Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](O)=[O:24])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:6]=1[CH3:37])=[O:4].[CH:38]([N:41]([CH:44]([CH3:46])C)[CH2:42]C)(C)C.[CH3:47][N:48](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:49].F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](=[O:24])[N:48]([CH2:49][CH2:46][CH2:44][N:41]([CH3:38])[CH3:42])[CH3:47])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)[C:6]=1[CH3:37])=[O:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)N(C)CCCN(C)C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
Intermediate 17 (57 mg, 0.11 mmol) was dissolved in DMF (1 mL), and then diisopropylethylamine (56 μL, 0.33 mmol) and HATU (63 mg, 0.17 mmol) were added. The reaction mixture was stirred at RT for 30 minutes, then N, N, N-trimethylpropanediamine (49 μL, 0.33 mmol) was added, and stirring was continued for a further 2 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% (2M NH3 in MeOH) in DCM to yield the title compound as a white solid (42 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:29][C:30]([NH2:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](=O)([O-])[O-].[K+].[K+].IC.C(Cl)(Cl)Cl>CN(C)C=O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH3:33])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:29][C:30]([NH2:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCCNCC3)cc2)cc1NCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN1CCCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
25 mg of 4-(benzylamino)-6-{[4-(1,4-diazepan-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 226) was dissolved in 0.3 mL of N,N-dimethylformamide, to which, under ice cooling, 10 mg of potassium carbonate and 4.3 mg of iodomethane were added, and stirred at the same temperature for 30 minutes and at room temperature for further 30 minutes. To the reaction mixture, chloroform was added, and the insoluble substances were filtered off. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 9 mg (35%) of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)=[O:3].[H-].[Na+].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C>[ClH:16].[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1)[N:20]=[CH:19][N:18]=[C:17]2[CH:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([S:2]([CH3:1])=[O:3])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: CS(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(S(C)=O)cc43)ncnc2cc1OCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
A solution of 5-methylsulphinyloxindole (303 mg, 1.55 mmol) in DMF (3.5 ml) was added to a suspension of sodium hydride (62 mg, 1.55 mmol, prewashed with hexane) in DMF (1.5 ml) and the mixture stirred for 30 minutes at ambient temperature. 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (175 mg, 0.51 mmol), (prepared as described for the starting material in Example 5), was added and the mixture was stirred for 1.5 hours at 50° C. and then partitioned between water and ether. The aqueous layer was adjusted to pH7-8 with 2M hydrochloric acid and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1). The semi-purified solid was dissolved in dilute hydrochloric acid (pH2) and purified by reverse phase C18 chromatography eluting with methanol/dilute hydrochloric acid (pH2) (gradient from 0/100 to 30/70). The methanol was removed by evaporation, the aqueous residue was freeze dried to give 6-methoxy-4-(5-methylsulphinyloxindol-3-yl)-7-(3-morpholinopropoxy)quinazoline hydrochloride (80 mg, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1)[CH3:2].[CH3:16][C:17]([CH3:24])([CH3:23])[C:18](=O)[CH2:19][C:20]#[N:21]>CCO>[C:17]([C:18]1[CH:19]=[C:20]([NH2:21])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:8][CH:9]=2)[N:14]=1)([CH3:24])([CH3:23])[CH3:16]
Reactant: CCOC(=O)CCc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 85.1 %

