Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([N:19]3[CH2:23][CH2:22][C:21]4([CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24]4)[CH2:20]3)[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=1.[NH2:30][CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33].CCN(CC)CC>CCO>[Cl:40][C:36]1[CH:35]=[C:34]([C@H:32]([OH:33])[CH2:31][NH:30][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:13][C:12]3[CH:14]=[C:15]([N:19]4[CH2:23][CH2:22][C:21]5([CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24]5)[CH2:20]4)[CH:16]=[C:17]([CH3:18])[C:11]=3[N:10]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4c3)C2)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(NC[C@@H](O)c6cccc(Cl)c6)cc[nH]c5=O)[nH]c4c3)C2)C1
Yield: 35.2 %

Procedure:
A solution of 4-chloro-3-[6-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyridin-2-one (53 mg, 0.13 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (27 mg, 0.156 mmol) and Et3N (26 mg, 0.26 mmol) in EtOH (0.5 mL) was heated at 80° C. for 18 h and then the reaction mixture was evaporated. The residue was purified by chromatography (150:8:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (25 mg, 35%). 1H NMR (MeOH-d4) δ 1.16 (t, J=8 Hz, 3H), 1.80-2.02 (4H), 2.48-2.80 (4H), 2.50 (s, 3H), 3.19-3.39 (4H), 3.63 (m, 2H), 4.81 (m, 1H), 4.95 (m, 2H), 6.18 (d, J=6 Hz, 1H), 6.38 (s, 1H), 6.44 (s, 1H), 7.17-7.31 (3H), 7.38 (d, J=6 Hz, 1H), 7.55 (s, 1H). ESI-MS m/z 547 (MH+).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:2][CH3:1])=[O:11])=[C:6]([CH2:10][OH:9])[CH:5]=1
Reactant: O=C1OCc2cc(Cl)ccc21
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ccc(Cl)cc1CO
Temperature: 25 °C

Procedure:
Methylamine gas was condensed into a sealed tube at −78° C., and a solution of 5-chloro-2-benzofuran-1(3H)-one (6.68 g, 39.8 mmol) in methanol (30 mL) was added. The solution was slowly warmed to room temperature overnight; The reaction was concentrated in vacuo, and the residue was partitioned between water and and chloroform. After three extractions with chloroform, the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-chloro-2-(hydroxymethyl)-N-methylbenzamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[CH2:8]1[C:22](=O)[C:21]2[C:12](=[C:13]([OH:27])[C:14]3[C:19]([C:20]=2[OH:24])=[C:18](O)[CH:17]=[CH:16][C:15]=3O)[C:10](=[O:11])[CH2:9]1>>[OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:15]1[C:14]2[C:13](=[O:27])[C:12]3[C:21](=[C:22]([NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][OH:1])[CH:8]=[CH:9][C:10]=3[OH:11])[C:20](=[O:24])[C:19]=2[C:18]([NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][OH:1])=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)c2c1c(O)c1c(O)ccc(O)c1c2O
Reactant: NCCNCCO
Product: O=C1c2c(O)ccc(NCCNCCO)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21

Procedure:
The reaction between 2-(2-hydroxyethylamino)ethylamine and leuco-1,4,5,8-tetrahydroxyanthraquinone is carried out as in Example 1 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15]>>[Cl:1][C:2]1[C:3]([O:9][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)=[CH:4][C:5]([O:8][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)=[N:6][CH:7]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Product: Cc1cccc(C(=O)Oc2cc(OC(=O)c3cccc(C)c3)c(Cl)cn2)c1
Yield: 44.3 %

Procedure:
The general procedure of Example 5 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 3.00 g of 3-methylbenzoyl chloride, thereby producing 1.64 g of the title compound in a yield of 32%.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[C:9]([Si](C)(C)C)[S:10][CH:11]=1.[C:16]([C:19]1[S:23][C:22]([CH3:24])=[N:21][C:20]=1[CH3:25])(=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:24][C:22]1[S:23][C:19]([C:16]([C:9]2[S:10][CH:11]=[C:7]([CH3:6])[N:8]=2)([OH:18])[CH3:17])=[C:20]([CH3:25])[N:21]=1
Reactant: Cc1csc([Si](C)(C)C)n1
Reactant: CC(=O)c1sc(C)nc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1csc(C(C)(O)c2sc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 5.1 ml ) was added dropwise to a stirred solution of 4-methyl-2-trimethylsilylthiazole (from 4-methylthiazole, n-butyllithium and trimethylsilylchloride) (2 g) in anhydrous tetrahydrofuran (40 ml ) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 5-acetyl-2,4-dimethylthiazole (2 g) in tetrahydrofuran (10 ml) was added dropwise. After 1 hour the mixture was allowed to warm to room temperature. After a further 2 hours, saturated aqueous ammonium chloride solution was added. The organic phase was separated, washed, dried and evaporated. The residue was dissolved in tetrahydrofuran (2 ml) and tetrabutylammonium fluoride (640 mg) was added. The mixture was stirred overnight and then worked up in the usual fashion to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16]C)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.O[Li].O>C1COCC1.CO.O>[I:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: COC(=O)Cc1ccc(-n2cnnn2)c(I)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(-n2cnnn2)c(I)c1
Temperature: 25 °C

