Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[CH:31]3)=[O:27])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])[N:32]=[CH:31]3)=[O:27])=[CH:37][CH:38]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(-n2ncc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Temperature: 90 °C
Yield: 22 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (110 mg, 0.468 mmol) and N-(4-chlorophenethyl)-1H-indazole-5-carboxamide (168 mg, 0.561 mmol) in DMSO (2 ml) was added K2CO3 (77.5 mg, 0.561 mmol). The reaction was heated to 90° C. overnight via an oil bath. The reaction was diluted with EtOAc and 10% aqueous sodium carbonate. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was purified over silica gel on a Biotage Horizon high-performance FLASH chromatography system (25+M silica gel cartridge) eluting with a gradient of 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to provide tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indazol-1-yl)-3-cyanophenyl)acetate (0.241 g, 0.103 mmol, 22%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][NH:10][C:9]1=[O:21])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>O1CCCC1.CN1CCCC1=O.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][N:10]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:9]1=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2ccccc2F)CN(CC(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a pre-cooled 0° C. solution of tert-butyl[(3S,5S)-5-(2-fluorophenyl)-2-oxopiperidin-3-yl]carbamate (0.59 g, 1.93 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 18 mL) was added lithium bis(trimethylsilyl)amide (2.29 mL, 2.29 mmol, 1 M in THF) and the mixture was stirred at 0° C. for 30 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.33 mL, 2.29 mmol) was added and the resulting mixture was stirred at 0° C. for 4 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→100% ethyl acetate/hexane) was followed by separation of the cis/trans diastereoisomers using normal-phase HPLC using a ChiralPak® AD column, eluting with 60% ethanol in hexanes to afford the title compound as the second diastereomer to elute. MS: m/z=391.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:23][CH3:24])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[C:4]1=[O:22].Br[C:26]1[CH:31]=[C:30](Br)[CH:29]=[C:28](Br)[CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH2:42]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1([O:23][CH3:24])[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:26]3[CH:31]=[C:30]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[C:11](=[O:42])[C:3]([O:23][CH3:24])([O:2][CH3:1])[C:4]5=[O:22])[CH:29]=[C:28]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[C:11](=[O:12])[C:3]([O:2][CH3:1])([O:23][CH3:24])[C:4]5=[O:22])[CH:27]=3)[CH:9]=2)[C:4]1=[O:22]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: COC1(OC)C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1=O
Reactant: O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC1(OC)C(=O)c2ccc(-c3cc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)cc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)c3)cc2C1=O
Temperature: 25 °C
Yield: 41 %

Procedure:
2,2-dimethoxyindan-1,3-dione-5-boronic acid pinacol ester (24) (470 mg, 1.41 mmol), 1,3,5-tribromobenzene (25) (126 mg, 0.40 mmol), Pd(PPh3)4 (58 mg, 0.050 mmol), and K3PO4 (513 mg, 2.41 mmol) were dissolved in a solvent mixture of 12 ml of toluene and 6 ml of ethanol, and the solution was mixed with 4 ml of water. After deaeration, the solution was refluxed in an argon atmosphere for 12 hours. The reaction liquid was cooled to room temperature. Thereafter, water was poured into the reaction liquid, which was then extracted with chloroform. The extracted liquid of organic phase was dried with sodium sulfate and then filtered to remove the drying agent. Thereafter, the solvent was removed at a reduced pressure. The crude product was purified by silica gel chromatography (the solvent was gradually changed from hexane to a 1:1 mixture of hexane:ethyl acetate), to obtain 280 mg (41%) of 1,3,5-tris(2,2-dimethoxy-1,3-dioxoindan-5-yl)benzene (26) in the form of a yellow solid. The readings for this compound are as follows.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH:21]=[CH2:22])[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][CH3:19])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[CH2:6][NH2:7])[CH:2]=[CH2:3].Br[CH2:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO>[NH3:4].[CH2:20]([N:4]([CH2:1][CH:2]=[CH2:3])[CH:5]([C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][CH2:18][CH3:19])(=[O:15])=[O:16])=[CH:12][CH:13]=1)[CH2:6][N:7]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:21]=[CH2:22]
Reactant: C=CCN(CC=C)C(CN)c1ccc(S(=O)(=O)CCC)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCN(CC=C)C(CN1CCCC1)c1ccc(S(=O)(=O)CCC)cc1
Product: N
Temperature: 25 °C
Yield: 102.4 %