Procedure:
A mixture of 3-(4-hydrazinophenyl)propionic acid ethyl ester (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxopentanenitrile (6.9 g, 55 mol) in EtOH (150 mL) was heated at reflux overnight. The reaction solution was evaporated under vacuum. The residue was purified by column chromatography to yield ethyl 3-(4-(3-t-butyl-5-amino-1H-pyrazol-1-yl)phenyl)propanoate (14.3 g, 85% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6); δ 7.44 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 5.34 (s, 1H), 5.11 (s, 2H), 4.04 (q, J=7.2 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 1.19 (s, 9H), 1.15 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 316 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16](O)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:16]1[C:17]2[S:22][CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc(N2CCN(c3nc(O)c4c(n3)CCS4)CC2)cc1
Product: Oc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
1.11 g (3.36 mmol) of 2-[4-(4-hydroxyphenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is placed in 5 mL of phosphorus oxychloride, then stirred for 4 hours at 120° C. Excess phosphorus oxychloride is then distilled off and the residue is combined with water. The precipitate formed is suction filtered, washed with plenty of water, and dried. 1.18 g of product III is obtained as a brown powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:41]=[CH:40][C:8]2[NH:9][C:10]([C:12]3[N:13]=[C:14]([C:36]([F:39])([F:38])[F:37])[S:15][C:16]=3[N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:34])[CH2:24][N:25]4[C:29]5=[N:30][CH:31]=[CH:32][CH:33]=[C:28]5[N:27]=[CH:26]4)[C@H:19]([CH3:35])[CH2:18]3)=[N:11][C:7]=2[CH:6]=1)=O.[CH2:42]([Mg]Br)[CH3:43]>C1COCC1.C(Cl)Cl.C([O-])(O)=O.[Na+].CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[OH:2][C:3]1([C:5]2[CH:41]=[CH:40][C:8]3[NH:9][C:10]([C:12]4[N:13]=[C:14]([C:36]([F:37])([F:38])[F:39])[S:15][C:16]=4[N:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:34])[CH2:24][N:25]5[C:29]6=[N:30][CH:31]=[CH:32][CH:33]=[C:28]6[N:27]=[CH:26]5)[C@H:19]([CH3:35])[CH2:18]4)=[N:11][C:7]=3[CH:6]=2)[CH2:43][CH2:42]1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc2[nH]c(-c3nc(C(F)(F)F)sc3N3CCN(C(=O)Cn4cnc5cccnc54)[C@H](C)C3)nc2c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2sc(C(F)(F)F)nc2-c2nc3cc(C4(O)CC4)ccc3[nH]2)CCN1C(=O)Cn1cnc2cccnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Example 167 (25 mg) in THF (1.15 mL) was added Ti(OiPr)4 (0.0126 mL). Ethylmagnesium bromide (1M in THF, 0.513 mL) was added dropwise over 30 min at RT. The reaction mixture was stirred at RT for 20 h and diluted with DCM and 1M NaHCO3. The phases were separated. The org. phase was washed with water, dried (Na2SO4), filtered off and evaporated in vacuo. The residue was purified by preparative LC-MS (III) to afford 1 mg of pale yellow solid. LC-MS (B): tR=0.65 min; [M+H]+: 583.18.
Reaction SMILES: Cl[C:2]1[C:3]([OH:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].CCN(C(C)C)C(C)C>CS(C)=O.O>[CH2:17]([N:19]([CH2:20][CH3:21])[C:2]1[C:3]([OH:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[CH3:18]
Reactant: CCNCC
Reactant: COC(=O)c1ccc2nc(O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1O
Temperature: 70 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
To a solution of methyl 3-chloro-2-hydroxyquinoxaline-6-carboxylate (450 mg, crude) in DMSO (5 mL) was added diethylamine (550 mg, 7.52 mmol), DIEA (492 mg, 3.81 mmol). After stirring for 2 h at 70° C., the resulting solution was diluted with water (50 mL), extracted with ethyl acetate (4×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford methyl 3-(diethylamino)-2-hydroxyquinoxaline-6-carboxylate as a yellow solid (160 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][NH:12][CH3:13]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]([N:12]([CH3:13])[CH3:11])=[O:9])[CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1cnnc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cnnc(Cl)c1
Reaction time: 1 h

Procedure:
The 6-chloropyridazine-4-carbonyl chloride (0.18 g, 1.04 mmol was dissolved in methylene chloride (12.0 mL) and a 2.0 M dimethylamine in THF (1.4 mL) was added at room temperature. The reaction was stirred for 1 h and was complete. The reaction was partitioned between EtOAc and water. The organic layer was washed with 1 N HCl, brine, dried over magnesium sulfate and concentrated to give the crude product as an amber oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give 6-chloro-N,N-dimethylpyridazine-4-carboxamide as a colorless viscous oil, (0.16 gm, 60%). LCMS calculated for C7H9ClN3O (M+H)+: m/z=186.0. found: 185.9.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:7]=1)C.C([NH2:26])=O.CO[Na]>CN(C=O)C.CO.C(O)(C)C>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:8]2[N:7]=[C:6]([CH2:5][C:4]([NH2:26])=[O:3])[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:17][CH2:18]1
Reactant: CCOC(=O)Cc1nc(N2CCN(C)CC2)cc2ccccc12
Reactant: NC=O
Agent: CO[Na]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(C)O
Product: CN1CCN(c2cc3ccccc3c(CC(N)=O)n2)CC1
Temperature: 100 °C

Procedure:
To a solution of [3-(4-Methyl-piperazin-1-yl)-isoquinolin-1-yl]-acetic acid ethyl ester (1.7 g, 5.4 mmol) in DMF, formamide (0.72 ml, 18.1 mmol) is added under argon. After heating up to 100° C. 5.4N MeONa in methanol (1 ml) is added in 10 portions (0.1 ml each) over a period of 45 minutes. After 60 minutes at 100° C. the reaction is cooled to RT and diluted with isopropanol (100 ml). The solvents are removed under reduced pressure, the residue is dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate solution (5%). The organic phase is dried (Na2SO4) and concentrated. The resulting crude is purified on silica gel using methylene chloride/methanol (90/10→80/20) as eluent obtaining the product as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:13]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[CH2:14][CH3:15]>CN(C=O)C.O>[N:1]1([CH:13]([C:16]2[N:21]=[CH:20][C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCC(Br)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(c1ccc(-c2ccc(C(N)=O)cc2)cn1)n1ccnc1
Temperature: 57.5 °C
Yield: 13 %

