Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>CN(C=O)C>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:25][CH2:24]2)[C:11](=[O:16])[C:10]3=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2ccc(C3CCCCC3)cc2C1=O
Reactant: ClCCN1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCN2CCN(Cc3ccccc3)CC2)c2ccc(C3CCCCC3)cc21
Temperature: 25 °C
Yield: 64.7 %

Procedure:
5-Cyclohexyl-1H-indole-2,3-dione (3.45 g) in dry DMF at 0° C. was treated with sodium hydride (80% dispersion in mineral oil, 550 mg). The mixture was allowed to warm to room temperature and 1-(2-chloroethyl)-4-(phenylmethyl) piperazine (3.9 g) in dry DMF (25 ml) was added. The reaction mixture was then heated in an oil bath at 70° C. for 2 hours. The mixture was evaporated under reduced pressure and the residue passed through a pad of silica gel to yield the title compound as a red oil (4.2 g, 65%).
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][C:8](=[O:10])[CH3:9])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Br:17]Br>CO>[Br:17][CH2:9][C:8](=[O:10])[CH2:7][CH2:6][N:5]1[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]2[C:1]1=[O:16]
Reactant: BrBr
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Solvent: CO
Product: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 130 g (0.6 mole) of 4-phthalimido butan-2-one (7a) in 1000 ml of absolute methanol is added 96 g (0.6 mole) of bromine and the reaction mixture is stirred for 24 hours at room temperature.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1(=[O:19])[N:17]2[C:18]3[C:14]([CH:15]=[CH:16]2)=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][NH:8][CH2:7]1.CN([CH:23]=[O:24])C>>[O:19]=[C:6]1[N:17]2[C:18]3[C:14]([CH:15]=[CH:16]2)=[C:13]([CH:23]=[O:24])[CH:12]=[CH:11][C:10]=3[CH2:9][NH:8][CH2:7]1
Reactant: O=C1CNCc2cccc3ccn1c23
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c3c1ccn3C(=O)CNC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
POCl3 (16.37 g, 106.76 mmol) was slowly added to DMF (225 mL) at 0° C. The mixture was stirred for 15 minutes and then treated with a solution of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 42, 1.46 g, 7.85 mmol) in DMF (10 mL). The reaction mixture was warmed to rt and stirred for 17 h. After removing all solvent, the residue was taken up in H2O, made basic (pH 12-14) using 50% aqueous NaOH and extracted with EtOAc several times. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 1.6 g (95%) of a pale-yellow solid: 1H NMR (DMSO-d6) δ 3.58-3.61 (m, 2H), 4.48 (bs, 2H), 7.37 (t, 1H, J=7.5 Hz), 7.97 (d, 1H, J=7.5 Hz), 8.33-8.35 (m, 2H), 8.43-8.45 (m, 1H), 9.95 (s, 1H). HRMS calcd. for C12H10N2O2 (M+) 214.0742, found 214.0737. Anal. (Cl2H10N2O2.0.1H2O) C, H, N.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=3)[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCc1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-(bromomethyl)-3-nitrobenzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.81 (s, 2H), 8.40 (s, 1H), 8.19 (ddd, 1H), 7.99 (d, 1H), 7.95 (d, 1H), 7.68 (t, 1H), 7.24 (d, 1H), 5.20 (s, 2H), 4.65 (s, 1H), 3.94 (s, 3H); MS (ESI): 487.8.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:12])[CH2:10][CH3:11]>>[C:9]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: O=c1cc(O)cc[nH]1
Reactant: CCC(=O)Cl
Product: CCC(=O)Oc1cc[nH]c(=O)c1
Yield: 23 %