Procedure:
A solution of methyl [3-iodo-4-(1H-tetrazol-1-yl)phenyl]acetate (1 g, 2.9 mmol) in a co-solution 50 mL of THF/methanol/water (2:2:1) was added added LiOH.H2O (0.6 g, 14.5 mmol), and the mixture was stirred at ambient temperature over night. Concentrated and the residue was dissolved in water and then adjusted pH=3 with 2N HCl. Extracted with DCM, and orgianc layers were washed with water, brine and dried over anhydrous sodium sulfate, concentrated to get crude product [3-iodo-4-(1H-tetrazol-1-yl)phenyl]acetic acid, which was used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].Br[CH2:8][CH2:9][CH2:10][CH3:11].Cl>C(O)(C)C>[CH2:8]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])[CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(N)CO
Reactant: CCCCBr
Agent: Cl
Solvent: CC(C)O
Product: CCCCNC(C)(C)CO
Yield: 26.8 %

Procedure:
A solution of 2-amino-2-methylpropan-1-ol (14 g, 157 mmol) in isopropanol (100 ml) was treated with 1-bromobutane (37 g, 272 mmol). The mixture was refluxed for 12 hrs, treated with 8 ml of concentrated HCl, then distilled to remove volatiles. The remaining residue was basified with 20% of NaOH, and extracted with Et2O (2×). The Et2O layers were combined and distilled to afford 6.1 g (27%) of the title compound (124-126° C. @54-56 Torr). 1H NMR (400 MHz, CDCl3) δ ppm 0.92 (t, J=7.36 Hz, 3H) 1.06 (s, 6H) 1.10 (s, 1H) 1.29-1.50 (m, 4H) 2.49 (t, J=6.75 Hz, 2H) 3.28 (s, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)=[O:35])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cccs1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccs3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-thiophenecarbonyl chloride: ESMS m/e: 490.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([NH2:31])=[CH:25][CH:24]=2>>[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([NH:31][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][C@H:15]([O:18][CH3:19])[CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:25][CH:24]=2
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: CO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: CO[C@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)c(C)c5c4)c3s2)C1

Procedure:
The title compound was prepared from (3S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone and 2,3-dimethyl-1H-indol-5-ylamine by a procedure analogous to Example 99. MS: 421.2 (MH+); HPLC Rf: 4.80 min.; HPLC purity: 99%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)=[N:4][C:5]([Cl:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:27][NH2:28]>C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:28][NH:27][C:13](=[O:14])[C:6]=2[C:5]([Cl:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1
Reactant: CCOC(=O)c1c(Cl)nc(-c2cccc(N)c2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc(-c2nc(Cl)c3c(=O)[nH][nH]c(=O)c3c2N)c1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 0.35 g of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-(3-aminophenyl)pyridine was added 7.5 ml of hydrazine monohydrate, and the mixture was stirred at 90° C. for 30 minutes. The reaction mixture was poured into ice water (100 ml), and the mixture was adjusted to pH 6 by adding acetic acid. The resulting precipitate was collected by filtration and washed with water, followed by reprecipitation from DMSO-H2O, to give 0.23 g of the title compound as orange powder.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.O1CCCC1.[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37](Cl)=[O:38]>>[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:38]
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cc2c(s1)-c1ccccc1OCC2)N1CCCc2ccccc21

