Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])[NH:4][C:3]=1[C:17]([O:19]C)=O.[OH-].[K+].[Li+].[OH-].[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C=O)C.CO>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:8])[NH:4][C:3]=1[C:17]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:19]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: COC(=O)c1[nH]c(C(=O)NCCN2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(=O)NCCN4CCCC4)cc3Cl)c2F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
Methyl 3-chloro-5-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)-1H-pyrrole-2-carboxylate (0.080 g, 0.268 mmol) was dissolved in THF and MeOH (2 mL of each). Potassium hydroxide (2 mL, 1 N) was added to the solution and heated to 60° C. After stirring overnight no reaction was observed. LiOH (2 mL, 1 N) was added and the reaction stirred at 60° C. overnight. The reaction mixture was evaporated to a solid and partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, filtered and evaporated to a solid. The solid was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.031 mL, 0.241 mmol) in DMF (2 mL). HATU (0.092 g, 0.241 mmol) was added to the mixture and the reaction stirred for 2 hours. The reaction mixture was partitioned between EtOAc and water and the layers separated. The organic layer was washed with 15% Na2CO3, dried over MgSO4 and evaporated. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.008 g, 9%) as a solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 7.81-7.95 (m, 2H), 7.64 (t, 1H), 7.45-7.52 (m, 1H), 7.41-7.45 (m, 1H), 7.39 (d, 2H), 6.77 (s, 1H), 4.72 (d, 2H), 3.51 (q, 2H), 2.72-2.78 (m, 2H), 2.59-2.69 (m, 4H), 1.71-1.80 (m, 4H). LCMS: m/z 577.9 (M+1).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccncc1
Reactant: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(-c3ccncc3)cccc2[nH]1

Procedure:
This compound is synthesized from compound 194 (see example 156) and pyridin-4-yl-boronic acid analogously to the method described in Example 156.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](O)[CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([O:9][C:16]1[CH:15]=[CH:14][C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)SCC(CC(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
2-[(Acetylthio)methyl]-4-methylpentanoic acid (5.1 g, see Example 1D) in 100 ml of ethyl acetate is cooled to 5° C. and treated with p-nitrophenol (3.5 g) followed by 5.1 g of dicyclohexylcarbodiimide, in portions. After stirring for four hours at 5° C., the dicyclohexylurea is filtered and the ethyl acetate is removed in vacuo. The resulting solid is washed with hexane to give the title compound, 8.0 g, as an oil.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][CH2:8][O:9][CH2:10][CH2:11][CH:12]1[CH2:14][O:13]1.[Cl:15][C:16]1[NH:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[N:20]=1>C(O)C>[Cl:15][C:16]1[N:17]([CH2:14][CH:12]([OH:13])[CH2:11][CH2:10][O:9][CH2:8][O:7][CH3:6])[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[N:20]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: COCOCCC1CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COCOCCC(O)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 78.2 %

Procedure:
Sodium acetate (3.51 g, 42.82 mmol) and 2-(2-methoxymethoxyethyl)oxirane (10.3 g, 77.86 mmol) were added to 2-chloro-4-nitro-1H-imidazole (5.74 g, 38.93 mmol) in ethanol (60 ml), and the resulting mixture was stirred under reflux for 13.5 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and then crystallized from methylene chloride-diisopropyl ether to afford 2-chloro-1-(2-hydroxy-4-methoxymethoxybutyl)-4-nitroimidazole (8.51 g, yield 78%) as a light yellow powder.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:13].[F-].[Cs+].[CH3:16]B(O)O>COCCOC.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>[F:13][C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[C:7]([F:8])[C:2]=1[CH3:16]
Reactant: CB(O)O
Reactant: NS(=O)(=O)c1cc(F)c(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1c(F)cc(S(N)(=O)=O)cc1F
Temperature: 120 °C
Yield: 93.6 %

