Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:4][C:3]=1[C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: Nc1c(C(=O)C2CCCCC2)cc(Br)cc1[N+](=O)[O-]
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)C2CCCCC2)cc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
To a solution of (2-amino-5-bromo-3-nitro-phenyl)-cyclohexyl-methanone (600 mg, 1.83 mmol) in DME (25 mL) was added, successively, pyridine-3-boronic acid 1,3-propanediol cyclic ester (388 mg, 2.38 mmol), (tetrakistriphenylphosphine) palladium(0) (212 mg, 0.18 mmol), and 1N NaHCO3 (3.7 mL, 3.7 mmol). The resulting mixture was stared at 90° C. for 90 minutes then cooled to room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and the filtrate concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, hexanes to 3:1 hexanes:EtOAc) to afford 527 mg (89%) of the title compound as a pale orange solid: 1H NMR (CDCl3, 500 MHz) δ 8.92 (d, 1H), 8.69 (d, 1H), 8.66 (d, 1H), 8.31 (d, 1H), 8.20 (d, 1H), 7.71 (dd, 1H), 3.36 (m, 1H), 1.88 (m, 3H), 1.77 (m, 1H), 1.40-1.61 (m, 3H), 1.24-1.32 (m, 2H), 0.89 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[C:5]1=[O:15])#[N:2].[Cl-].[NH4+].[N-:18]=[N+:19]=[N-:20].[Na+].Cl>CN(C)C=O>[NH:18]1[C:1]([CH2:3][N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6](=[O:14])[C:5]2=[O:15])=[N:2][N:20]=[N:19]1
Reactant: N#CCn1c(=O)c(=O)[nH]c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n(Cc2nnn[nH]2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 96.9 %

Procedure:
To a solution of 1-cyanomethylquinoxaline-2,3(1H,4H)-dione (0.60 g, 3.0 mmol) in 10 ml of N,N-dimethylformamide was added ammonium chloride (0.18 g, 3.4 mmol) and sodium azide (0.22 g, 3.4 mmol), and the mixture was stirred on an oil bath at 100° C. for 4 h. The mixture was cooled to room temperature and 25 ml of 1M hydrochloric acid was added. The precipitated solid was isolated by filtration and washed with water, ethanol and ether to give 0.71 g (97%) of the title compound. M.p. 320.4° C. (DSC); IR (KBr): 1700, 1650, 1600 cm-1 ; 1H-NMR (DMSO-d6): 5.62 (s, 2H, CH2), 7.08 (s, 4H, ArH), 12.2 (broad s, 1H, NH; only one exchangeable proton could be seen); MS (m/z): 244 (M+, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:32]=[C:31]([CH3:33])[O:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:32]=[C:31]([CH3:33])[O:30][N:29]=1)=[O:27]
Reactant: Cc1cc(C(=O)CBr)no1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(C)on2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-bromoacetyl-5-methylisoxazole (M. D. Amici et al., J. Org. Chem., 1989, 54, 2646).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:11][C:10](=[O:12])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=1)[CH2:4][CH2:5][CH3:6].Cl[CH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1>O1CCOCC1>[CH2:3]([C:7]1[N:11]([CH:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)[C:10](=[O:12])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: N#Cc1ccccc1-c1ccc2c(c1)CCC2Cl
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCC1=NC2(CCCC2)C(=O)N1C1CCc2cc(-c3ccccc3C#N)ccc21
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
Sodium hydride (53 mg, 2.3 mmol) was added to 2-butyl-1,3-diaza-spiro[4.4]non-1-en-4-one (458 mg, 2.36 mmol) in anhydrous 1,4-dioxane (3 mL). After 0.25 hour, a solution of 2-(1-chloro-indan-5-yl)-benzonitrile (300 mg, 1.18 mmol)in dioxane (1.0 mL) was added. The reaction mixture was heated at 110° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 50% ethyl acetate/hexanes to give 150 mg of a colorless oil. 1H NMR (250 MHz, CDCl3): d 7.80 (d, 1 H), 7.65 (q, 1 H), 7.48 (m, 4 H), 7.10 (d, 1 H), 5.75 (m, 1 H), 3.42 (m), 3.15 (m), 2.85 (m), 2.55 (m), 2.40-1.60 (m), 1.40 (m), 0.88 (t, 3 H).
Reaction SMILES: CC(C)=O.[CH3:5][N:6]1[C:10]([OH:11])=[C:9]([C:12](=[O:29])[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([CH:23](OC)[O:24]C)[C:14]=2[Cl:28])[CH:8]=[N:7]1>Cl>[CH3:5][N:6]1[C:10]([OH:11])=[C:9]([C:12](=[O:29])[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([CH:23]=[O:24])[C:14]=2[Cl:28])[CH:8]=[N:7]1
Reactant: COC(OC)c1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1Cl
Agent: Cl
Solvent: CC(C)=O
Product: Cn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C=O)c2Cl)c1O
Reaction time: 1 h