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (0.755 mmol) and triethylamine (0.105 mL, 0.755 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonylchloride (0.100 g, 0.378 mmol) portionwise as a solid. Reaction was stirred at room temperature with monitor for formation of desired product. The reaction was stirred overnight. After aqueous workup, the crude was taken into DMF at a concentrated of 100 mg/ml and purified by preparative RP-HPLC to give 218 (yield 80% of theoretical). MS: (ESI+) 362.2
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[N:7]=2)=[N:2]1.[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>O.CCOC(C)=O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:11]([C:8]3[N:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][N:2]=4)[O:10][N:9]=3)=[O:13])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: O=C(O)c1noc(-c2ccon2)n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1noc(-c2ccon2)n1
Yield: 0.9 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(isoxazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid (1.933 mmol, 0.35 g) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (1.610 mmol, 0.449 g) using DMF (10 ml) as the solvent. The reaction mixture was diluted with water and EtOAc, the phases were separated and the organic phase was washed with 2M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.0065 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.26 (d, 3H), 4.28 (dd, 1H), 4.46 (dd, 1H), 4.56-4.66 (m, 1H), 6.63 (d, 1H), 6.82 (d, 1H), 7.51 (d, 1H), 7.64 (dd, 1H), 7.84-7.86 (m, 1H), 7.88 (d, 1H), 8.51 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[N:8][OH:9])[C:4]([C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[N:3]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C1C=CC=CC=1>[C:18]([O:9][N:8]=[CH:7][C:5]1[C:4]([C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)=[N:3][N:2]([CH3:1])[CH:6]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc(C=NO)c(-c2ccc([N+](=O)[O-])o2)n1
Solvent: c1ccccc1
Product: CC(=O)ON=Cc1cn(C)nc1-c1ccc([N+](=O)[O-])o1
Yield: 83 %

Procedure:
Stir together 2.5 g of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehydeoxime, 1.27 g of acetic anhydride and 10 ml of benzene for 2 hours at from 80° to 85° C. Cool the resulting solution and vacuum filter to obtain 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-(O-acetyloxime) [m.p. 192° to 197° C (with decomposition) from toluene] with a yield of 83%.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[CH:6][S:7][CH:8]=1)([CH3:3])[CH3:2].[Li]CCCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].O>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred solution of 4-isopropylthiazole (9 g, 71 mmol) in anhydrous THF (100 mL) at −78° C. was added nBuLi (40 mL, 99 mmol). The reaction was stirred for 1 hr and the temperature reached −40° C. The reaction mixture was cooled to −78° C. and tri-n-butyltinchloride (23 g, 71 mmol) was added. The reaction mixture was stirred at room temperature for 48 hrs. Water was added and solvent was evaporated under reduced pressure. The residue was partioned between water and EtOAc. Organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 219 as colorless oil in 55% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.88-1.62 (m, 27H), 1.40 (s, 3H), 1.42 (s, 3H), 3.17-3.24 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29].CCOCC>O1CCOCC1>[ClH:29].[I:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Ic1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
5. To a 20 mL vial which contained a solution of the product from step 4 (200 mg, 0.4 mmol) in dioxane was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried under vacuo to yield the title product (150 mg, 95%); LCMS; APCI+ 99%, Calcd: 393.3; Found m/z: 392.3 (M−1); 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.77 (m, 1H), 1.86-2.04 (m, 2H), 2.05-2.16 (m, 1H), 3.14-3.23 (m, 2H), 3.84 (s, 2H), 3.83-3.89 (m, 1H), 4.07-4.11 (m, 1H), 4.20 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H):
Reaction SMILES: C(N(CC)CC)C.N1C=CC(CN)=CC=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([NH:30][CH2:31][CH3:32])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[O:33]1CCCC1>>[CH2:31]([NH:30][C:23]1[CH:22]=[C:21]2[C:26]([C:17](=[O:33])[NH:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28])[CH3:32]
Reactant: C1CCOC1
Reactant: CCNc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Agent: NCc1ccncc1
Solvent: CCN(CC)CC
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]

Procedure:
Triethylamine (10 ml, 72.1 mmol) and 4-picolylamine (4 ml, 39.4 mmol) were added to a tetrahydrofuran solution (20 ml) of 4-chloro-7-ethylamino-6-nitroquinazoline obtained from 7-ethylamino-6-nitro-4(3H)-quinazolone (737.9 mg, 3.15 mmol) according to the procedures in Reference Example 13 under ice-cooling. The mixture was stirred at room temperature for 13 hours and at 55° C. for 4 hours. After a solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=9:1) to give the title compound (780 mg, 76%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[N:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.COCCOC.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>[Br:7][C:5]1[CH:6]=[C:2]([C:11]2[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=2)[S:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Brc1csc(-c2ccncc2)c1
Yield: 51.5 %