Procedure:
To a solution of imidazole (0.077 g, 1.12 mmol), in DMF (15 mL) was added potassium carbonate (0.26 g, 1.87 mmol) and 4-(6-(1-bromopropyl)pyridin-3-yl)benzamide under nitrogen and the solution was heated to 55-60° C. for 6 h. The contents were cooled to rt, diluted with water (100 mL), extracted with ethyl acetate (2×100 mL), the layers separated, the organic layer washed with brine solution (2×30 mL), the organic layer dried over sodium sulphate and distilled off to get the crude product. The product was purified by preparative TLC (2000; 5% methanol in ethyl acetate) to give 4-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)benzamide (15 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.13 (d, 1H), 8.11 (s, 1H), 7.97 (d, 2H), 7.80 (t, 3H), 7.40 (d, 2H), 7.31 (s, 1H), 6.89 (s, 1H), 5.38 (q, 1H), 2.27 (m, 2H), 0.82 (t, 3H); LC-MS m/z calcd for [M+H]+ 307.37. found 307.3.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)([C:13]#[N:14])[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:21][Mg+].[Br-].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCCCC)CCC>[CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][C:10]([CH:13]([NH2:14])[CH3:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9][CH2:8]1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: C[Mg+]
Reactant: CCCS(=O)(=O)N1CCC(C#N)(c2ccccn2)CC1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCCCOCCCC
Product: CCCS(=O)(=O)N1CCC(c2ccccn2)(C(C)N)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 1-(propylsulfonyl)-4-pyridin-2-ylpiperidine-4-carbonitrile (5.0 g, 17 mmol) in toluene (130 mL) at room temperature was treated with MeMgBr (48.9 mL of a 1.0 M solution in dibutyl ether, 28.9 mmol). After 18 h, the reaction was cooled to 0° C. and treated with MeOH (29 mL). After 10 min, the reaction was treated with NaBH4 (1.0 g, 26.4 mmol), warmed to room temperature, and stirred an additional 10 min after which the reaction mixture was cooled to 0° C. and quenched with the dropwise addition of saturated aqueous NH4Cl (15 mL). The reaction was diluted with H2O (300 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and dissolved in pH 7 phosphate buffer (300 mL). The buffered solution was washed with EtOAc (200 mL) and the organic layer was extracted with fresh pH 7 buffer (2×150 mL). The combined buffer solutions were made basic with concentrated NH4OH and extracted with CH2Cl2 (3×200 mL), and these extracts were dried (Na2SO4) and concentrated under reduced pressure to afford {1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine. This material was fully resolved into 1R and 1S isomers (>99% ee) using a ChiralPak AD column. NOE analysis of Mosher's amides and single X-ray crystal analysis of a derivative confirmed the absolute stereochemistry of each isomer.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[S:11][CH3:12])=O.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([NH:21][C:22]([NH2:24])=[O:23])[CH:18]=[CH:19][CH:20]=1.[C:27]([O:33][CH2:34][CH:35]=[CH2:36])(=[O:32])[CH2:28][C:29]([CH3:31])=O>CC(OC)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:28]([C:27]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])=[C:29]([CH3:31])[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:25])([F:26])[F:13])[CH:16]=3)[C:22](=[O:23])[NH:24]2)=[C:4]([S:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: C=CCOC(=O)CC(C)=O
Reactant: CSc1cc(C#N)ccc1C=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Solvent: COC(C)(C)C
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1SC

Procedure:
The mixture was then diluted with MTBE (27 ml), and 4-formyl-3-(methylsulfanyl)benzonitrile (1.18 g, 6.70 mmol; Example 9A), 1-[3-(trifluoromethyl)phenyl]urea (1.37 g, 6.70 mmol) and allyl acetoacetate (1.43 g, 10.1 mmol) were added. The mixture was stirred under reflux overnight. For work-up, the solvent was removed under reduced pressure and the residue was suspended in diethyl ether and then filtered of with suction. This gave 978 mg (19% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[ClH:22].[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])C=1O>O>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([CH:9]([C:10]([O:12][C:13]2[C:26]([Cl:31])=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Cl:23])=[O:11])[C:14]([O:16][C:17]2[C:24]([Cl:22])=[CH:29][C:28]([Cl:30])=[CH:27][C:26]=2[Cl:31])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(C(=O)OC)c1cccc(C(F)(F)F)c1
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Oc1c(Cl)cc(Cl)cc1Cl)C(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.13 h
Yield: 50.43 %

