Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([F:22])[CH:13]=2)[CH2:9][C:10]#[N:11])=[N:6][CH:7]=1.[NH2:30][OH:31]>CCO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[C:14]([F:22])[CH:13]=2)([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:9]/[C:10](/[NH2:11])=[N:30]/[OH:31])=[N:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)N[C@](CC#N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: NO
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N[C@](C/C(N)=N/O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 70 °C

Procedure:
(S)-N-((R)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl) phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.030 g, 0.067 mmol) was dissolved in EtOH (1 mL) in a 2 dram vial. NH2OH (1 mL, 50% solution in water) was added and the sealed screw capped vial was heated to 70° C. for 3 h. The cooled solution was diluted with DCM (10 mL) and transferred to a separation funnel. The organic layer was separated and the aqueous portion was washed further with DCM (5 mL). The combined organic portions were dried, decanted and concentrated yielding (R,Z)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-N′-hydroxy-3-((S)-2-methylpropan-2-ylsulfinamido)propanamidine as a tan oil (0.032 mg, quantitative yield). LCMS: 1.50 min [M+1] 481.1 (2 min gradient, MeOH/H2O 0.1% TFA). The crude oil was dissolved in dry DCM (1 mL), cooled to 0° C. and TEA (25pL) was added followed by acetic anhydride (11 μL). The reaction mixture was allowed to reach room temperature with stirring over 18 h. The solution was diluted with DCM (10 mL), transferred to a separation funnel, washed with sat. NaCl (10 mL), dried, decanted and concentrated yielding a white solid. LCMS: 1.87 min [M+1] 523.1 (2 min gradient, MeOH/H2O 0.1% TFA). The intermediate N-((R,Z)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(hydroxyimino)-3-((S)-2-methylpropan-2-ylsulfinamido)propyl)acetamide was redissolved in anhydrous THF (2 mL) and anhydrous Cs2CO3 was added (0.063 g). The solution was heated to 105° C. for 3 h whereupon the solvent evaporated leaving a pale brown solid which was dissolved in MeOH (1 mL) and purified by prep HPLC (YMC ODSA30×100 mm, 0-100% over 10 min, MeOH/H2O/0.1% TFA) yielding (S)-N-((R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide as a colorless oil (0.015 g, 44% yield over 3 steps). LCMS: 1.96 min [M+1] 505.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.80 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 96%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([I:1])=[C:10]([CH3:11])[CH:9]=3)[CH:5]=[N:6]2)=[CH:15][CH:14]=1
Reactant: Cc1cc2[nH]ncc2cc1I
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1I
Yield: 51.1 %

