Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)#[N:25]>C1C=CC=CC=1>[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[CH:28][CH:27]=1)#[N:25]
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: N#Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: N#Cc1ccc(CN2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Yield: 6.7 %

Procedure:
To a mixture of 1.2 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 50 ml of benzene was added 688 mg of 4-cyanobenzyl chloride and the mixture was stirred under reflux for 3 hours. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography to give 105 mg of 5-[4-(4-cyanobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 96.4 %

Procedure:
A solution of [3-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (6 g, 16.6 mmol) in TFA (30 ml) was stirred for 1.5 h. The solution was concentrated using benzene to azeotrope, diluted with EtOAc, washed (1.0 N NaOH), dried (Na2SO4), filtered, and concentrated to afford the title compound (4.2 g, 97%) as a crude solid. Mass Spectrum (ES+) (m/z) 263.1 [M+1].
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:15])[C:5]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.Cl>CO>[Cl:3][C:4]1[C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[C:6]([OH:15])[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=C1C(Cl)=C(Oc2ccc([N+](=O)[O-])cc2)C(=O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)c(O)c3ccccc3c2O)cc1
Yield: 81.3 %

Procedure:
1 g of sodium borohydride was added, whilst ice-cooling, to a solution of 11 g of 3-chloro-2-(4-nitrophenoxy)-1,4-naphthoquinone (prepared as described in Preparation 17) in 150 ml of methanol, and the mixture was stirred, whilst ice-cooling, for 30 minutes. The mixture was then poured into a mixture of ice and 15 ml of 2N aqueous hydrochloric acid to give a precipitate, which was collected by filtration, washed with water and dried under reduced pressure in the presence of phosphorus pentoxide, to give 9 g of 3-chloro-1,4-dihydroxy-2-(4-nitrophenoxy)naphthalene.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])c(O)ccn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of 3-nitro-pyridine-2,4-diol (5.0 g, 32.3 mmol) in DMF (50 mL) at 0° C. was added NaH (2.6 g, 64.0 mmol 60% in mineral oil). After stirring at 0° C. for 15 min, benzyl bromide (6.03 g, 35.2 mmol) was added and the reaction was stirred at 55° C. for 17 h. The mixture was cooled to room temperature, poured into ice water, and filtered to remove insoluble material. The filtrate was acidified with 1 N HCl, extracted with CH2Cl2, dried with MgSO4, and concentrated. The product was washed with EtOH to give 1-benzyl-4-hydroxy-3-nitro-1H-pyridine-2-one (3.30 g, 42% yield). 1H-NMR (DMSO): δ 7.90 (d, 1H, J=7.6 Hz), 7.27–7.38 (m, 5H), 6.12 (d, 1H, J=7.6 Hz), 5.08 (s, 2H). MS: calculated for C12H10N2O4+H 247.1; found: 247.2.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[CH2:10]([NH2:12])[CH3:11]>O>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:12][CH2:10][CH3:11])=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: CCN
Solvent: O
Product: CCNC(=O)c1csc(Br)c1
Yield: 70 %

Procedure:
5-Bromo-N-ethyl-3-thiophenecarboxamide was prepared from 5-bromo-3-thiophenecarboxylic acid (2.1 g, 10 mmol) and 70% ethylamine in water according to the methods of steps a and b of Example 248 in 70% yield.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[N:38]([CH:39]6[CH2:44][CH2:43][O:42][CH2:41][CH2:40]6)[N:37]=[CH:36][C:19]=5[C:20](=[O:35])[N:21](CC5C=CC(OC)=CC=5OC)[C:22]=4[CH:23]=3)=[C:9]([CH3:45])[CH:8]=2)[CH2:3][CH2:2]1.C1COCC1.[H][H]>C(O)C.[C].[Pd]>[CH3:13][C:11]1[CH:12]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=[C:9]([CH3:45])[C:10]=1[C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:38]([CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:37]=[CH:36][C:19]=3[C:20](=[O:35])[NH:21][C:22]=2[CH:23]=1
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)cc(C5=CCOCC5)cc4C)cc32)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C2CCOCC2)cc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCOCC3)c12
Temperature: 60 °C
Reaction time: 14 h
Yield: 44.5 %

