3]([CH2:2][NH:12][CH2:10][CH3:11])=[N:4]1
Reactant: CCN
Reactant: Cc1cn(C)nc1CCl
Solvent: C1CCOC1
Product: CCNCc1nn(C)cc1C

Procedure:
prepared by reaction of 3-chloromethyl-1,4-dimethyl-1H-pyrazole (Calderwood E. F. et al Synth. Commun. 2004, 34, 19, 3455-3464) with 2M ethylamine in THF.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](OCC)=[O:10])[N:5]=[C:4]([CH3:14])[N:3]=1.[BH4-].[Na+]>C(O)(C)C>[OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[N:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CCOC(=O)Cc1cc(O)nc(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc(O)cc(CCO)n1
Yield: 50.2 %

Procedure:
A solution of ethyl (4-hydroxy-2-methylpyrimid-6-yl)acetate (0.38 g.) in isopropanol (10 ml.) was heated under reflux and treated with sodium borohydride (0.2 g.). The mixture was heated under reflux for 4 hours with the addition of two further portions (0.1 g.) of sodium borohydride after 2 and 3 hours. The mixture was evaporated to dryness and the residue was partitioned between water and ether. The aqueous phase was acidifed with HOAc and then extracted with EtOAc in a continuous extractor for 24 hours. The extract was dried and then evaporated to dryness to give 4-hydroxy-6-(2-hydroxyethyl)-2-methylpyrimidine (0.15 g.) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14](O)=[O:15])[CH:13]=[C:8]2[C:7]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:6]1.C(OCC1C2C(=CN=C([C:44]([NH:46][OH:47])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1>>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:46]([OH:47])[CH3:44])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:6]1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CN(C)Cc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)O)cc12
Product: CN(C)Cc1cn(Cc2ccc(F)cc2F)c2cnc(C(=O)N(C)O)cc12

Procedure:
1-(2,4-Difluorobenzyl)-3-dimethylaminomethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid. The title compound was prepared by hydrolysis of ethyl 1-(2,4-difluorobenzyl)-3-dimethylaminomethyl-1H-pyrrolo[2,3]-ccarboxylate in a manner similar to step (b) of example 1. 1H NMR (DMSO-d6) δ: 8.91 (s, 1H), 8.43 (s, 1H), 7.74 (s, 1H), 7.29-7.37 (m, 2H), 7.04-7.10 (m, 1H), 5.62 (s, 2H), 3.70 (s, 2H), 2.22 (s, 6H). LCMS (API-ES, M+H+): 346.3. (b) 1-(2,4-Difluorobenzyl)-3-dimethylaminomethyl-N-hydroxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. The title compound was prepared by coupling of 1-(2,4-difluorobenzyl)-3- dimethylaminomethyl-1H-pyrrol (DMSO-d6)δ: 9.44 (broad s, 1H), 8.96 (s, 1H), 8.26 (s, 1H), 7.93 (s, 1H), 7.44 (m, 1H), 7.28-7.35 (m, 1H), 7.10 (m, 1H), 5.66 (s, 2H), 4.47 (s, 2H), 3.32 (s, 3H), 2.72 (s, 6H). LCMS (APCI, M+H+): 375.0. HRMS calcd for C19H21F2N4O2. (M+H) 375.1633, found 375.1632. HPLC: 97.62% purity.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([N:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N-methylpiperazine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.35 (m, 2H) 1.54-1.67 (m, 3H) 1.72-1.84 (m, 5H) 2.83 (s, 3H) 3.31 (d, J=3.2 Hz, 3H) 3.91 (d, J=4.6 Hz, 3H) 3.95-4.33 (m, 10H) 4.39-4.54 (m, 1H) 7.06 (dd, J=8.1, 2.0 Hz, 1H) 7.13 (d, J=110 Hz, 1H) 8.10-8.18 (m, 1H) 8.22 (d, J=3.0 Hz, 1H). [M+H] calc'd for C27H35F2N7O3 544. found 544.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[N:28])[C:17]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[N:28])[C:17]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][C:13]=2[NH:12][C:11](=[S:39])[CH2:10][N:9]=1
Reactant: COCCOCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COCCOCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-(2-methoxyethoxy)ethoxy)-2H-1,4-benzodiazepin-2-thione (IIn) was prepared by reacting 0.00089 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-(2-methoxyethoxy)ethoxy)-2H-1,4-benzodiazepin-2-one (lactam In) with Lawesson's reagent in a manner analogous to Example 38. MH+/Z=430.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([CH3:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH3:14])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(C)c(-c3ccccc3)c2c1
Product: COc1ccc2c(Cl)nc(C)c(-c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
A mixture of 6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one (3.0 g) and 12 mL of POCl3 was heated to reflux for 1 h, then cooled to room temp and poured into ice. The mixture was extracted with EtOAc (3×). The combined organic solutions were washed with brine (1×) and saturated aqueous sodium carbonate (1×), then dried (Na2SO4) and concentrated. Flash chromatography (10% EtOAc/hexanes) gave 2.6 g of 1-chloro6-methoxy-3-methyl-4-phenylisoquinoline.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[Cl:31][C:32]1[C:33]([CH:42]=O)=[N:34][CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:31][C:32]1[C:33]([CH2:42][NH:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH:21]3[C:30]4[N:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:24][CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[N:34][CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=Cc1ncc(C(F)(F)F)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1cnc(CNCc2ccc(CN(Cc3nc4ccccc4[nH]3)C3CCCc4cccnc43)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.4 %