Procedure:
A mixture of 4-bromo-3,5-difluorobenzenesulfonamide (1.09 g, 4 mmol), CsF (1.34 g, 3 eq), methylboronic acid (494 mg, 2 equiv) and Pd(PPh3)4 (140 mg, 0.3 eq) in 1,2-dimethoxyethane (16 mL) was heated to 120° C. under microwave irradiation for 4 h. After cooling, solids were removed by filtration and washed with EtOAc. The filtrate was concentrated and then purified by column chromatography (silica, EtOAc-Hex, 1:4 to 4:1) to give 3,5-difluoro-4-methylbenzenesulfonamide (776 mg). 1H NMR (400 MHz, CD3OD) δ 7.65 (d, 2H), 2.46 (s, 3H); GC-MS (ES) m/z 207 (M).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4](F)[N:3]=1.CO.[CH3:12][NH:13][CH3:14]>[Cl-].[Na+].O>[Br:1][C:2]1[N:3]=[C:4]([N:13]([CH3:14])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC
Reactant: Fc1ccc(F)c(Br)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(F)c(Br)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-Bromo-3,6-difluoro-pyridine (300 mg, 1.5 mmol) was dissolved in a 2M solution of dimethylamine in MeOH (7.8 mL, 15.56 mmol) and stirred at 80° C. in a sealed tube for 16 hours. The mixture was treated with brine and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield (6-bromo-5-fluoro-pyridin-2-yl)-dimethyl-amine as a dark oil that was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:4]=1[C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:6].[Cl-].[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=1)=[O:6]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)c1ccc(C#N)cc1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: N#Cc1ccc(C(=O)c2cc(C(F)(F)F)ccc2O)cc1
Yield: 58.9 %

Procedure:
Following the procedure described in Preparation IVb and starting from 13.5 g (0.049 mol) of 4-(2-methoxy-5-trifluoromethylbenzoyl)benzonitrile and 31 g (0.27 mol) of pyridinium chloride, an amount of 8.4 g of the expected product (yield: 65%) is obtained after purification by flash chromatography using a hexane/ethyl acetate mixture (5/1 v/v) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[CH:15](C(OCC)=O)[C:14](=[O:21])[C:13](=[O:22])[N:12]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.[Na+].[Cl-]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)[C:13](=[O:22])[C:14](=[O:21])[CH2:15]1
Reactant: CCOC(=O)C1C(=O)C(=O)N(Cc2ccc(OC(F)(F)F)cc2)C1c1c(OC)cccc1OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(OC)c1C1CC(=O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(2,6-dimethoxyphenyl)-4,5-dioxo-1-(4-(trifluoromethoxy)-benzyl)pyrrolidine-3-carboxylate (11.400 g; 23.68 mmol) and NaCl (2.767 g; 47.36 mmol) in DMSO (111 ml) and water (37 ml) was refluxed, under nitrogen, for 3 h. After cooling to rt, water (150 ml) was added, and the mixture was extracted with AcOEt (3×150 ml). The mixed organic layers were washed with brine (50 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Addition of Et2O and trituration allowed the precipitation of the product. Subsequent filtration, and drying of the obtained solid under HV afforded 5-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)pyrrolidine-2,3-dione as a pink solid. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 410.15 g/mol.
Reaction SMILES: [NH2:1][C:2]1[S:14][C:13]2[CH2:12][C@@H:11]3[C@H:6]([CH2:7][C@@H:8]([C:16]([N:18]([CH2:27][CH2:28][CH3:29])[C:19]([NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[O:20])=[O:17])[CH2:9][N:10]3[CH3:15])[CH2:5][C:4]=2[C:3]=1[C:30]#[N:31].[C:32](O)(=[O:34])[CH3:33]>>[C:30]([C:3]1[C:4]2[CH2:5][C@@H:6]3[C@@H:11]([CH2:12][C:13]=2[S:14][C:2]=1[NH:1][C:32](=[O:34])[CH3:33])[N:10]([CH3:15])[CH2:9][C@H:8]([C:16]([N:18]([C:19](=[O:20])[NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:27][CH2:28][CH3:29])=[O:17])[CH2:7]3)#[N:31]
Reactant: CC(=O)O
Reactant: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(N)c3C#N)C[C@H]2N(C)C1
Product: CCCN(C(=O)NCCN(C)C)C(=O)[C@@H]1C[C@@H]2Cc3c(sc(NC(C)=O)c3C#N)C[C@H]2N(C)C1
Temperature: 135 °C

Procedure:
To 1-{[(4aR*,6R*,8aR*)-2-amino-3-cyano-8-methyl-4H,4aH,5H,6H,7H,8H, 8aH,9H-thieno[3,2-g]quinolin-6-yl]carbonyl}-3-[2-(dimethylamino)ethyl]-1-propylurea (example 1-15) (100 mg) was added acetic acid (2 mL) and the mixture was heated at 135° C. and refluxed for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and a saturated aqueous solution of sodium bicarbonate. After the separated organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-5% methanol/ethyl acetate, gradient elution) to give the title compound (26 mg). The structure was illustrated in Table 11.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[N:16]=[CH:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19](Br)=[CH:20][C:11]=3[C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[N:16]=[CH:15][C:14]2[NH:13][C:12]3[N:17]=[CH:18][C:19]([C:33]4[CH:32]=[CH:31][C:30]([CH2:29][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:35][CH:34]=4)=[CH:20][C:11]=3[C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Yield: 30.1 %