Procedure:
10% palladium carbon (50% wet, 15 mg) was added to a solution of 7-[4-(3,6-dihydro-2H-pyran-4-yl)-2,6-dimethylphenyl]-5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (44 mg) in ethanol (2 mL)-THF (2 mL). The reaction mixture was stirred at mom temperature for four hours and 35 minutes in a hydrogen atmosphere. The catalyst was removed from the reaction mixture by filtration, and the filtrate was then concentrated under reduced pressure. TFA (1.5 mL) was added to the resulting residue. The reaction mixture was stirred at 60° C. for 14 hours. The reaction mixture was returned to room temperature, and the reaction mixture was then concentrated under reduced pressure. Chloroform and a saturated aqueous sodium bicarbonate solution were added to the residue, and the organic layer was separated. The aqueous layer was re-extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform 100%, then ethyl acetate 100%). The target fraction was collected and concentrated. Ethyl acetate and MTBE were added to the resulting residue. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (14.8 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]=3)[N:9]=[CH:10][C:3]=12.[CH:18]1([O:22][CH2:23][C@H:24]([OH:35])[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=2)=[O:26])[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([O:22][CH2:23][C@H:24]([O:35][C:2]2[C:3]3[CH:10]=[N:9][N:8]([C:11]4[C:16]([CH3:17])=[N:15][CH:14]=[CH:13][N:12]=4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][N:29]=2)=[O:26])[CH2:19][CH2:20][CH2:21]1
Reactant: Cc1nccnc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC2CCC2)nc1
Product: Cc1ccc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2nccnc2C)nc1

Procedure:
Prepared using an analogous procedure to that described for Example 106 using 4-Chloro-1-(3-methylpyrazin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate I4) with (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate U1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCCCCCCCCCCC=O
Product: CCCCCCCCCCCCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12
Yield: 80 %

Procedure:
The compound was prepared as described in example 2/4, reacting the indole with tetradecane aldehyde. Yield 80%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][C:35]1[C:40]2[O:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=3[C:39]=2[C:38]([CH:51](OC(=O)C2C=CC=CC=2)[CH2:52][C:53]2[C:58]([Cl:59])=[CH:57][N:56]=[CH:55][C:54]=2[Cl:60])=[CH:37][CH:36]=1>O1CCCC1.CN(C1C=CN=CC=1)C>[Cl:59][C:58]1[CH:57]=[N:56][CH:55]=[C:54]([Cl:60])[C:53]=1[CH2:52][CH:51]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([F:17])[F:18])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:7]=1)[C:38]1[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[C:40]([O:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)[CH:39]=1
Reactant: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (268 mg, 1.04 mmoles) is dissolved in dry tetrahydrofuran (30 mL) and EDC (237 mg, 1.24 mmoles), HOBT (190 mg, 1.24 mmoles), TEA (0.172 mL, 1.24 mmoles), DMAP (30 mg) are added to the solution. The mixture is stirred at room temperature for 40 minutes, then Benzoic acid 1-(4-methoxy-8-nitro-dibenzofuran-1-yl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester is added and the reaction mixture is stirred at 70° C. for 32 hours. The solvents are then evaporated and the crude mixture is purified by chromatography on SiO2 (hexane:AcOEt from 10:1 to 7:3) to afford 300 mg of the pure title compound.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10]CC)=O)[N:7]=1>C1COCC1>[Br:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:10])[NH2:1])[N:7]=1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
THF (10 ml) and 20 ml of 30% aqueous ammonia were added to 1.51 g of 2-bromo-4-ethoxycarbonylthiazole, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated to give 1.31 g of 2-bromo-4-carbamoylthiazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[C:18]([O-])([O-])=O.[K+].[K+].IC.[H-].[Na+]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][C:6]2([CH3:18])[C:14]([O:16][CH3:17])=[O:15])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)C1(C)CCOc2cc(F)c(C#N)cc21
Temperature: 60 °C
Yield: 33.4 %

Procedure:
Methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (from Example 3, Step E; 28 mg, 0.12 mmol) was diluted with acetonitrile (1 mL) followed by the addition of K2CO3 (49 mg, 0.36 mmol) and iodomethane (0.023 mL, 0.36 mmol). The reaction was then heated at 60° C. for 1 hour, then cooled and NaH (8.6 mg, 0.36 mmol) was added. The reaction was deemed complete by LC. The reaction was loaded onto a Biotage 25 samplet and purified running a gradient 5% ethyl acetate/hexane to 100% ethyl acetate/hexane to yield the title compound (10 mg, 34% yield).
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O.O1CCCC1>[Cl:25][C:16]1[C:15]([F:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a mixture of N,N,N′,N′-tetramethylethylenediamine (8.40 mL) and tetrahydrofuran (75 mL) was added sec-butyllithium (1.0 mol/L cyclohexane solution, 55.7 mL) under an argon atmosphere at −78° C., and the mixture was stirred for 30 min. A mixture of 3,4-difluorobenzoic acid (4.00 g) and tetrahydrofuran (25 mL) was added dropwise to the reaction mixture at the same temperature over 30 min. After the reaction mixture was stirred for 30 min, a mixture of hexachloroethane (24.0 g) and tetrahydrofuran (40 mL) was added dropwise to the reaction mixture at the same temperature over 30 min. After stirring for 30 min while raising the temperature to room temperature, the reaction mixture was poured into water. The aqueous layer was washed with diisopropyl ether, acidified with 6 mol/L hydrochloric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was washed with diethyl ether to give the title product as a solid (yield: 2.95 g).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>[Ni].C(O)(=O)C>[C:15]([NH:1][C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:17])[CH3:16]
Reactant: O=[N+]([O-])c1cccc2c1CCCCC2
Reactant: CC(=O)OC(C)=O
Agent: [Ni]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1CCCCC2