Procedure:
To acetone in a volume of 40 ml, was dissolved 1-methyl-5-hydroxy-4-(2-chloro-4-methanesulfonyl- 3-dimethoxymethylbenzoyl)pyrazole in an amount of 1.8 g (4.7 mmol), and hydrochloric acid in an amount of 2 ml was then added to the resulting solution. The mixture was stirred for 1 hour under heating reflux, and the solvent therein was removed by distillation. Crystals precipitated was washed with ether to obtain 1-methyl-5-hydroxy-4-(2-chloro-4-methanesulfonyl-3-formylbenzoyl)pyrazole in an amount of 1.5 g. The melting point of this compound is in a range of from 140° to 142° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20]Br>>[CH3:15][CH:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: OCCCCCCCCCCCCBr
Reactant: CC(C)CCCCBr
Product: CC(C)CCCCCCCCCCCCCCCCO
Yield: 44 %

Procedure:
17-methyloctadecan-1-ol was prepared from 12-bromo-1-dodecanol and 5-methylhexylbromide in 44% yield. 1H NMR δ 0.86 (6H), 1.10-1.40 (32H), 3.64 (2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[C:17]([O:26][CH3:27])[CH:16]=2)[N:3]=1.C1COCC1.[CH3:33][NH2:34]>>[CH3:27][O:26][C:17]1[CH:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([NH:34][CH3:33])[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)[CH:20]=[CH:19][C:18]=1[C:21]1[O:25][CH:24]=[N:23][CH:22]=1
Reactant: CN
Reactant: COc1cc(Nc2nc(Cl)nc(-c3ccccc3)n2)ccc1-c1cnco1
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-c3cnco3)c(OC)c2)nc(-c2ccccc2)n1
Temperature: 80 °C
Yield: 83 %

Procedure:
4-Chloro-N-[3-methoxy-4-(5-oxazolyl)phenyl]-6-phenyl-1,3,5-triazin-2-amine, 103, (27 mg, 0.07 mmol) was suspended in 2M methylamine in THF (1 mL, 2 mmol) was added and the reaction mixture heated in a sealed tube at 80° C. overnight. The product was filtered and purified by flash column chromatography (2% methanol in methylene chloride) to yield 22 mg (83%) of the title compound LCMS (Ret Time=3.15 min, HPLC condition B) M+H+=375.23 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCCCCCCCBr)cc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCCCCCCCN3CCCC3)cc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1280 mg (2.2 mmol) of [2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-(8-bromo-octyloxy)phenyl]methanone and 470 mg (6.6 mmol) of pyrrolidine were dissolve in 20 mL of dimethylformamide (DMF). The reaction mixture was heated to 100° C. and stirred under a nitrogen atmosphere. After 30 minutes, the reaction was allowed to cool and evaporated to dryness in vacuo. The crude product was chromatographed on a silica gel column eluted with a linear gradient begining with CHCl3 and ending with CHCl3—MeOH (19:1) (v/v). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 890 mg (72%) of the title compound as a tan, amorphous powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-dimethylamino-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M21) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (158 mg).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:25][CH3:26]>C1COCC1>[C:10]([O:9][C:7]([N:5]1[CH2:6][C:3]([C:1]#[N:2])([CH2:25][CH3:26])[CH2:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: -76 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
In a 100 mL 2-neck round-bottomed flask, tert-butyl 3-cyanoazetidine-1-carboxylate (0.80 g, 4.4 mmol) was dissolved in THF (16 mL). The colorless solution was cooled to −76° C. and lithium bis(trimethylsilyl)amide (1.0M solution in THF, 4.8 mL, 4.8 mmol) was added dropwise over 20 min. The yellow solution was stirred at −76° C. for 30 min then iodoethane (0.50 mL, 6.2 mmol) was slowly added. The reaction mixture was stirred at −76° C. for 30 min and then warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with 10 mL of saturated NH4Cl and diluted with 10 mL of water then extracted with ˜100 ml EtOAc (2×). The combined organic layers were washed with ˜10 mL water and ˜10 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 40 g silica gel with EtOAc/hexanes, (gradient: 0-20% EtOAc). All fractions containing product were combined and concentrated to afford 0.84 g (91%) of 3-cyano-3-ethyl-azetidine-1-carboxylic acid tert-butyl ester as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](C)=COC)=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1.BrC1C=CC([O:36]CC2N(C3C(Cl)=CC=CC=3Cl)N=CC=2C(C)C)=CC=1C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:36])=[C:18]([CH3:27])[CH:17]=2)=[C:12]([CH:28]([CH3:30])[CH3:29])[CH:11]=[N:10]1
Reactant: COC=C(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C=O
Yield: 75 %