Procedure:
Using General Procedure B: To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (133 mg, 0.34 mmol) and 3-chloro-5-(trifluoromethyl)-pyridine-2-carboxaldehyde (66 mg, 0.32 mmol) in CH2Cl2 (5 mL) was added NaBH(OAc)3 (93 mg, 0.44 mmol) and the mixture was stirred at room temperature for 16 h. Purification of the crude material by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 75:1:1) afforded the desired amine (48 mg, 26%) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][CH:12]=[C:11]2[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:34][C:35]=2I)=[O:29])=[N:25][CH:26]=1>C(O)(C)C.ClCCl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]=[CH:13][CH:12]=[C:11]2[O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:34][C:35]=2[NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:29])=[N:25][CH:26]=1
Reactant: COCCN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(I)ccn(-c5ccccc5)c4=O)nc3)c2cc1OC
Solvent: CC(C)O
Solvent: ClCCl
Product: COCCNc1ccn(-c2ccccc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cn1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
2-methoxyethylamine (137 μl, 1573 μmol) was added to a suspension of N-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (122 mg, 197 μmol) in iso-propanol (1 mL). The reaction mixture was heated at 100° C. for 80 min. An aliquot was taken and analyzed by LCMS: The reaction was done. The reaction mixture was diluted with dichloromethane. The crude was adsorbed on silica and purified by MPLC (CH2Cl2/MeOH: 100/0 to 95/5) to afford the title compound N-(5-(6,7-dimethoxyquinolin-4-yloxy)pyridin-2-yl)-4-(2-methoxyethylamino)-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (84 mg, 148 μmol, 75% yield). MS (ESI pos. ion) m/z: 568 (MH+). Calc'd exact mass for C31H29N5O6: 567. 1H NMR (400 MHz, DMSO-d6) 13.28 (s, 1 H), 10.80-10.71 (m, 1 H), 8.49 (d, J=5.2 Hz, 1 H), 8.34 (d, J=9.1 Hz, 1 H), 8.30 (d, J=2.8 Hz, 1 H), 7.79 (dd, J=9.2, 3.1 Hz, 1 H), 7.73 (d, J=7.8 Hz, 1 H), 7.58-7.37 (m, 7 H), 6.53 (d, J=5.2 Hz, 1 H), 6.32 (d, J=8.1 Hz, 1 H), 3.95 (s, 3 H), 3.94 (s, 3 H), 3.64-3.54 (m, 4 H), 3.34 (s, 3 H).
Reaction SMILES: [CH:1]([NH2:14])([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.C(N(CC)CC)C.[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>ClCCl>[CH:1]([NH:14][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][Br:22])=[CH:29][CH:28]=1)(=[O:31])=[O:32])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(NC(c1ccccc1)c1ccccc1)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzhydrylamine (640 μL) was dissolved in dichloromethane (5.0 mL). To the solution, triethylamine (645 μl) and 4-(bromomethyl)benzenesulfonyl chloride (1.0 g) were added at 0° C., and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, water (10 mL) was added, and the resultant mixture was then extracted with chloroform (30 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to obtain the title compound (753 mg).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CCOC(C)=O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]=2)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)CC1
Temperature: 80 °C
Yield: 88 %

Procedure:
1-(5-Fluoro-2-nitro-phenyl)-piperidine (100 mg, 0.44 mmol) was treated with N-methylpiperizine (3 mL) and heated to 80° C. overnight. The reaction was diluted with EtOAc (10 mL), washed with water (2×10 mL), dried (Na2SO4) and concentrated in vacuo to afford 118 mg (88%) of 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine as an oil. The 1-methyl-4-(4-nitro-3-piperidin-1-yl-phenyl)-piperazine (22 mg, 0.07 mmol) was stirred with 13 mg 5% Pd—C in 1 mL of MeOH under H2 for 2 h. The mixture was filtered through SiO2, eluting with 10% MeOH—CHCl3, and the solvent was concentrated in vacuo to give 17 mg (86%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C16H26N4, 275.22 (M+H), found 275.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[N:15]=1>>[C:21]1(=[O:30])[N:20]([C:16]2[N:15]=[C:14]([NH:13][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[CH:19]=[CH:18][CH:17]=2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(N2C(=O)c3ccccc3C2=O)n1
Product: O=C(Nc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1[N+](=O)[O-]
Yield: 80.2 %