Procedure:
The product of Step C was added to a solution of NaOH (25 g) in water (75 mL), and the reaction mixture was vigorously stirred under a nitrogen atmosphere at 60° C. for 8 minutes. The reaction mixture was then added to ice (100 g), and aqueous 6 N HCl was added until a pH of 1 was reached. The solution was extracted with ethyl acetate (3×100 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Dichloromethane (200 mL) was added to the resulting white solid, followed by the addition of oxalyl chloride (5 mL) and N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of 2,4,6-trichlorophenol (10.528 g, 53.32 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure. Methanol was added to the resulting residue, and a solid slowly precipitated from the solution. The solid was collected by filtration to provide 8.161 g (50.43%) of the title product as a solid. 1H NMR (CDCl3) δ 7.91 (s, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 7.59 (t, 1H), 7.37 (s, 4H), 5.38 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.ClC1C=CC(OC)=CC=1N.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[N:39]2[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)[CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH:42]3[CH2:41][CH2:40][N:39]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:38]=4[N:29]=[CH:30][CH:31]=[CH:32]5)[CH2:44][CH2:43]3)[CH2:17][CH2:18]2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: COc1ccc(N2CCNCC2)c2ncccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: COc1ccc(Cl)c(N)c1
Agent: [Na+]
Product: COc1ccc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12

Procedure:
Using the synthetic methods described in previous examples, 5-methoxy-8-(piperazin-1-yl)quinoline (prepared from 2-chloro-5-methoxyaniline using the methodology described for the preparation of Example N, Step 3, above) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a beige solid; MP. 218-220° C.; MS (ES) m/z (relative intensity) 454 (M+H)+ (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[NH2:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2N)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 4-(3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (633 mg) was then diluted with MeOH/EtOAc (1:1, 10 mL) and to the resulting solution was added Pd on carbon (5% Pd). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide 4-(3-amino-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a solid form. HPLC-MS RT=1.10 min, mass calculated for formula C14H22N4O2 278.17, observed LCMS m/z 279.28 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=2)[C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][S:39][C:37](=[O:40])[CH3:38])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: CC([O-])=S
Reactant: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCOS(=O)(=O)c3ccc(C)cc3)c3ccccc32)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2c(C(=O)OC)c(CCSC(C)=O)c3ccccc32)c1
Yield: 106.5 %

Procedure:
A solution of 1-(3-methoxycarbonyl-phenyl)-3-[2-(toluene-4-sulfonyloxy)-ethyl]-1H-indole-2-carboxylic acid methyl ester (0.37 g, 0.73 mmol) and potassium thioacetate (0.092 g, 0.8 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with saturated NaHCO3, dried over Na2SO4, and concentrated to give 0.32 g of 3-(2-acetylsulfanyl-ethyl)-1-(3-methoxycarbonyl-phenyl)-1H-indole-2-carboxylic acid methyl ester as a yellow oil (100% crude yield): 1H NMR (CDCl3, 300 MHz) δ 2.36 (s, 3H), 3.20 (q, J=6.87 Hz, 2H), 3.40 (q, J=6.87 Hz, 2H), 3.74 (s, 3H), 3.91 (s, 3H), 7.01 (d, J=7.82 Hz, 1H), 7.20–7.31 (m, 3H), 7.44 (d, J=8.02 Hz, 1H), 7.48–7.52 (m, 1H), 7.59(t, J=7.82 Hz, 1H), 7.88 (d, J=7.82 Hz, 1H), 7.97(t, J=1.53 Hz, 1H); 8.13 (dt, J=7.82, 1.34 Hz, 1H).
Reaction SMILES: [C:1](=[Fe:3])=[O:2].[O-2].[O-2].[O-2].[Fe+3].[Fe+3]>>[C-:1]#[O+:2].[C-:1]#[O+:2].[C-:1]#[O+:2].[C-:1]#[O+:2].[C-:1]#[O+:2].[Fe:3]
Reactant: O=C=[Fe]
Agent: [Fe+3]
Agent: [O-2]
Product: [C-]#[O+]
Product: [Fe]
Reaction time: 0.33 h

Procedure:
"C" grade carbonyl iron powder, 6-8 micron size from GAF was mixed with iron ore concentrate and the blend was then agglomerated by briquietting at 51,000 psi into briquettes 12.5 mm×12.5 mm diameter. The briquettes were indurated by heating from room temperature to 600° C. in 25 minutes, held by 600° C. for 20 minutes and then air quenched to room temperature. The compressive strength of the briquettes was then determined. Table I below sets forth the results obtained with different levels of iron carbonyl added, with three different types of iron ore concentrates.