Procedure:
2,4-Dibromothiophene (2.97 g, 12.28 mmol), pyridine-4-boronic acid (1.50 g, 12.28 mmol), potassium carbonate (5.52 g, 39.91 mmol) and tetrakis(triphenylphosphine)palladium (0) (426 mg, 0.38 mmol) were refluxed in ethanol/1,2-dimethoxyethane (1:4 v/v; 100 mL) at 100° C. for 7 hours. The solution was allowed to cool, and then filtered and evaporated. The residue was purified by flash chromatography using a gradient of ethyl acetate in hexane to give a yellow solid as the sub-title compound (1.52 g), m/z 240, 242 (MH+).
Reaction SMILES: C([O:4][P:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([Cl:41])[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:31][CH:30]=4)=[CH:28][C:22]=3[N:21]=2)([F:19])[F:18])[CH:12]=1)(=[O:10])[O:6]C(C)C)(C)C.C[Si](N[Si](C)(C)C)(C)C.Br[Si](C)(C)C>C(Cl)Cl>[C:32]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:27]2[C:26]([Cl:41])=[CH:25][C:23]3[NH:24][C:20]([C:17]([F:19])([F:18])[C:13]4[CH:12]=[C:11]([P:5](=[O:4])([OH:10])[OH:6])[CH:16]=[CH:15][CH:14]=4)=[N:21][C:22]=3[CH:28]=2)=[CH:34][CH:33]=1
Reactant: CC(C)OP(=O)(OC(C)C)c1cccc(C(F)(F)c2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)c1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: O=P(O)(O)c1cccc(C(F)(F)c2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 15-2 (32 mg, 0.054 mmol) in 2 mL CH2Cl2 was added hexamethyldisilizane (0.3 mL), followed by bromo trimethylsilane (71 μL, 0.54 mmol). The reaction was allowed to stir for 18 h at ambient temperature. The organic solvent was removed in vacuo, followed by the addition of H2O (2 mL). The crude product was purified by prepatory HPLC using a 30-80% CH3CN with 0.05% trifluoroacetic acid gradient over 20 min. The pure fractions were combined and lyophilized to give the title compound 15-3. 1H NMR 7.42 (1H, t), 7.50-7.56 (4H, m), 7.65-7.94 (10H, m); LC-MS: m/e 511(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:3]=1.[CH:21](O)=[O:22].ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl>O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:4]2[CH:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[CH2:6][C:2]([NH:1][CH:21]=[O:22])=[N:3]2)=[CH:15][CH:16]=1
Reactant: NC1=NN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)C1
Reactant: O=CO
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O
Product: O=CNC1=NN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)C1
Reaction time: 2 h

Procedure:
A mixture of 1.85 g. of 3-amino-1,5-bis(p-chlorophenyl)-2-pyrazoline (prepared as described above) and 10.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to remain at room temperature for 2 hours, then water is added and the mixture is filtered to collect a semi-solid. The solid is dissolved in dichloromethane and the solution is columnized and recrystallized twice as for Example 26 (A) to yield 1.10 g. of the product of the Example as off-white crystals, m.p. 198°-200° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([C:21](=[O:23])[NH2:22])[N:14]=2)=[CH:9][C:8]=1[F:24])(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:43]([CH3:48])[C:44]([O:46][CH3:47])=[O:45])[CH:31]=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1.[Cl-].[Li+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.CO>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:33]3[CH:32]=[CH:31][C:30]([CH:43]([CH3:48])[C:44]([O:46][CH3:47])=[O:45])=[CH:29][C:28]=3[Cl:27])=[C:8]([F:24])[CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]
Reactant: COC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)c(Cl)c1
Reactant: Cc1nc(C)c(-c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)nc1C(N)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)c1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(Cl)c1
Temperature: 85 °C
Yield: 86.1 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl trifluoromethanesulfonate (Intermediate 6-4; 703 mg, 1.79 mmol) and methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (Intermediate 8-2; 580 mg, 1.79 mmol), lithium chloride (133 mg, 3.13 mmol) and potassium phosphate, tri-basic (455 mg, 2.14 mmol) in DME (20 mL), methanol (10 mL) and water (5 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (73.0 mg, 0.09 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 85° C. for 17 hours. The reaction mixture was allowed to cool and evaporated, the residue was partitioned between EtOAc (100 mL), and water (75 mL) and the aqueous layer was further extracted with EtOAc (100 mL). The organic layers were combined and washed with saturated brine (100 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-2′-fluorobiphenyl-4-yl)propanoate (681 mg, 86%) as a cream solid.