Procedure:
8.7 gm of 1-nitro-6,7,8,9-tetrahydro-5H-benzocycloheptene [J. Am. Chem. Soc., 5820 (9169)] was dissolved into a mixed solvent of 150 ml of acetic anhydride and 50 ml of acetic acid. The mixture was catalytically hydrogenated with the addition of 10 ml of raney nickel. After removing the catalyst by filtration, the reaction mixture was concentrated, the residue was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The product was concentrated to produce 6.17.gm of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(NS(=O)(=O)c2ccccc2)c1
Reaction time: 16 h
Yield: 86 %

Procedure:
To 6.17 g (44.7 mmol) of 3-nitroaniline and 8.41 mL (48.2 mmol) of N,N-diisopropylethylamine in 150 mL of anhydrous diethyl ether was added 5.14 mL (40.2 mmol) of benzenesulfonyl chloride. The mixture was heated to reflux under nitrogen with stirring for 16 h, cooled and the resulting two-phase mixture scratched to crystallize the insoluble oil. After decanting the ether layer, the derived solid was dissolved in 300 mL of dichloromethane and the solution washed with 2 N HCl (3×200 mL), saturated NaHCO3 (200 mL), brine (200 mL), dried (Na2SO4) and concentrated to give 9.62 g (86%) of the title compound as a light tan solid. 1H-NMR (300 MHz, CDCl3) δ 7.96 (m, 2 H), 7.86 (m, 2 H), 7.41-7.63 (m, 5 1), and 7.30 (br s, 1 H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C12H10N2O4S: 301.0 (M+Na). Found: 301.1.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12]>>[CH3:12][CH:11]([CH3:13])[CH2:10][NH:14][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)CN
Product: CC(C)CNc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and isobutylamine.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH2:12]([O:19][C@@H:20]1[CH2:23][C@H:22]([NH2:24])[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CC#N>[CH2:12]([O:19][C@@H:20]1[CH2:23][C@H:22]([NH:24][C:2]2[C:3]([NH2:9])=[CH:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: N[C@H]1C[C@@H](OCc2ccccc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ccc(F)cc1N[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.92 mL, 8.36 mmol) in CH3CN (60 mL) were added cis-3-benzyloxycyclobutylamine (1.48 g, 8.36 mmol) and DIPEA (1.46 mL, 8.36 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo to afford the title compound as yellow oil (3.2 g, quantitative). To a solution of the product thus obtained (1.6 g, 5.03 mmol) in MeOH (20 mL) was added Iron powder (1.13 g, 20.12 mmol), NH4Cl (1.56 g, 30.18 mmol) and H2O (8 mL) and the reaction mixture stirred at 90° C. for 2 h under a nitrogen atmosphere. The resulting dark green mixture was filtered through a pad of Celite® and the filtrate concentrated in vacuo giving a dark brown solid. The crude material was partitioned between EtOAc (50 mL) and water (30 mL). Aqueous layer extracted with EtOAc (2×30 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to afford the title compound as a dark brown gum (1.13 g, 78%). 1H NMR (CDCl3, 300 MHz): δ 7.25-7.30 (5H, m), 6.6 (1H, dd, J=14.0, 2.8 Hz), 6.35-6.26 (1H, m), 6.26-6.18 (1H, m), 4.43 (2H, s), 3.95-3.83 (1H, m), 3.50-3.37 (1H, m), 2.90-2.78 (2H, m), 1.92-1.79 (2H, m). NMR: 328138. LCMS (Method B): RT 2.87 min [M+H]+ 287.
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].CC(C)([O-])C.[Na+]>CS(C)=O>[CH:2]1([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[CH2:13]3)[C:9]2=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Fc1ccccc1Br
Reactant: O=C1N(C2CCCCC2)CCC12CCCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1N(C2CCCCC2)CCC12CCCN(c1ccccc1F)C2