Procedure:
Using the procedure described in Example 93, Part A, 2-nitrobenzoyl chloride (2.3 mmol) and 2-amino-6-phthalimidopyridine (2.1 mmol) yielded 654 mg (80%) of the title compound.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][C:7]([Si:10]([CH3:19])([CH3:18])[O:11][CH2:12][CH2:13][O:14][CH2:15]CO)([CH3:9])[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:5][CH2:1][CH2:15][O:14][CH2:13][CH2:12][O:11][Si:10]([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCOCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOCCBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
18.2 g of carbon tetrabromide is added over 15 minutes at −15°/−20° C. to a mixture containing 11.2 g of the product of Stage A and 14.4 g of triphenylphosphine in 100 cm3 of methylene chloride. Agitation is carried out for 1 hour 15 minutes at −15° C., the solvent is evaporated off, followed by taking up in pentane, agitating at ambient temperature, separating, washing with pentane and drying at 50° C. under reduced pressure. 10.1 g of expected product is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:11]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:10]=1.Br[CH2:35][C:36]([NH2:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:9]1[N:10]=[C:11]([N:28]2[CH2:29][CH2:30][N:31]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:32][CH2:33]2)[C:12]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[CH:21]=[CH:20][C:19]=2[CH3:27])=[C:13]([CH3:15])[N:14]=1
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCNCC1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-4-methyl-6-piperazin-1-yl-pyrimidine trifluoroacetic acid salt (722 mg), 2-bromoacetamide (290 mg, 2.11 mmol) and potassium carbonate (871 mg, 6.30 mmol) in DMA (10 mL) is stirred at room temperature for 3 h. The reaction mixture is partitioned between EtOAc (30 mL) and water (10 mL), the organic layer is separated, washed with water (10 mL×2), brine (10 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to yield a yellow oil. Purification by chromatography on silica gel affords the title compound as a colorless oil that solidifies on standing. 1H NMR (CDCl3) δ=7.10 (d, 1H), 6.92 (br s, 1H), 6.82 (d, 1H), 6.74 (s, 1H), 5.54 (br s, 1H), 4.83 (s, 2H), 3.61, (m, 4H), 3.04 (s, 2H) 2.90 (m, 1H), 2.63 (m, 4H), 2.47 (s, 3H), 2.14 (s, 3H), 1.27 (d, 6H).
Reaction SMILES: O=[C:2]([CH2:8][S:9][C:10]#[N:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:12][NH:13][CH3:14]>C1COCC1>[CH3:12][N:13]([CH3:14])[C:10]1[S:9][CH:8]=[C:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[N:11]=1
Reactant: CNC
Reactant: COC(=O)CC(=O)CSC#N
Solvent: C1CCOC1
Product: COC(=O)Cc1csc(N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 3-oxo-4-thiocyanatobutanoate (350 mg, 2.02 mmol) in THF (4 ml) was added a vessel containing dimethylamine in THF (2M; 1.01 ml, 2.02 mmol), the reaction mixture was stirred at rt for 3 h. LCMS showed that the desired product was detected, the mixture was concentrated to give the residue, the residue was purified by a standard method to give the desired product.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C.C(Cl)Cl>C(OCC)(=O)C>[C:14]1([P:7](=[C:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.3 %

Procedure:
The t-butyl (triphenylphosphoranylidene)propionate was prepared as follows: Triphenylphosphine (33 g), t-butyl 2-bromopropionate (22 g) and triethylamine (12.7 g) were dissolved in ethyl acetate (150 ml), and stirred and heated under reflux for 48 hr, under an atmosphere of nitrogen. Methylene chloride (300 ml) was added to the cooled solution: the mixture was thoroughly washed with sodium hydroxide solution (10% w/w, 300 ml), water (200 ml) and brine; and dried (MgSO4). The solvent was evaporated and the residual oil triturated with hexane (2x200 ml) to give t-butyl (triphenylphosphoranylidene)propionate (33 g, 67%) as a yellow powder; mp 144°-151° C.; partial NMR (250 MHz, CDCl3): 1.0(br signal, 9H, t-butyl), 1.55(d, J=14.4 Hz, 3H, CH3), 7.3-7.9(complex m, 15H, ArH).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=2[C:10]=1[OH:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:25]>>[NH2:25]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:20])[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13]\1
Reactant: COc1ccc2c(O)c(C(=O)c3ccccc3)sc2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COc1ccc2c(c1)S/C(=C(/N)c1ccccc1)C2=O
Yield: 64 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-6-methoxy-benzo[b]thiophen-3-ol and ammonium acetate with a yield of 64% of theory.