Procedure:
N1,N1-Diallyl-1-[4-(propylsulphonyl)phenyl]ethane-1,2-diamine (445 mg, 1.38 mmol), 1,4-dibromobutane (0.18 mL, 1.51 mmol) and sodium hydrogencarbonate (0.26 g, 3.09 mmol) were heated in toluene at reflux for 17 h. The reaction mixture was allowed to cool to ambient temperature, filtered through Celite and the filter cake washed with ethyl acetate. The filtrate was washed with water and then brine before being dried (MgSO4) and concentrated. The crude product was purified using an SCX cartridge eluting with dichloromethane, then methanol and finally 2M ammonia in methanol to give the title compound as a pale yellow oil (266 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ 1.00 (3H, t, J=7.5 Hz), 1.69-1.80 (6H, m), 2.45-2.54 (4H, m), 2.83-3.00 (4H, m), 3.05-3.09 (2H, m), 3.21 (2H, dd, J=14.4, 6.0 Hz), 4.07 (1H, dd, J=8.3, 5.2 Hz), 5.11-5.19 (4H, m), 5.76-5.84 (2H, m), 7.58 (2H, d, J=8.3 Hz), 7.83 (2H, d, J=8.4 Hz); m/z (ES+) 377 (M+H), 280 (M−N[allyl]2).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].N1C=CN=[CH:15]1>CN(C=O)C>[O:5]([CH2:1][C:2]#[C:3][CH2:4][CH3:15])[Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: c1c[nH]cn1
Reactant: C#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CCC#CCO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 3-butyn-1-ol (g) (10.0 g) in DMF (80 ml) were added t-butyldimethylsilyl chloride (21.5 g) and imidazol (10.6 g), and the resultant mixture was kept at 35° C. for 7 hours. The reaction mixture was treated in the conventional manner and the obtained crude product was distilled to give the title compound (h).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[C:11](=[O:21])[O:10][N:9]=2)=[N:5][O:6][N:7]=1.CCN(C(C)C)C(C)C.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:1][CH2:2][C:3]1[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[C:11](=[O:21])[O:10][N:9]=2)=[N:5][O:6][N:7]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1onc(-c2nonc2CNS(=O)(=O)CCCCl)n1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.7 %

Procedure:
To a solution of 3-[4-(aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (100 mg, 0.32 mol) in DCM (2 mL) under an atmosphere of nitrogen was added DIPEA (168 μL, 0.96 mmol), and 3-chloropropane-1-sulfonyl chloride (117 μL, 0.66 mmol). The reaction was stirred at 25° C. for 5 min. The reaction was quenched with MeOH and purified by preparative HPLC to yield the desired product (38 mg, 20%). 1H NMR (400 MHz, CDCl3): δ 7.5 (m, 1H), 7.3 (m, 2H), 4.8 (d, 2H), 3.7 (t, 2H), 3.25 (t, 2H), 2.3 (m, 2H). MF═C14H12Cl2FN5O5S; LCMS calculated for C14H13Cl2FN5O5S(M+H)+: m/z=452.2
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:6]([CH2:12]Cl)=[N:7]2.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:12][C:6]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:4](=[O:21])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(Cl)c2c(=O)n1-c1ccccc1F
Yield: 50 %

Procedure:
Prepared according to Procedure C using Intermediate 2k (210 mg, 0.650 mmol), adenine (97 mg, 0.715 mmol), K2CO3 (99 mg, 0.715 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 137 mg of a tan solid (50%), mp 295.6-295.8° C. (decomposes). 1H NMR (DMSO-d6) δ: 8.05 (s, 1H); 8.04 (s, 1H); 7.75 (t, J=7.6 Hz, 1H); 7.74 (t, J=7.9 Hz, 1H); 7.62-7.69 (m, 1H); 7.61 (d, J=7.6 Hz, 1H); 7.47-7.55 (m, 1H); 7.48 (d, J=7.8 Hz, 1H); 7.41 (d, J=8.0 Hz, 1H); 7.24 (br s, 2H); 5.19 (d, J=17 Hz, 1H); 5.03 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 158.7, 157.6 (d, J=250 Hz), 156.2, 152.8, 152.4, 150.0, 149.2, 141.8, 135.4, 133.3, 132.5 (d, J=8.0 Hz), 131.0, 130.4, 127.3, 126.2 (d, J=3.5 Hz), 123.1 (d, J=14 Hz), 118.4, 117.6, 117.2 (d, J=19 Hz), 45.1. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O.0.05C2H6O: C, 56.92; H, 3.16; Cl, 8.36; N, 23.12. Found: C, 56.79; H, 3.20; Cl, 8.46; N, 22.79.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br>CN(C)C=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH2:35][CH:37]1[CH2:38][O:39]1)[N:19]=[CH:18][CH:17]=[C:16]2[O:15][C:4]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: BrCC1CO1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (97 mg) was dissolved in N,N-dimethylformamide (4 ml), potassium carbonate (107 mg) and epibromohydrin (0.07 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (99 mg, yield 89%).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4](C=O)=[CH:5][CH:6]=1.C1COCC1.Cl.[NH2:15][N:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21].[OH-].[Na+]>O>[Br:1][C:2]1[O:3][C:4](=[N:15][N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:5][CH:6]=1
Reactant: NN1CCNC1=O
Reactant: O=Cc1ccc(Br)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCCN1N=C1CC=C(Br)O1
Reaction time: 8 h