Procedure:
A mixture of 2-cyclohexyl-2,7-diazaspiro[4.5]decan-1-one hydrochloride (0.025 g, 0.000092 mol), 1-bromo-2-fluorobenzene (0.032 g, 0.00018 mol), and sodium tert-butoxide (0.026 g, 0.00027 mol) in DMSO (0.5 mL) was microwave irradiated at 180° C. for 5 min. After cooling the reaction mixture to ambient temperature the crude product was purified by prep.-HPLC. LC-MS: 331.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[C@H:3]([NH:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:5].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[NH:49][C:48]([C@@H:50]3[CH2:54][CH2:53][CH2:52][N:51]3[C:55](=[O:66])[C@@H:56]([NH:60][C:61]3[S:62][CH:63]=[CH:64][N:65]=3)[CH:57]([CH3:59])[CH3:58])=[N:47][CH:46]=2)=[CH:41][CH:40]=1.C([O-])(O)=O.[Na+]>COCCOC.O.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:19]1([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[N:49]=[C:48]([C@@H:50]4[CH2:54][CH2:53][CH2:52][N:51]4[C:55](=[O:66])[C@@H:56]([NH:60][C:61]4[S:62][CH:63]=[CH:64][N:65]=4)[CH:57]([CH3:59])[CH3:58])[NH:47][CH:46]=3)=[CH:41][CH:40]=2)[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C@@H:7]3[CH2:8][CH2:9][CH2:10][N:6]3[C:4](=[O:5])[C@@H:3]([NH:31][C:32]3[S:33][CH:34]=[CH:35][N:36]=3)[CH:2]([CH3:37])[CH3:1])[NH:15][CH:14]=2)=[CH:17][CH:18]=1
Reactant: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)[C@H](Nc1nccs1)C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](Nc5nccs5)C(C)C)n4)cc3)cc2)c[nH]1
Temperature: 80 °C
Yield: 1.7 %

Procedure:
A mixture of (S)-3-methyl-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-(thiazol-2-ylamino)butan-1-one (275 mg, 0.527 mmol), (S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-2-(thiazol-2-ylamino)butan-1-one (250 mg, 0.527 mmol), NaHCO3 (133 mg, 1.582 mmol) and Pd(Ph3P)4 (60.9 mg, 0.053 mmol) in DME (3 mL) and Water (1 mL) was degassed by passing a stream of N2 through the mixture. The vessel was sealed and the reaction was heated at 80° C. overnight. The reaction mixture was diluted with H2O and extracted with EtOAc containing ca. 5% MeOH (×3). The combined org layers were concentrated, dissolved in MeOH and loaded onto an MCX cartridge. The cartridge was washed with MeOH and then NH3 in MeOH (2M). The appropriate fractions were concentrated in vacuo and the residue was purified by prep HPLC (CH3CN—H2O—NH4OAc). The material was purified by column chromatography (biotage) eluting with 0 to 20% MeOH in EtOAc. Further purification by prep HPLC (CH3CN—H2O—NH4OAc) followed by lyophilization afforded the title compound as a colorless solid (6.9 mg, 2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]([CH3:21])[CH2:19][OH:20])[CH2:11][CH2:10]2.[H-].[Na+].[CH3:27]I.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]([CH3:21])[CH2:19][O:20][CH3:27])[CH2:11][CH2:10]2
Reactant: CI
Reactant: CC(CO)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Yield: 45.4 %

Procedure:
To a mixture of 6-(3-Fluoro-benzyloxy)-2-(2-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinolin-1-one (0.020 g, 0.061 mmol) and sodium hydride (55%, 2.2 mg, 0.067 mmol) in N,N′-dimethylformamide (0.2 mL), methyl iodide (0.009 mL, 0.152 mmol) was added. Water was added and the reaction was extracted with ethyl acetate. After drying of the organic layer with MgSO4, filtration and evaporation, the residue was purified by chromatography (SiO2, hexane/ethyl acetate 9:1 v:v) to give the title compound as a white solid (0.0095 g, 43%). MS: m/e=344.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]([OH:16])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].S(Cl)([Cl:19])=O>ClC(Cl)Cl>[Cl:19][C:14](=[O:16])[CH2:13][CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCC(CCC(=O)O)CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a stirred mixture of 200 parts of 1-(ethoxycarbonyl)-4-piperidinepropanoic acid and 750 parts of trichloromethane were added 320 parts of thionyl chloride. The whole was stirred for 18 hours at room temperature. The reaction mixture was evaporated with methylbenzene. The residue was distilled, yielding 102.6 parts (47%) of ethyl 4-(3-chloro-3-oxopropyl)-1-piperidinecarboxylate; bp. 165-170 at 399 Pa (int. 45).