Procedure:
5-Iodo-6-methylindazole (1.3 g, 5.0 mmol), p-fluorobenzeneboronic acid (1.4 g, 10 mmol), anhydrous copper(II) acetate (1.4 g, 7.5 mmol) and pyridine (0.80 mL, 10 mmol) were stirred in dichloromethane (30 mL) overnight. Additional portions of p-fluorobenzeneboronic acid (0.47 g, 3.4 mmol), anhydrous copper(II) acetate (0.45 g, 2.5 mmol) and pyridine (0.27 mL, 3.4 mmol) were added. The mixture was filtered through celite after stirring for an additional night. The filtrate was concentrated and purified by column chromatography (SiO2, toluene) to give the subtitle compound (0.90 g, 51%) as a light orange powder.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1B(O)O.O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: Cc1ccncc1B(O)O
Reactant: Nc1ccc(I)c(OCC(F)(F)F)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccncc1-c1ccc(N)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
A pressure vessel charged with a mixture of tetrakis(triphenylphosphine) palladium(0) (200 mg, 0.173 mmol), Intermediate 29C (550 mg, 1.735 mmol), potassium phosphate tribasic (1.103 g, 5.2 mmol) and Intermediate 1A (356 mg, 2.6 mmol) was stirred at room temperature for 5 min under a nitrogen atmosphere, followed by addition of 1,4-dioxane (6.7 mL) and water (2.6 mL). The reaction mixture was degassed for 2 min, heated at 85° C. overnight and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative HPLC using a PHENOMENEX® Luna 30×100 mm S5 column eluting with aqueous MeOH containing 0.1% TFA, gradient 20 to 70%, gradient time 12 min) The collected fractions were concentrated and then applied on a 1 g MCX cartridge. The cartridge was washed with methanol, and then eluted with 2M solution of ammonia in methanol (30 mL). The evaporation of the collected eluent under reduced pressure provided Intermediate 29 (117 mg, 23.9% yield) as a beige powder. MS (ES): m/z=283.14 [M+H]+. Intermediate 29 was used in the synthesis of Examples 183 and 184.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([CH3:7])[N:6]=1.C[Mg+].[Br-].[CH3:13]COCC>C1COCC1>[Br:1][C:2]1[S:3][C:4]([CH:8]([OH:9])[CH3:13])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOCC
Reactant: Cc1nc(Br)sc1C=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of 2-bromo-4-methylthiazole-5-carbaldehyde of preparation 98 (1.8 g, 8.8 mmol) in dry THF (50 mL) was added dropwise MeMgBr in Et2O (3M, 2.9 mL, 8.8 mmol) at −40° C. under N2. After the addition, the mixture was stirred at room temperature for 1 hr. TLC (petroleum ether/EtOAc=5:1) showed most of the starting material was consumed. To the reaction mixture was added saturated NH4Cl (60 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate and concentrated in vacuum. The residue was purified by a Biotage silica gel cartridge (EA/PE 48%, Rf=0.5) to give the title compound as a yellow oil (1.7 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42]([NH:44][CH2:45][C:46](O)=[O:47])=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH:22][C:46](=[O:47])[CH2:45][NH:44][C:42]([O:41][CH2:40][CH:38]1[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:39]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:43])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NNC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide in 10 ml of dimethylformamide was treated with 1.24 g of N-(9-fluorenylmethyloxycarbonyl)-glycine and 0.80 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrogen chloride, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate followed by evaporation and trituration with diethyl ether gave 1.54 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-[N-(9-fluorenylmethyloxycarbonyl)-glycinyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=O)=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]#[N:21])=[CH:23][CH:24]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1)C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C#N)Oc1ccc(Oc2cnc3cc(Cl)ccc3c2)cc1

Procedure:
2-[4-(7-Chloroquinolin-3-yloxy)phenoxy]propionamide (see Example 23) (1.2 g) was added slowly with stirring to phosphorus oxychloride (10 ml) at 20° C. The mixture was heated briefly to the boiling point then poured on to water and neutralized carefully with aqueous sodium bicarbonate solution. Extraction with ethyl acetate gave, after drying and evaporation, the crude product as a pale yellow oil. Purification by chromatography on silica gel gave 2-[4-(7-chloroquinolin-3-yloxy)phenoxy]propionitrile, characterised by its proton magnetic resonance spectrum (Table 3).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.O.O.O.C([O-])(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>[Zn].O>[N:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=[C:11]([C:12]#[N:13])[CH:2]=1
Reactant: N#Cc1cc2c(nc1Cl)CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cnc2c(c1)CCCC2
Temperature: 60 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A mixture of commercially available 2-chloro-5,6,7,8-tetrahydroquinoline-3-carbonitrile [CAS no 65242-27-5] (1 g, 5.19 mmol), zinc dust (activated) (602 mg, 9.2 mmol) and sodium acetate trihydrate (694 mg, 479 μl, 5.1 mmol) in acetic acid (5.19 g, 4.95 ml, 86.4 mmol) was stirred at 60° C. for 2 hours. Water (2.5 ml) was added and the mixture stirred at 60° C. for another 5 hours. After cooling to 23° C., the mixture was basified with aqueous 1 M NaOH solution, filtered through Celite®, the filtrate extracted with THF, the organic layers dried over Na2SO4 and the solvent evaporated leaving a yellow liquid. The crude material was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the 5,6,7,8-tetrahydroquinoline-3-carbonitrile as a white solid (433 mg, 53% yield). MS (ISP): m/z=159.1 [(M+H)+].
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[CH2:15]([C:19]1[CH:24]=[CH:23][C:22](Cl)=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C>CCCCC>[CH2:15]([C:19]1[CH:24]=[CH:23][C:22]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCCCc1ccc(Cl)cc1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 24 h
Yield: 87 %

Procedure:
Using a THF solution of 4-fluorophenylmagnesium bromide (1.46 mL, 1.03 M, 1.5 mmol), 4-butylchlorobenzene (168.7 mg, 1.0 mmol), FeF3.3H2O (6.68 mg, 0.04 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (51.2 mg, 0.12 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours in the same manner as in Example 2. After performing silica gel column chromatography (pentane), the above compound was obtained as a white solid (0.199 g, yield=87%, purity=>97% (GC analysis)).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:14][C:13](=[O:15])[NH:12][NH:11][C:10](=[O:16])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:14][C:13](=[O:15])[N:11]([N:12]=[CH:30][C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=3)[C:10](=[O:16])[CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(C=O)n1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)CC(=O)NN1
Solvent: c1ccccc1
Product: Cc1cccc(C=NN2C(=O)CN(C(c3ccccc3)c3ccccc3)CC2=O)n1