Procedure:
33.5 pts. by wt. of 2-bromofuran-5-aldehyde, dissolved in 100 pts. by vol. of THF, are added to a solution of 1-amino-2-oxo-imidazolidine hydrochloride in 350 pts. by vol. of water, which has been adjusted to pH 5 with sodium hydroxide solution, and the mixture is stirred overnight. The precipitate is filtered off, washed with water and recrystallised from methanol. 30.0 pts. by wt. of 1-(5-bromofurylideneamino)-2-oxo-imidazolidine of dec. pt. 153°-158° C. are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:19])[N:14]([CH:16]1[CH2:18][CH2:17]1)C)=O)(C)(C)C.[C:20](O)(C(F)(F)F)=O>C(Cl)Cl>[CH:18]1([CH2:16][NH:14][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:19])[CH2:17][CH2:20]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C1CC1
Solvent: ClCCl
Product: O=C(NCC1CC1)[C@@H]1CCCN1

Procedure:
A solution of (S)-2-(cyclopropyl-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 50% TFA in DCM was stirred at rt for 4 hours. The reaction was concentrated and purified to give (S)-pyrrolidine-2-carboxylic acid cyclopropylmethyl-amide.
Reaction SMILES: N#N.O=O.O=O.[N-:7]=[C:8]=[O:9].[C:10]([O:15]CCO)(=[O:14])[C:11]([CH3:13])=[CH2:12].C([C:23]1C=C(C)C=C(C)[C:24]=1[OH:31])(C)(C)C>>[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[NH2:7][C:8]([O:31][CH2:24][CH3:23])=[O:9]
Reactant: C=C(C)C(=O)OCCO
Reactant: Cc1cc(C)c(O)c(C(C)(C)C)c1
Reactant: [N-]=C=O
Agent: N#N
Agent: O=O
Product: C=C(C)C(=O)O
Product: CCOC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.2 mol of ®Voranol CP 6055 (DOW), 0.4 mol of hydroxyethyl methacrylate (HEMA), 500 ppm of 2,6-di-tert-butyl-4-methyl-phenol, based on the predicted amount of the final product, 0.46 mol of IPDI (isophorone diisocyanate) and 2*10−3 mol of dibutyltin dilaurate (DBTDL) are used as initial charge in a round-bottomed flask with reflux condenser, thermometer, stirrer, and dropping funnel, and are stirred at room temperature for one hour. The temperature of the mixture is then raised continuously to 80° C. within one hour. The temperature is then kept at 80° C. for about 5 hours until the content of isocyanate groups has fallen below 0.1%, with, above the mixture, a nitrogen-oxygen mixture using about 7% by volume of oxygen. If, despite prolonged continued reaction time, the isocyanate content fails to decrease below 0.1%, residual amounts of isocyanate groups are reacted with a stoichiometric amount of HEMA. 500 ppm of 2-tert-butyl-4,6-dimethylphenol, based on the total mass of the final product, are then added to the mixture. This reaction gives a mixture of urethane methacrylates, and this mixture can be used in further reactions without further work-up.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.[O:17]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][CH2:32][CH3:33])[CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:31]([C:26]1[CH:25]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1)[CH2:32][CH3:33]
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Reactant: COC(=O)Cc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(CC(=O)OC)cc1

Procedure:
A solution of the product from Step A (11.0 g, 38.58 mmol), 4-phenoxy-2-propylphenol (PCT Application WO97/28115; 8.0 g, 35.07 mmol) and cesium carbonate (12.0 g, 36.82 mmol) in DMF (80 mL) was stirred at 40° C. overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with 10% of ethyl acetate in hexane to afford the title compound.
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCCCC.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].Cl[C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1>C(NCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N+:41]([C:38]1[CH:39]=[CH:40][C:35]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:36][CH:37]=1)([O-:43])=[O:42]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])cc1
Yield: 89 %

