Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[NH:19][NH2:20].C1C=CC=CC=1>O>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[NH:19][N:20]=[C:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)CC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(CC)=NNc1c(Cl)cc(Cl)cc1Cl

Procedure:
A reaction mixture consisting of 11 g. (0.085 mole) ethyl 2-oxobutyrate, 17 g. (0.077 mole) (2,4,6-trichlorophenyl)hydrazine, and 200 ml. benzene was heated at the reflux temperature with a Dean and Stark water trap attached to the reaction vessel. When all the water produced by the reaction had been removed, the benzene was removed by evaporation under reduced pressure. The oily residue that remained was dissolved in hot technical hexane, and this solution was allowed to cool. Crystals of the desired product separated and 15.2 g. were recovered. Recrystallization from methanol gave an analytical sample of ethyl 2-oxobutyrate 2-(2,4,6-trichlorophenyl)hydrazone having a melting point at 97° to 99° C.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]([CH2:18][CH3:19])[C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]([CH2:18][CH3:19])[C@H:8]([O:17][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:20][CH:21]=1
Reactant: CC[C@H](Oc1ccc(Br)cc1)[C@H](O)CCc1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Yield: 40 %

Procedure:
To a solution of (3R,4S)-4-(4-bromophenoxy)-1-pyridin-3-yl-hexan-3-ol (1.34 g, Example 87d)) in dry N,N-dimethylformamide (30 ml) was added tertbutyldimethylsilyl chloride (0.80 g) and imidazole (0.77 g) and the resulting solution heated at 50° C. for 20 hours. The solution was concentrated in vacuo. The residue was made basic by addition of saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate:isohexane (1:1) to give the sub-title compound as an oil (0.71 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([Cl:13])[N:3]=1.FC(F)(F)C1C(C(O)=O)=NC=CC=1.CCN=C=NCCCN(C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:50][C:51]1[C:56]([C:57](O)=[O:58])=[CH:55][CH:54]=[CH:53][N:52]=1>ClCCl.O.C(N(CC)CC)C>[Cl:50][C:51]1[N:52]=[CH:53][CH:54]=[CH:55][C:56]=1[C:57]([NH:12][CH2:11][C:8]1([C:7]2[C:2]([Cl:1])=[N:3][C:4]([Cl:13])=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)=[O:58]
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCC1(c2ccc(Cl)nc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)c1ncccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NCC1(c2ccc(Cl)nc2Cl)CC1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 14 h

Procedure:
0.45 ml of C-[1-(2,6-dichloro-pyridin-3-yl)-cyclopropyl]-methylamine was dissolved in 1.5 ml of dichloromethane under argon and 0.11 ml of triethylamine was added at ambient temperature. Ther reaction mixture was cooled at 0° C. and 383 mg of 3-(trifluoromethyl)pyridine-2-carboxylic acid, 145 mg of EDCI.HCl, 103 mg of HOBT hydrate and 59 mg of 2-chloropyridine-3-carboxylic acid were added sequentially. The reaction mixture was stirred at ambient temperature for 14 hours. Then water was added, the phases were separated and the aqueous phase was extracted with dichloromethane. The organic layers were combined, dried with anhydrous sodium sulphate, filtered and concentrated. Crude material was obtained as a yellow sticky solid, which was purified by trituration in diethyl ether to give 60 mg of the desired 2-Chloro-N-[1-(2,6-dichloro-pyridin-3-yl)-cyclopropylmethyl]nicotinamide as white solid. 1H-NMR (CDCl3): 8.45 ppm (m, 1H), 8.04 ppm (m, 1H), 7.68 ppm (d, 1H), 7.34 ppm (m, 1H), 6.53 ppm (m, 1H), 3.72 ppm (d, 2H), 1.19 ppm (m, 2H), 0.96 ppm (m, 2H).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9](C(=O)[C@H]3CCCN3S(C3C=CC(C)=CC=3)(=O)=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)(=O)C>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)N2CC(c3ccccc3)c3ccccc32)cc1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc(C2CNc3ccccc32)cc1