Procedure:
Using 1.00 g of 4-hydroxy-2-pyridone and 0.94 ml of propanoyl chloride and following the general procedure of Example 12, 350 mg of the title compound was obtained in a yield of 23%.
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]2=[N:6]1)[CH2:2][C:3]#[CH:4].C([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26]C=2N=N1)CC#C>>[N:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[N:6]=[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]2=[N:9]1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: C#CCCn1nnc2ccccc21
Product: C(#Cc1ccccn1)CCn1nc2ccccc2n1
Yield: 8 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(C), from 90 mg (0.53 mmol) of 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole and 1-(but-3-ynyl)-1H-benzo[d][1,2,3]triazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 10 mg (42 μmol, 8%) of 2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil with a purity of 82%. Another fraction yielded after SCX column (DCM, DCM/MeOH 98:2, DCM/MeOH/NH4OH 95:4:1 to 94:4:2) 19 mg (76 μmol, 14%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:21]Br>C(#N)C>[Br:21][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc2c(cnn2-c2ccc(C)cc2)c1
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)c(Br)nn2-c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Methyl 1-(4-methylphenyl)-1H-indazole-5-carboxylate (327.1 mg, 1.228 mmol) was dissolved in acetonitrile (12.300 mL) at 25° C. Bromine (158 μL, 3.0575 mmol) was added dropwise and the reaction mixture was allowed to stir for 30 min. The reaction was stopped, quenched by addition of saturated aqueous sodium hydrogen carbonate (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×20 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 40 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-45%). The title compound (407.3 mg, 1.180 mmol, 96% yield) was recovered as a light yellow/white solid. LC-MS: [M+1]=346.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](O)[CH:6]=[CH2:7])=[O:4].[O:9]1C=[CH:13][CH2:12][CH2:11][CH2:10]1.ClCCl.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CC1C=CC(S(O)(=O)=O)=CC=1.O.O>[O:2]1[CH2:1][CH2:7][CH2:6][CH2:5][CH:3]1[O:4][CH:11]([CH:12]=[CH2:13])[CH2:10][OH:9]
Reactant: C1=COCCC1
Reactant: C=CC(O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: C=CC(CO)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
DL-2-Hydroxy-3-butenoic acid methyl ester (5 g, 43.06 mmol), 3,4-dihydro-2H-pyran (19.6 mL, 215.3 mmol), p-TsOH.H2O (40 mg, 0.22 mmol) and dichloromethane (200 mL) were mixed, and stirred at room temperature for 3 hours. The solution was concentrated. The dried residue was dissolved in THF (250 mL) at 0° C. LiAlH4 (3.27 g, 86.12 mmol) was added portionwise under N2. The reaction mixture was slowly warmed up from 0° C. to room temperature, stirred overnight and cooled to 0° C. H2O (5 mL) was added dropwise via syringe. The solvent was removed under reduced pressure. The residue was extracted with THF (500 mL). The solution was filtered, and dried with silica gel powder (20 g), and purified by flash chromatography eluting with 20% ethyl acetate in hexanes (2 L) to give the title compound (6.80 g, 89%). MS (DCI) m/z 177.44 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.44–1.62 (m, 4 H) 1.71 (m, 1 H) 1.84 (m, 1 H) 3.40–3.62 (m, 3 H) 3.88 (m, 1 H) 4.16 (m, 1 H) 4.62–4.81 (m, 2 H) 5.11–5.36 (m, 2 H) 5.81 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](I)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH:24]([P:34]([O:39][CH2:40][CH3:41])(=[O:38])[O:35][CH2:36][CH3:37])([P:26]([O:31][CH2:32][CH3:33])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:25]>C1COCC1>[CH2:36]([O:35][P:34]([CH:24]([P:26]([O:31][CH2:32][CH3:33])([O:27][CH2:28][CH3:29])=[O:30])[CH2:25][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]2=[N:17][CH:16]=1)(=[O:38])[O:39][CH2:40][CH3:41])[CH3:37]
Reactant: CCOP(=O)(OCC)C(C)P(=O)(OCC)OCC
Reactant: Ic1cnc2c(OCc3ccccc3)cccn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Cc1cnc2c(OCc3ccccc3)cccn12)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
As shown in FIG. 6, 8-Benzyloxy-3-iodo-imidazo[1,2-α]pyridine 31 (Example 20).(7.0 g, 20 mmol) in anhydrous THF (200 mL) was stirred at −78° C., under argon, then n-BuLi (2.5 M, 16.0 mL, 40 mmol) in hexanes was added slowly, keeping the temperature below −70° C. . The resulting mixture was stirred for 10 min, then tetraethyl ethene-1,1-bisphosphonate 3 (6.0 g, 20.0 mmol) in anhydrous THF (20 mL) was added slowly, keeping the temperature below −70° C. The reaction mixture was stirred for an additional 10 minutes, cooled to room temperature, and then quenched with saturated NH4Cl (100 mL). The mixture was then extracted with CH2Cl2 (200 mL×3) and the organic phase washed with water (200 mL×2). The resultant organic phase was then dried with Na2SO4, concentrated under reduced pressure and purified on silica gel (CombiFlash, EtOAc/MeOH elution) to afford [2-(8-Benzyloxy-imidazo[1,2-α]pyridin-3-yl)-1-(diethoxy-phosphoryl)-ethyl]-phosphonic acid diethyl ester 35 as yellowish brown oil. 7.18 g, 69% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[NH:13][C:28](=[O:29])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]=2[CH:8]=1)=[O:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CCNc1cc(C(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Product: CCOC(=O)CCn1c(=O)[nH]c2ccc(C(=O)OC(C)(C)C)cc21