Procedure:
A degassed mixture of tert-butyl-{3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-carbamate (229 mg, 0.631 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (207 mg, 0.946 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (51.5 mg, 6.31 μmol, 10.0 mol %) in 1,4-dioxane (12.4 mL) and 2M aqueous cesium carbonate (1.32 mL) was heated under reflux for 5 h. The mixture was allowed to cool to room temperature, diluted with DCM and water, and filtered to remove the precipitate. The filtrate layers were separated and the aqueous phase was extracted with DCM, and the combined organic phase concentrated in vacuo. The resultant residue was dissolved in 20% methanol in DCM and absorbed onto silica gel for purification by flash chromatography (silica, 11 g column, Biotage, 1-20% methanol in DCM) to afford the title compound as a beige solid (86.9 mg, 30%). 1H NMR (DMSO-D6, 400 MHz): 11.96 (s, 1H), 9.55 (s, 1H), 8.99 (d, J=1.9 Hz, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.57 (d, J=7.8 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.35 (m, 4H), 1.55-1.45 (m, 4H), 1.52 (s, 9H), 1.39 (m, 2H). LCMS (Method D): RT=9.11 min, M+H+=458.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][C@H:3]1[OH:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=O)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]>ClCCCl.CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:21])[CH2:4][C@H:3]2[OH:22])[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]
Reactant: O=Cc1cnc(CO)c(Cl)c1
Reactant: N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Solvent: ClCCCl
Solvent: CO
Product: O=c1ccc2ncc(F)cc2n1CCN1CC[C@H](NCc2cnc(CO)c(Cl)c2)[C@H](O)C1

Procedure:
A mixture of 1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 31 as a free base: 60 mg, 0.196 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 33.6 mg, 0.196 mmol) in DCE (5 ml) and Methanol (0.5 ml) was stirred at rt for 5 h. LCMS showed desired compound Rt 2.16 [M+H]+ 460 and not starting material, sodium triacetoxy borohydride (125 mg, 0.588 mmol) was added. The mixture was stirred under nitrogen at room temperature overnight. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (62.3 mg, 0.294 mmol) was added. The mixture was stirred at room temperature for 3 h. Full conversion to the amine was observed by LCMS desired compound Rt 2.02 [M+H]+ 462. It was quenched with saturated NaHCO3, extracted with dichloromethane, dried (MgSO4), filtered, and concentrated affording 78.5 mg of crude material. Purification by manual flash chromatography using a 5 g Merck silica gel cartridge, and DCM/MeOH 9/1 as eluent afforded 1-{2-[(3R,4S)-4-({[5-chloro-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (35 mg, 0.072 mmol, 36.8% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][CH:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: [H][H]
Reactant: Cc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc(CC2c3ccccc3CCc3ccccc32)c1
Reaction time: 17 h

Procedure:
Add 5-(3-methyl-benzylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.18 g, 0.61 mmol), to a mixture of 10% Pd/C (0.045 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (2.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrated the filtrate to give the title product. MS (m/e): 298 (M+). HPLC (ISO80-10M) t=1.00 (98%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNc1ccccc1N
Reaction time: 5 h

Procedure:
A mixture of tert-butyl 2-(2-nitrophenylamino)ethylcarbamate (400 mg) and palladium (10% on activated carbon, 20 mg) in ethanol (50 mL) was stirred under hydrogen (1 atm) for 5 h. The mixture was filtered through Celite and washed with methanol. The solvent was removed and the product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)=[O:28])=[C:22]([C:39]([F:42])([F:41])[F:40])[CH:21]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][C:22]=3[C:39]([F:42])([F:40])[F:41])=[CH:31][CH:32]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(Br)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(Br)cc3)cc2)c(C(F)(F)F)c1
Yield: 91 %