Procedure:
A 5.0 g portion of the 3-phenyl-1-(N-tosyl-D-prolyl)-indoline obtained above was suspended in a mixed solution of 40 ml acetic acid and 15 ml concentrated hydrochloric acid, and heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure and washed with toluene, and then the aqueous layer was made basic with an aqueous sodium hydroxide solution and extracted with diethyl ether. The extract was dried and concentrated to obtain 1.52 g of (+)-3-phenylindoline as yellow crystals.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc([N+](=O)[O-])ccc1F)C1CC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Cyclopropanecarbonyl chloride (5.4 mL, 60 mmol) was added dropwise over 5 min to a stirred solution of 2-fluoro-5-nitroaniline (1.56 g, 10.0 mmol) and solid NaHCO3 (7.65 g, 90 mmol) in DCM (50 mL) at room temperature under nitrogen. The mixture was stirred overnight then diluted with DCM (50 mL) and H2O (100 mL) and stirred for 30 min. The aqueous and organic layers were partitioned and the aqueous layer extracted with DCM (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent removed under vacuum to leave a crude residue. The residue was dry-loaded onto silica gel and purified by column chromatography on silica gel using EtOAc/heptane (1:9 to 4:6) as eluent to give the product (2.2 g, 98% yield) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][NH2:34].C(O)C>C(OCC)(=O)C>[CH3:33][NH:34][C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:28])[F:30])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Reactant: CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 90 °C
Yield: 98 %

Procedure:
A mixture of 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188, 40 mg, 0.08 mmol) and 8M methyl amine solution in ethanol (408 uL, 3.26 mmol) and was heated to 90° C. in a sealed tube for 48 h. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo to give a crude residue which was diluted with ethyl acetate and washed with water, sat. NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude residue which was purified by flash column chromatography using Amine-Silica to yield the desired product as a white solid (39 mg, 98%). MS (ESI): 485.2 (MH+).
Reaction SMILES: C(=O)C.[CH3:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:9]=[CH:8][C:7]=1[OH:27].C(O)(=O)/C=C\C(O)=O.[CH2:36]([N:39]([C:43]1[NH:44][CH:45]=[C:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=12)[CH2:40][CH2:41]C)[CH2:37]C>>[CH3:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:9]=[CH:8][C:7]=1[OH:27].[CH2:36]([N:39]([C:43]1[NH:44][CH:45]=[C:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=12)[CH2:40][CH3:41])[CH3:37]
Reactant: CCCN(CCC)c1[nH]cc2c1CCCC2
Agent: CC=O
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C(O)/C=C\C(=O)O
Product: CCN(CC)c1[nH]cc2c1CCCC2

Procedure:
Following the above procedure but substituting propionaldehyde for acetaldehyde, dl-5-di-n-propylamino-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole maleate was prepared, melting at 134°-136° C. after recrystallization from an isopropanol-ether solvent mixture.