Procedure:
To a solution of 4-Amino-3-(2-Ethoxycarbonyl-ethylamino)-benzoic acid tert-butyl ester (900 mg, 2.92 mmol) in THF (20 ml) was added CDI (997 mg, 6 mmol). The solution was heated at 90 degrees for 30 minutes. The reaction mixture was evaporated to dryness, and then taken up in Ethyl Acetate. The organic phase was washed with brine, dried over MgSO4, filtered, evaporated to dryness. The residue was purified by flash Chromatography eluded with 5% methanol in CH2Cl2. After evaporation of the desired fractions, 800 mg was obtained (82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:25])[CH:12]2[CH2:20][CH2:19][C:18]3[NH:17][C:16]4[CH:21]=[CH:22][CH:23]=[N:24][C:15]=4[C:14]=3[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[C:33]([O:37][C:38](=[O:41])[CH2:39]Br)([CH3:36])([CH3:35])[CH3:34]>CO>[C:33]([O:37][C:38](=[O:41])[CH2:39][N:17]1[C:18]2[CH2:19][CH2:20][CH:12]([N:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH3:25])[CH2:13][C:14]=2[C:15]2[N:24]=[CH:23][CH:22]=[CH:21][C:16]1=2)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C1CCc2[nH]c3cccnc3c2C1)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C1CCc2c(c3ncccc3n2CC(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 1 h
Yield: 19 %

Procedure:
A solution of 4-fluoro-N-methyl-N-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indol-8-yl)-benzenesulfonamide (2.8 g, 7.8 mmol) and DMF (22 mL) was cooled to 0° C. Sodium hydride (340 mg, 8.6 mmol, 60% dispersion in mineral oil) was added at 0° C. and after 30 min, tert-butylbromoacetate (1.3 mL, 8.9 mmol) was added at 0° C. After 1 hour, MeOH was added and the reaction mixture was filtered. The organic layer was concentrated and the residue purified by reverse phase preparative HPLC to afford 700 mg of {8-[(4-fluoro-benzenesulfonyl)-methyl-amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indol-5-yl}-acetic acid tert-butyl ester. Mass spectrometric data [M+H]+=474.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:32][OH:33])[CH:22]=[C:23]([C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])[CH:24]=1>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:18][C:19]2[CH:20]=[C:21]([CH2:32][OH:33])[CH:22]=[C:23]([C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])[CH:24]=2)=[N:3][CH:4]=1
Reactant: Nc1cc(CO)cc(C(F)(F)C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(F)ccc1-c1nc(Nc2cc(CO)cc(C(F)(F)C(F)(F)F)c2)ncc1F