Procedure:
Prepared from INT-60 and INT-18. To a stirring solution of tert-butyl 2-((4-bromobenzyl)amino)acetate INT-60 (2.7 g, 8.99 mmol), 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (3.18 g, 8.99 mmol) and TEA (2.507 mL, 17.99 mmol) in DMF was added PyBOP (4.91 g, 9.44 mmol) at room temperature. After 2 h the reaction mixture was diluted with EA (200 mL) and washed with 1 M HCl (100 mL), NaHCO3 (200 mL) and brine (200 mL). The organics were dried over MgSO4, pre-absorbed onto silica gel and purified by chromatography (EA/hexanes) to afford 5.2 g (91%) of tert-butyl 2-(N-(4-bromobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-81 as a white foamy solid. LCMS-ESI (m/z) calculated for C30H30BrF3N2O5: 635; found 579/581 [M-tBu+H]+, tR=2.83 min (Method 10).
Reaction SMILES: Br.Cl[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([NH2:18])[S:16][CH:17]=2)=[CH:9][CH:8]=1.[C:19]([C:21]1[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:23][CH:24]=[CH:25][CH:26]=1)#[N:20].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[C:19]([C:21]1[C:22]([N:27]2[CH2:28][CH2:29][N:30]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]4[N:14]=[C:15]([NH2:18])[S:16][CH:17]=4)=[CH:9][CH:8]=3)[CH2:31][CH2:32]2)=[N:23][CH:24]=[CH:25][CH:26]=1)#[N:20]
Reactant: Nc1nc(-c2ccc(CCCCCl)cc2)cs1
Reactant: N#Cc1cccnc1N1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1N1CCN(CCCCc2ccc(-c3csc(N)n3)cc2)CC1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 2.37 g (6.81 mmol) 4-(4-(4-chlorobutyl)phenyl)-2-aminothiazole hydrobromide, 1.28 g (6.81 mmol) 3-cyano-2-piperazinylpyridine, 2.38 ml (13.6 mmol) diisopropylethylamine, 1.44 g (13.6 mmol) sodium carbonate, 2 mg sodium iodide, and 40 ml methylisobutylketone. The reaction was refluxed 4 days, cooled, and evaporated. The residue was triturated with ethyl acetate and the resulting solid chromatographed on silica gel with methylene chloride/ethyl acetate. The product fractions were dissolved in ethyl acetate, precipitated with ethyl acetate saturated with HCl, and the precipitate filtered and dried to give a solid, 1.84 g (55%), m.p. 155-162° C. NMR (DMSO-d6) 1.6-1.8 (m, 4H), 2.67 (t, 2H), 3.1-4.4 (m, 10H), 7.34 (s, 1H), 7.1-8.5 (m, 7H), 11.3 (bs, 2H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[O:17][C:18]1[N:19]=[C:20]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[C:21]([C:26]([NH2:28])=[O:27])=[N:22][C:23]=1[CH2:24][CH3:25].O.NN.O1CCCC1>C(O)C>[NH2:3][C@H:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[O:17][C:18]1[N:19]=[C:20]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:37][CH2:38][CH:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:40][CH2:41]3)=[CH:34][CH:35]=2)[C:21]([C:26]([NH2:28])=[O:27])=[N:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCC[C@@H]1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
A mixture of 5-{[(1R,2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopentyl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (322 mg), hydrazine monohydrate (99 mg), tetrahydrofuran (6.44 mL), and ethanol (6.44 mL) was stirred at 80° C. overnight. The insoluble matter was separated by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; chloroform:methanol=99:1-97:3) to obtain 5-{[(1R,2S)-2-aminocyclopentyl]oxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (117 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]([N+:25]([O-:27])=[O:26])=[CH:11][CH:10]=1>CO.C(Cl)Cl>[CH3:1][O:16][C:15](=[O:17])[C:14]1[C:9]([F:8])=[CH:10][CH:11]=[C:12]([N+:25]([O-:27])=[O:26])[C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
Trimethylsilyldiazomethane (2M in hexane, 7.24 mL, 14.5 mmol) was added dropwise to a solution of 6-fluoro-3-nitro-2-phenylaminobenzoic acid (2.0 g, 7.24 mmol) in MeOH (5 mL) and DCM (40 mL) at RT. The solution was stirred at RT for 45 min then the volatiles were removed under reduced pressure to afford the title compound (2.1 g, quantitative). 1H NMR (CDCl3, 400 MHz): δ 9.67 (1H, br s), 8.32 (1H, dd, J=9.47, 5.75 Hz), 7.36-7.30 (2H, m), 7.23-7.07 (3H, m), 6.64 (1H, dd, J=9.47, 8.33 Hz), 3.27 (3H, s)