Reaction SMILES: N1C=CC=CC=1.Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.Cl[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Ni](Cl)Cl.[Zn].C1(C)C=CC=CC=1>[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)#[N:19]
Reactant: Cc1ccc(Br)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Into a 1 l four necked flask, 500 ml of dry pyridine, 44.3 g (0.259 mol) of 4-bromotoluene, 35.6 g (0.259 mol) of 2-chlorobenzonitrile, 3.24 g (0.025 mol) of anhydrous nickel chloride, 13.1 g (0.05 mol) of triphenylphosphine and 67.6 g (1.034 mol) of zinc powder were charged under a nitrogen atmosphere and stirred at room temperature for 30 minutes. The temperature was raised to 80° C., and the mixture was reacted for 6 hours. Then, 400 ml of toluene was added thereto, and the solid was filtered off while it was still hot. The toluene layer was analyzed by gas chromatography. The results are shown in Table 1. Then, pyridine and toluene were recovered under reduced pressure. Then, 500 ml of toluene was added to the residue, and the solid was filtered off while it was still hot and washed with 100 ml of toluene. The warm toluene layer was washed with 300 ml of 5% hydrochloric acid, then with 300 ml of a 5% sodium hydrogencarbonate aqueous solution and further twice with 300 ml of warm water. The toluene layer was concentrated to obtain 54 g of a crude product. This product was distilled to obtain 28.4 g (yield: 57%, purity: 97.4%) of white crystals of 2-cyano-4'-methyl-1,1'-biphenyl.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH:16]=[O:17])([O-:12])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:16]=[O:17])([O-:12])=[O:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1ccc(OC(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
To a solution of benzoyl chloride (2.50 mL, 20.0 mmol) in methylene chloride (100 mL) cooled at 0° C. was added 3-nitro-4-hydroxybenzaldehyde (3.00 g, 19.0 mmol) and triethylamine (2.80 mL, 20.0 mmol). After 1 hour the mixture was washed with water and concentrated to an oil, in vacuo. The product was crystallized from ethyl acetate-hexane giving 1.70 g (33.0%); mp110.5-112° C. 1H NMR (CDCl3): 10.05 (s,1H,CHO), 8.59 (s,1H) 8.20 (m,3H), 7.62 (2,1H), 7.38 (m,3H). MS (DCl) 272 (MH+). C14H9NO5.
Reaction SMILES: Br[C:2]1[C:3]2[S:14][C:13]([CH3:15])=[CH:12][C:4]=2[NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].O.[CH3:17][N:18]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:2]1[C:3]2[S:14][C:13]([CH3:15])=[CH:12][C:4]=2[NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:18]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)c1[nH]c2cc(C)sc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(C)sc2c1C#N
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.96 g) in N-methylpyrrolidone (10 mL) were added zinc cyanide (1.17 g) and tetrakis(triphenylphosphine)palladium (0.38 g), and the mixture was stirred at 150° C. for 30 minutes using microwave reactor. To the reaction solution was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.64 g).
Reaction SMILES: BrC1C(F)=C2C([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=3)=CNC2=NC=1.N1CCC[C@@H](NC(=O)OC(C)(C)C)C1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN1CCCC1=O.C(Cl)Cl.C(OCC)(=O)C>[F:21][C:19]([F:20])([F:22])[C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH2:11])=[O:23])=[N:14][CH:15]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(C(F)(F)F)cn1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.3 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl) picolinamide (195 mg, 0.48 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (290 mg, 1.45 mmol) and DIEA (0.17 mL, 0.97 mmol) in N-methylpyrrolidone (“NMP”; 2 mL) were stirred at 148° C. (bath) for 18 hours and at 160° C. for 5 hours. Ethyl acetate (20 mL) was added, and the mixture was washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 45-85% CH3CN/water gradient; 30 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2, 3-1)]pyridin-3-yl)-5-(trifluoromethyl)picolinamide (24 mg, 8% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.77 (s, 1H), 8.15 (s, 1H), 8.11 (d, 1H), 7.95 (d, 1H), 7.82 (s, 1H), 3.74 (m, 1H), 3.59 (m, 1H), 3.48 (m, 1H), 3.32 (m, 1H), 2.88 (m, 1H), 2.22 (m, 1H), 2.03 (m, 1H), 1.79 (m, 1H), 1.53 (m, 1H); LCMS (APCI+) m/z 483 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C1C=CC=CC=1.C(O)=O.N>CCO.[Pd]>[C:25]1([CH2:24][CH2:23][CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C(=Cc1ccccc1)CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: N
Solvent: CCO
Solvent: O=CO
Product: c1ccc(CCCC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