Procedure:
Intermediate 46.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and [3-amino-5-(pentafluoro-ethyl)phenyl]methanol. The residue was purified by chromatography (hexane/ethyl acetate 6:4) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:29][C:30]#[N:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1
Yield: 95.8 %

Procedure:
(3,4-dimethoxyphenyl)-(4-methoxyphenyl)methanone (2.00 g, 7.35 mmol), cyanomethylphosphonic acid diethyl ester (2.31 ml, 14.69 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 14.69 ml, 14.69 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give 3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile as a pink oil (2.08 g, 96%): 1HNMR (DMSO-d6) δ 7.34-6.7 (m, 7H, Ar), 6.14 (s, 0.50H, double bond proton of one isomer), 6.08 (s, 0.45H, double bond proton of the other isomer), 3.83-3.73 (multiple singlets, 9H, 3OCH3); 13C NMR (CDCl3) δ 162.6, 162.5, 161.6, 161.2, 151.2, 150.7, 149.0, 148.8, 132.2, 131.7, 131.5, 130.3, 129.8, 129.5, 123.2, 122.3, 118.8, 118.8, 114.1, 114.0, 112.9, 111.5, 110.9, 91.9, 91.8, 56.2, 56.1, 56.1, 55.5, 55.5; Anal. Calcd. For C18H17NO3: C, 71.92; H, 6.19; N, 4.32 (+0.04H2O). Found: C, 71.95; H, 6.04; N, 4.54.
Reaction SMILES: [Br-:1].[CH3:2][N+:3]([CH3:23])([CH2:20][CH2:21]O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].P(Br)(Br)[Br:25]>C1C=CC=CC=1>[Br-:25].[CH3:2][N+:3]([CH3:23])([CH2:20][CH2:21][Br:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCCCCC[N+](C)(C)CCO
Agent: [Br-]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC[N+](C)(C)CCBr
Reaction time: 24 h
Yield: 213.3 %

Procedure:
A total of 3.95g (0.010 mole) of dimethyl-(2-hydroxy)ethyl-hexadecyl ammonium bromide and 0.9910g (0.00366 mol phosphorous tribromide was slurried in 20 ml of benzene and allowed to react at room temperature (about 25° C.) with stirring for 24 hours under nitrogen. The solvent was removed in vacuo and the residue washed several times with anhydrous ether. The resulting amorphous solid was recrystallized from ethyl acetate, filtered and dried to yield 3.57g (77%) of the desired product. Calc. % C 52.51, % H 9.49, %N 3.06, %Br 34.93; Found % C 51.80, H 10.06, %N 3.06, % Br 34.18; m.p. 185°-190° C. The 1H NMR and IR agree with the proposed structure.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>C1C=CC=CC=1>[OH:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][OH:33])[C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCCO
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCC(=O)N(CCO)CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension is prepared containing 17.8 grams (0.1 mole)-β-benzoyl-propionic acid in 500 ml of anhydrous benzene; then are added in this order and at room temperature 10.5 grams triethylamine, 15 grams ethyl chlorocarbonate and 21 grams (0.2 moles) diethanolamine. The suspension is stirred for over two hours, always at room temperature, and it is then filtered to remove the triethylamine hydrochloride. The liquid is concentrated, at reduced pressure, to about half of the initial volume and it is left to rest about 12 hours at 5°-10° C. temperature. The crystallized solid is filtered, vacuum dried at reduced pressure, about 40° C., and is recrystallized from ethanol. 17.5 grams of N,N-bis(2- hydroxy-ethyl)-β-benzoyl-propionamide with m.p. 98° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][NH:5][C:4](Br)([CH3:9])[CH:3]=1.[CH3:11][NH2:12]>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH2:9][NH:12][CH3:11])[CH:3]=1
Reactant: CC1(Br)C=C(Cl)C(F)=CN1
Reactant: CN
Solvent: CO
Product: CNCc1cc(Cl)c(F)cn1
Temperature: 25 °C
Reaction time: 26 h
Yield: 70 %