Procedure:
The title compound (1.51 g, 75%) is prepared essentially according to the preparation of 1-(2,6-Dichloro-phenyl)-4-isopropyl-5-[4-(2-methoxy-1-methyl-vinyl)-3-methyl-phenoxymethyl]-1H-pyrazole using 5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole. 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.73 (s, 1H), 7.68 (d, 1H, J=8.8 Hz), 7.44-7.40 (m, 2H), 7.31 (dd, 1H, J=8.6, 7.3 Hz), 6.71 (dd, 1H, J=8.6, 2.4 Hz), 6.61 (d, 1H, J=2.4 Hz), 4.89 (s, 2H), 3.01 (sept, 1H, J=6.6 Hz), 2.60 (s, 3H), 1.32 (d, 6H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([C:14]2[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)=[CH2:13])[CH2:11][O:10]1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1.C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]([C:14]1[CH:15]=[CH:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1)=[CH2:13])[CH2:11][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1
Reactant: C=C(c1ccc(SC)nc1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(c1ccc(SC)nc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 50 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
A solution of the product of part (vi) (3.6 g, 13 mmol) in DMF (30 ml) was added to potassium carbonate (2.0 g, 15 mmol) and 1H-1,2,4-triazole (1.0 g, 15 mmol). The mixture was stirred at 50° C. for 20 hours then poured into ethyl acetate (200 ml) and washed with water (2×100 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. Flash chromatography of the residue on silica by elution with ethyl acetate gave the title compound as an oil, (3.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[CH2:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.C(N(CC)CC)C.[Na+].[I-].[K+].[Br-]>CC(=O)CC.CCO>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][CH2:16][CH2:15][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=2)[CH2:13][CH2:12]1
Reactant: ClCCCC1OCCO1
Reactant: Fc1cnc(N2CCNCC2)nc1
Agent: [Br-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1cnc(N2CCN(CCCC3OCCO3)CC2)nc1
Temperature: 23 °C

Procedure:
A mixture of 4-(5-fluoro-2-pyrimidinyl)piperazine (7.29 g, 40.0 mmol), 2-(3-chloropropyl)-1,3-dioxolane (6.62 g, 5.8 mL, 44.0 mmol) and triethylamine (12.5 mL, 90.0 mmol) in 2-butanone (250 mL) was heated to reflux and treated dropwise (1h) with a solution of NaI (3.0 g, 20.0 mmol) in 2-butanone (70 mL). The reaction mixture was refluxed for 12 h then treated dropwise (1 h) with a solution of NaI (3.0 g, 20.0 mmol) in 2-butanone (70 mL) and refluxed for another 12 h. After cooling at 23° C., the solvent was evaporated in vacuo leaving a residue which was solubilized in EtoAC (400 mL). The organic solution was washed with aqueous NaOH solution (20 mL, 2N); the aqueous phase was extracted with EtoAC (2×50 mL). The organic extracts were combined, dried (MgSO4) and concentrated to dryness. The solution was chromatographed on a silica gel column (4.5×15 cm) using a mixture of 20% MeCN in EtoAc. Appropriate fractions were concentrated in vacuo leaving a pale yellow syrup which crystallized on standing, 10.5 g, mp 54°-55° C. (89%). Recrystallization from EtoAC-pet.ether mixture (1;14) gave an analytical sample, mp 55°-56° C.; 1HNMR (CDCl 3, 200 MHz) δ: 1.5-1.9 (m, 4H), 2.3-2.7 (m, 6H), 3.6-4.1 (m, 8H), 4.8-5.0 (m, 1H), 8.16 (s, 2H); IR (KBr) ν: 1610, 1555, 1489 cm-1 ; UV (EtOH) λ: 244 (ε 17239), 332 (ε 1948);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:19])[CH2:10][C:11](=O)[CH2:12][C:13]([O:15]CC)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CCO>[CH2:21]([N:28]1[C:13](=[O:15])[CH:12]=[C:11]([CH2:10][N:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:19])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CC(=O)CN(C)c1cc(Cl)cc(Cl)c1
Reactant: NNCc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(Cc1cc(=O)n(Cc2ccccc2)[nH]1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of ethyl 4-((3,5-dichlorophenyl)(methyl)amino)-3-oxobutanoate (304 mg, 1.0 mmol) and benzyl hydrazine chloride (388 mg, 2.0 mmol) in EtOH (5 mL) was added anhydrous triethylamine (570 uL, 4.0 mmol). The resulting solution was stirred at room temperature overnight. After evaporating the volatiles, the residue was purified on a silica gel column, eluting with a mixture of MeOH and dichloromethane (1% to 2% MeOH) to afford the product as a pale yellow solid (320 mg, 88%). The solid was then recrystallized in dichloromethane/hexane to give the product as a white solid. 1H NMR (DMSO-d6, 500 MHz): δ=11.00 (br s, 1H), 7.28 (t, J=7.0 Hz, 2H), 7.23 (d, J=7.0 Hz, 1H), 7.11 (d, J=7.0 Hz, 2H), 6.74 (d, J=1.5 Hz, 2H), 6.69 (s, 1H), 5.12 (s, 1H), 5.01 (s, 2H), 4.33 (s, 2H), 2.98 (s, 2H); 13C NMR (DMSO-d6, 125 MHz): δ=152.7, 151.0, 146.8, 138.0, 134.4X2, 128.4X2, 127.1, 127.0X2, 114.4, 110.6X2, 84.6, 50.3, 49.2, 38.9 ppm; MS (ESI): m/z 284.0 [M+H]+; CHN calculated for C18H17Cl2N3O: C, 59.68; H, 4.73; N, 11.60. found: C, 59.79; H, 4.68; N, 11.48.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][S:2]([O:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[CH:7]=1)(=[O:3])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Oc1cnc2ccccc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxyquinol-3-yl methanesulphonate (0.48 g) and potassium carbonate (0.28 g) in dry dimethylformamide (20 ml) was stirred for 2 hours at ambient temperature. Methyl iodide (0.15 ml) was then added and the stirring at ambient temperature continued overnight. The solvent was removed under reduced pressure and the residue was triturated with water (10 ml). The resultant mixture was extracted extracts were evaporated to dryness. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (39:1) followed by crystallisation from industrial methylated spirit (10 ml) to give the novel compound ]-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 206°-208°.
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH2:3][CH2:2]1.Cl.[NH2:11]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]1([C:4]2[O:9][N:11]=[C:6]([CH3:7])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C2CC2)on1
Yield: 81.3 %