Combine (S)-1,4-dibenzyl-2-(4-phenyl-but-3-enyl)-piperazine (2.12 g, 5.3 mmol), 10% Pd/C (300 mg, 0.027 mmol) and ammonia formate (1.67 g, 26.5 mmol) in EtOH (50 mL), heat to reflux for 3 hours 30 minutes, and cool to room temperature. Remove the catalyst via filtration, and concentrate the filtrate to a residue. Purification by flash chromatography on silica gel using 2N NH3 in MeOH and dichloromethane (5%–15%) to give the title compound (780 mg, yield 67%): mass spectrum (Electrospray): m/z=219.2 (M+1); 1H NMR (CDCl3): δ7.30–7.15 (m, 5H), 2.96–2.55 (m, 8H), 2.37–2.30 (m, 1H), 1.64–1.60 (m, 2H), 1.39–1.29 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][C:35](=[O:36])[CH3:34])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)CC(N(CCCN1CCN(C)CC1)C(=O)Nc1ccc(F)c(Cl)c1)CC2
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (from Preparative Example 27, 0.033 g, 0.070 mmol) in CH2Cl2 (0.2 mL) at 0° C. were added Ac2O (0.0066 mL, 0.070 mmol) and DIEA (0.036 mL, 0.21 mmol). The mixture was stirred from 0° C. to room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 0.030 g (83%) of N-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2yl)-acetam ide as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.60 (dd, 1H, J=6.9, 2.4 Hz), 7.38 (d, 1H, J=2.1 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1 Hz), 7.15 (t, 1H, J=9.0 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.31 (m, 1H), 3.60 (m, 8H), 3.47 (m, 2H), 3.24 (t, 2H, J=7.2 Hz), 2.97 (m, 7H), 2.14-2.00 (m, 7H). MS-ESI: 516.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:16][O:17][C:18](=[O:33])[C@H:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH2:20]>>[CH3:16][O:17][C:18](=[O:33])[C@H:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[NH:20][C:12](=[O:14])[CH:10]([CH3:11])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above) and Nε-BOC-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a oil. The reaction was monitored by tlc (Rf=0.23 in 45% ethyl acetate/hexanes).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:28])(=O)[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][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O>[C:5]([Cl:3])(=[O:28])[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][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 45 °C
Reaction time: 1.17 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 7.88 ml (108 mmol) of thionyl chloride, and a water condenser, is placed 20.44 g (60 mmol) of docosanoic acid. Addition of the thionyl chloride is completed with heating to about 45° C. over the course of about 30 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 70 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, docosanoyl chloride. This acyl chloride, 21.60 g (60 mmol), is put into a dry separatory funnel and combined with 100 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[N:13]1[C:18]2[CH:19]=[CH:20][O:21][C:17]=2[C:16](=[O:22])[C:15]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:14]1>[Pd].C(O)C.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[N:13]1[C:18]2[CH2:19][CH2:20][O:21][C:17]=2[C:16](=[O:22])[C:15]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:14]1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2F)c2ccoc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2F)c2c1OCC2
Temperature: 50 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A suspension of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)furo[3,2-c]pyridazin-4(1H)-one (100 mg) and 10% palladium on carbon (100 mg) in ethanol/THF (3/1, 40 mL) was stirred at 50° C. for 12 hr under a hydrogen atmosphere. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) and crystallized from hexane/ethyl acetate to give the title compound (74 mg).
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[C:8]([Cl:23])[CH:7]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[Cl:23][C:8]1[CH:7]=[C:6]([CH:4]([NH2:1])[CH3:5])[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: CC(N=[N+]=[N-])c1cc(Cl)c2cccnc2c1-c1ccccc1F
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-5-chloro-8-(2-fluorophenyl)quinoline (0.037 g, 0.11 mmol) in tetrahydrofuran (0.3 mL) and water (0.0813 mL) was added 1.00 M trimethylphosphine in tetrahydrofuran (0.135 mL, 0.135 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue showed two peaks by LCMS with the same desired mass and was used directly in the next step (28 mg, 82%). LCMS calculated for C17H15ClFN2(M+H)+: m/z=301.1; found: 301.0.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](O)=O>>[Br:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(F)c(Br)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-bromo-4-fluorobenzoic acid: MS (ESI): m/z 465 (M+1).