Procedure:
Reacting 5-diphenylmethyl-3,7-diketo-1,2-dihydro-1,2,5-triazepine with 6-methylpyridine-2-carboxaldehyde in the presence of benzene at reflux temperature and a reaction time of 4 hours to afford 1-diphenylmethyl-4-(6-methyl-2-pyridylmethyleneamino)-3,5-diketopiperazine;
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17](Cl)(=[O:19])=[O:18])[C:5](=[O:21])[CH2:4]1)[CH3:2].[NH2:22][C:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:19])=[O:18])[C:5](=[O:21])[CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2cc(F)ccc2S(=O)(=O)Cl)C(=O)C1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C(=O)C1
Reaction time: 17 h
Yield: 60.3 %

Procedure:
A solution of 2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 174, 0.368 g) and methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.219 g) in pyridine (3 mL) and DCM (3 mL) was left to stand at room temperature for 17 hours. The mixture was evaporated in vacuo and the residue was dissolved in water and DCM and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 50-100% to give a gum which was triturated with ether and filtered to give methyl (1aRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.312 g) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[N:8]=[C:9]2[CH:14]=[C:13]([C:15]3[NH:16][N:17]=[C:18]([CH3:20])[N:19]=3)[CH:12]=[CH:11][N:10]2[CH:21]=1)=[O:5])[CH3:2].F[C:23](F)(F)C(N)=O.CN(C(C=C)=O)C>C(O)C>[CH3:23][N:17]1[C:18]([CH3:20])=[N:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]3[CH:21]=[C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[N:8]=[C:9]3[CH:14]=2)=[N:16]1
Reactant: CCNC(=O)Nc1cn2ccc(-c3nc(C)n[nH]3)cc2n1
Reactant: NC(=O)C(F)(F)F
Agent: C=CC(=O)N(C)C
Solvent: CCO
Product: CCNC(=O)Nc1cn2ccc(-c3nc(C)n(C)n3)cc2n1
Temperature: 125 °C

Procedure:
A mixture of nitrile 4 (0.500 g, 1.7 mmol), 0.50 g trifluoroacetamide and 0.25 g dimethylaminoacrolein in 5 mL ethanol was heated to 125° C. for 2 h by microwave irradiation (CEM, 300 watt). The reaction was then evaporated in vacuo and the residue was purified by silica gel chromatography (gradient elution: 0-20% ethyl acetate/dichloromethane) to give pyrimidine 5.
Reaction SMILES: [ClH:1].Cl.CN1CCN(C2CCCCC2(C(C2C=CC(OC3C=CC=CC=3)=CC=2)C)O)CC1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](=O)[CH:40]([C:54]2([OH:60])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH:40]([C:54]2([OH:60])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]2)[C:41]2[CH:42]=[CH:43][C:44]([O:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:45][CH:46]=2)[CH2:35][CH2:34]1
Reactant: CN1CCN(C(=O)C(c2ccc(Oc3ccccc3)cc2)C2(O)CCCCC2)CC1
Agent: CC(c1ccc(Oc2ccccc2)cc1)C1(O)CCCCC1N1CCN(C)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(Oc3ccccc3)cc2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 1, step 2 1-[2-(4-methylpiperazin-1-yl)-1-(4-phenoxyphenyl)ethylcyclohexanol dihydrochloride was prepared from 1-[2-(4-methylpiperazin-1-yl)-1-(4-phenoxyphenyl)-2-oxoethy]cyclohexanol. MS(ESI) m/z 395 ([M+H]+). Anal Calcd for C25H34N2O22HCl 0.9H2O: C, 62.08; H, 7.88: N, 5.79. Found: C, 62.26; H, 8.11; N, 5.70.
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:32][NH:33][C:34](=O)[CH2:35][N:36]([CH3:38])[CH3:37].C[O-].[Na+]>CO>[CH3:37][N:36]([CH2:35][C:34]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:32][N:33]=1)[CH3:38]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)NCCC4CCCCN4)c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)NCCC5CCCCN5)c4)c3c2)n1
Temperature: 105 °C