Procedure:
0.005 mol % of Pd(OAc)2, 0.01 mol % of hexyldiadamantyl-phosphine and 1 mol % of Cu(I)I are added to a mixture of 12 mmol of trimethylsilylacetylene and 10 mmol of 4-chloronitrobenzene in 40 ml of diethylamine. The mixture is stirred under reflux until conversion is complete. The readily volatile constituents are then removed under vacuum. The residue is dissolved in toluene and washed with water. After chromatography on silica gel, 89% of 1-(4-nitrophenyl)-2-trimethylsilylacetylene is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH:29][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Cc1ncccc1OCCN
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cccnc3C)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 16.3 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(2-methylpyridin-3-yloxy)ethylamine hydrochloride (547 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2-methylpyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile dihydrochloride (87 mg).
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH:31]=1)CCC>CN(C=O)C.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:11][C:10]1[C:2]([C:30]2[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH:31]=2)=[N:3][C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(F)c(Cl)nc1Nc1ccc(N2CCOCC2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(=O)CCC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(F)c(C2=CC(=O)CCC2)nc1Nc1ccc(N2CCOCC2)cc1
Yield: 23.5 %

Procedure:
A solution of 6-chloro-5-fluoro-2-(4-morpholinophenylamino)nicotinamide (80 mg, 0.228 mmol), 3-(tributylstannyl)cyclohex-2-enone (105 mg, 0.274 mmol) (synthesized according to literature procedure: Tet. Lett., 31:1837-1840 (1990)), and dichloro bis(triphenylphosphine)palladium (II) (16.05 mg, 0.023 mmol) in DMF (2 mL) was microwaved at 160° C. for 1 h. The reaction mixture was diluted with methylene chloride, washed with satd. NaHCO3, water, and concentrated. The residue was purified prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, and extracted with methylene chloride twice. The combined organic fractions were washed with water, concentrated, and further purified by MPLC (ISCO, 5% ammonia/methanol/methylene chloride, 40 g silica gel column) to give 22 mg brown solid. LC-MS: (M+H)+=411.25. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.76-10.84 (1H, m), 8.28-8.39 (1H, m), 8.13-8.21 (1H, m), 7.83-7.91 (1H, m), 7.45-7.53 (2H, m), 6.88-6.96 (2H, m), 6.52-6.57 (1H, m), 3.67-3.77 (4H, m), 3.04 (4H, d, J=4.95 Hz), 2.76-2.85 (2H, m), 2.39-2.46 (2H, m), 2.01-2.09 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:11]=1[NH2:12]>>[ClH:1].[ClH:1].[CH3:9][C:10]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=1[NH:12][C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: ClC1=NCCCCC1
Product: Cc1cc(N)ccc1NC1=NCCCCC1
Product: Cl

Procedure:
The title compound was prepared by the methods of Examples 8 and 9 using 2-chloroazacyclohept-1-ene (0.2 mole), prepared as in Example 3, and 15.2 g (0.1 mole) of 2-methyl-4-nitroaniline. Structure assignment was supported by elemental analysis.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:17](O)=[O:18].N>CC(=O)OCC>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:17]([NH2:3])=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Agent: N
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C(N)=O)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
CDI (42.2 g, 260.4 mmol) was cautiously added to a solution of 3-bromo-5-methylbenzoic acid (16.0 g, 74.4 mmol) in EA (300 mL), and then the mixture was kept at reflux for 3 h. After cooled to room temperature, NH3 (g) was passed though for 1 h. The mixture was filtered and the organic layer was washed with HCl (10%, 100 mL) and water (100 mL). The organic phase was dried over Na2SO4 and concentrated in vacuum to obtain 15.0 g of 3-bromo-5-methylbenzamide as white crystals (yield: 94%). 1H NMR (400 MHz, CDCl3): δ 7.73-7.72 (m, 1 H), 7.56-7.55 (m, 1H), 7.50-7.49 (m 1 H), 2.39 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[N:23]1(C(OC(C)(C)C)=O)[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[N:23]1([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:5])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCCNCC1
Yield: 68 %

Procedure:
The synthesis was carried out according to the method described in (a) above using 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (B) and tert-butyl 1-homopiperazinecarboxylate to yield 4-[3-([1,4]diazepane-1-carbonyl)benzyl]-2H-phthalazin-1-one (4) as a yellow crystalline solid (5.3 g, 68%); m/z [M+1]+ 381 (97% purity); δH 2.6-3.8 (10H, m), 4.4 (2H, s), 7.2-7.5 (3H, m), 7.7-8.0 (3H, m), 8.2-8.3 (1H, m), 12.6 (1H, s).