Procedure:
A mixture of 1-cyclopropylbutan-1,3-dione (65.3 g), hydroxylamine hydrochloride (36.6 g) and anhydrous potassium carbonate (71.8 g) in ethanol (375 ml) was stirred and heated at reflux for 2 hours. The mixture was cooled and filtered and the filtrate was evaporated to dryness. The residue was distilled under reduced pressure to give 5-cyclopropyl-3-methyl isoxazole containing approximately 20% 3-cyclopropyl-5-methylisoxazole (51.85 g) as a clear oil, b.p. 74° C. /12 mm.Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:20]1[O:21][CH:15]([C:14]2[CH:17]=[CH:18][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)=[CH:12][CH:13]=2)[O:16][CH2:19]1
Reactant: OCCO
Reactant: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(C3OCCO3)cc2)nc1

Procedure:
To a solution of 4-[(5-nitro-2-pyridyl)oxy]benzaldehyde (5.00 g, 20.5 mmol) in benzene (100 mL) were added ethylene glycol (2.28 mL, 41.0 mmol) and p-toluenesulfonic acid (0.50 g), and the resulting solution was heated to reflux for 3 hours while removing water with a Dean-Stark. The reaction solution was washed with a saturated sodium bicarbonate solution, and subsequently washed with brine. The benzene layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 5.88 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:24][C:18]3[N:19]=[CH:20][N:21]=[C:22](O)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:24][C:18]3[N:19]=[CH:20][N:21]=[C:22]([Cl:27])[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Product: Clc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Temperature: 140 °C
Reaction time: 3 h

Procedure:
After adding 200 ml of phosphorus oxychloride to 20 g of the 6-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol synthesized in Production Example 153-2, the mixture was stirred at 140° C. for 3 hours and the reaction mixture was cooled to room temperature and the reaction mixture was concentrated. Ice water was added to the residue, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated to dryness to obtain 12 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[N+:28]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Zn].[NH4+].[Cl-]>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1N
Yield: 95.2 %

Procedure:
Prepared from [4-(6-benzyloxy-pyridin-3-yl)-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example E3) (768 mg, 1.82 mmol) by reduction with Zn/NH4Cl according to the general procedure G (method c). Obtained as a light brown solid (678 mg).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[Cl:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-N-(3-chloro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 204.1) and pyrimidin-5-ylboronic acid to afford a white foam. HPLC (Condition 4) tR=5.17 min, UPLC-MS (Condition 3) tR=1.03 min, m/z=480.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (m, J=3.90 Hz, 1H) 1.79-1.93 (m, 1H) 2.88 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.10, 4.50 Hz, 2H) 3.37 (m, J=7.00 Hz, 1H) 4.11-4.25 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.55 (d, J=8.99 Hz, 1H) 7.72-7.86 (m, 1H) 8.10 (dd, J=15.84, 2.54 Hz, 2H) 8.74-8.81 (m, 1H) 8.88 (s, 2H) 9.19 (s, 1H) 10.27 (s, 1H).