Procedure:
4-Chloro-5-fluoro-alpha-bromo-2-picoline (1.37 g, 6.1 mmol), from Step 1 was dissolved in 15 mL of methanol in a pressure tube. Methylamine (3 mL of 40% aqueous solution) was added to the tube and the tube was sealed. The reaction mixture was stirred at ambient temperature for 26 hours and then the solvent was removed under reduced pressure. To the residue was added 50 mL of 10% aqueous sodium carbonate solution and the resultant aqueous mixture was extracted with 3×50 mL of methylene chloride. The organic combined extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressur. The residue was dried in vacuo to give 754 mg g (70% yield) of the title compound; MS DCI-NH3M/Z: 175 (M+H)+ base; 1H NMR (CDCl3) d 2.50 (s, 3H), 3.90 (s, 2H), 7.47 (d, 1H), 8.42 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=3)[O:35]2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:40]=3)[O:35]2)=[CH:30][CH:29]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(Cl)cc1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccc(Cl)cc2)O3)nc1

Procedure:
2-(4-Chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 330 mg of 2-(4-chlorophenyl)chroman-4,6-diol. The product was purified by column chromatography using heptane-ethyl acetate (2:1) as an eluant. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.54-7.47 (m, 4H), 7.25 (d, 1H, J 2.8 Hz), 7.22 (d, 1H, 9.1 Hz), 7.02 (dd, 1H, J 8.8, 2.8 Hz), 6.89 (d, 1H, J 8.8 Hz), 5.65 (d, 1H, J 6.4 Hz), 5.33 (d, 1H, J 10.6 Hz), 4.98 (m, 1H), 2.34 (m, 1H), 1.94 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:14]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:41]([O:45][C:46]([N:48]1[C:56]2[C:51](=[CH:52][C:53]([Cl:57])=[CH:54][CH:55]=2)[CH:50]=[C:49]1[CH2:58]Br)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CC#N.C(OCC)C.O>[C:41]([O:45][C:46]([N:48]1[C:56]2[C:51](=[CH:52][C:53]([Cl:57])=[CH:54][CH:55]=2)[CH:50]=[C:49]1[CH2:58][N:9]1[CH2:8][C:7](=[O:11])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([N:21]=[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:14]=2)[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)n1c(CBr)cc2cc(Cl)ccc21
Reactant: COC(=O)C1CNCC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a mixture of (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (630 mg, 1.39 mmol) and K2CO3 (380 mg, 2.78 mmol) in anhydrous CH3CN (5 mL) at 0° C. is added 2-bromomethyl-5-chloro-indole-1-carboxylic acid tert-butyl ester (720 mg, 2.09 mmol), EXAMPLE 21, in CH3CN (4 mL). The reaction mixture is allowed to warm to ambient temperature then maintained for 16 hours. The reaction mixture is diluted with diethyl ether/water and the layers are separated. The organic phase is washed twice with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is chromatographed on silica (CH2Cl2 to 2% MeOH/CH2Cl2) to provide 550 mg (55%) of the title compound which is used directly in the next reaction without further characterization.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=2)=[N:19]1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][CH2:16][NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])[N:19]=2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: Cc1cc(-c2ccn(CCN)n2)ccc1C#N
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Product: Cc1cc(-c2ccn(CCNC(=O)c3cc(-c4ccncc4)n[nH]3)n2)ccc1C#N
Yield: 6.9 %

Procedure:
The title compound was synthesized from 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (303 mg, 1.60 mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (362 mg, 1.60 mmol) using the method of Example 34(d). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-20% MeOH/DCM) to obtain 44 mg (6%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.49 (s, 3H), 3.71 (q, 2H), 4.37 (t, 2H), 6.84 (d, 1H), 7.31 (s, 1H), 7.74 (m, 2H), 7.70 (s, 1H), 7.79 (dd, 1H), 7.83 (d, 1H), 7.88 (s, 1H), 8.55 (br s, 1H), 8.63 (m, 2H), 13.99 (s, 1H).