Procedure:
To a suspension of (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-(2-piperidylethyl)carboxamide.3HCl (412 mg, 0.78 mmol) and N-amino-2-(dimethylamino)acetamide (275 mg, 2.35 mmol) in anhydrous methanol (5.0 mL) in a screw-top pressure tube was added sodium methoxide (626 mL of a 25% w/w in methanol). The tube was sealed, heated in a 105° C. oil bath for 48 h and then concentrated to dryness. Purification of the residue by preparatory TLC using 40% ethyl acetate in methanol gave the desired product after precipitation from methanol/ethyl acetate with ethyl ether (12 mg, 3% yield) 1H NMR (DMSO-d6) δ 13.7 (br s, 1H), 8.7 (br s, 2H), 8.4 (s, 1H), 8.1–8.0 (m, 2H), 7.85 (br d, 1H), 7.7–7.6 (m, 2H), 3.6 (s, 2H), 3.5–3.3 (m, 2H), 2.5–2.2 (m, 6H), 2.2 (s, 6H), 1.6–1.3 (m, 6H); ES-MS (m/z) 473 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9](O)=[O:10])[CH3:4])[CH3:2].C1CN([P+](O[N:33]2[N:41]=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NN>C1COCC1.CC(=O)OCC>[CH2:1]([N:3]([CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9]([NH:33][NH2:41])=[O:10])[CH3:4])[CH3:2]
Reactant: CCN(C)Cc1cc(C)cc(C(=O)O)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)Cc1cc(C)cc(C(=O)NN)c1
Yield: 278.1 %

Procedure:
To a solution of 3-[(ethyl-methyl-amino)-methyl]-5-methyl-benzoic acid (215 mg, 1.04 mmol) in THF (5 mL), PyBOP (541 mg, 1.04 mmol) followed by DIPEA (269 mg, 2.08 mmol) is added. The mixture is stirred until all solid material has dissolved and is then transferred into a 1M solution of hydrazine in THF (8.3 mL; 266 mg, 8.33 mmol). The resulting suspension is stirred at rt for 1 h before it is diluted with EA and washed with water. The org. extract is concentrated and dried to give the crude title compound as a white solid (640 mg). LC-MS: tR=0.35 min, [M+1]+=222.05.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:35]=[C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[CH:31][CH:30]=3)[N:34]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2)CC1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)s1

Procedure:
By condensation between 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-[4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine nitrate. Light yellow solid. 1H-NMR (CDCl3) δ: 2.37 (s, 3H, CH3), 2.61 (m, 4H, CH2), 2.69 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.20 (m, 4H, CH2), 6.88 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.94 (s, 1H, NH), 6.96 (d, 2H, J=8.8 Hz, Ph-H), 7.51 (d, 2H, J=8.8 Hz, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[O:23])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[C:5]2=[CH:4][CH:3]=1.[NH:36]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C([O-])([O-])=O.[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([N:36]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[CH:3][CH:4]=2)[CH:8]=[C:9]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:23]
Reactant: O=C(OCc1cccc(C(F)(F)F)c1)c1cc2nc(Cl)ccc2n1Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(C(=O)OCc3cccc(C(F)(F)F)c3)n2Cc2cccc(C(F)(F)F)c2)n1
Temperature: 110 °C

Procedure:
A degassed mixture of 3-(trifluoromethyl)benzyl 5-chloro-1-[3-(trifluoromethyl)benzyl]-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (3.2 g, 6.2 mmol, prepared as in Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (1.6 g, 6.9 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.58 g, 0.74 mmol, Aldrich) and Cs2CO3 (2.2 g, 6.9 mmol) in toluene (71 mL) was heated at 110° C. for 2 hours. Upon cooling, water was added, and the layers were separated. The aqueous layer was further extracted with three portions of EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-50% EtOAc in hexanes was used to purify the product. Yield: (0.28 g, 6% over the two steps). LCMS (M+H)+: 709.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[CH3:21][Mg]Br>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]([OH:19])[CH3:21])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(C)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
Treat a solution of 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (400 mg, 1.44 mmol) in THF (10 mL) at 0° C. with methylmagnesium bromide (3.0 M in diethyl ether, 0.58 mL, 1.73 mmol). Stir at 0° C. for 1 h and quench with saturated aqueous ammonium chloride solution. Extract with ethyl acetate (100 mL), dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 40:60 to 70:30 ethyl acetate:hexanes) to give the title compound (250 mg, 59%).