Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11](/[CH:13]=[CH:14]/[CH:15]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]1[CH2:23][C:21](=[O:22])[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:18]1=[S:19].[Cl-].[NH4+].N>C(O)C>[NH:1]([C:8]1[S:9][CH:10]=[C:11](/[CH:13]=[CH:14]/[CH:15]=[C:23]2[S:17][C:18](=[S:19])[N:20]([CH2:24][C:25]([OH:27])=[O:26])[C:21]2=[O:22])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C/C=C/c1csc(Nc2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=C/C=C/c2csc(Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 0.4 g of (2E)-3-(2-anilinothiazol-4-yl)acrylaldehyde, 0.29 g of rhodanine-3-acetic acid, 0.22 g of ammonium chloride, 0.2 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was a reddish-brown powder having the following physical properties.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([C:10]([F:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]([CH3:20])[C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[Cl:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>O1CCCC1.CN(C)C1C=CN=CC=1.O>[Cl:27][CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:5][C:4]2[C:6]([CH3:20])=[CH:7][C:8]([C:10]([F:19])([C:11]([F:14])([F:13])[F:12])[C:15]([F:16])([F:17])[F:18])=[CH:9][C:3]=2[CH2:1][CH3:2])=[O:34])=[CH:31][CH:30]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CCl)cc1
Yield: 82.5 %

Procedure:
2-Ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylaniline (0.50 g) and pyridine (0.20 g) were dissolved in tetrahydrofuran (10 ml). To the solution, 4-(chloromethyl)benzoyl chloride (0.33 g) and 4-dimethylaminopyridine (0.02 g) were added and the mixture was refluxed under heating for 3 hours. After adjusting to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid and dried over Mg(SO4). After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was washed with hexane to obtain 4-(chloro methyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro-propan-2-yl)-6-methylphenyl]benzamide (0.62 g, yield 74%).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:34][CH:35](O)[CH3:36]>>[CH:35]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:33])=[CH:17][C:18]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)([CH3:36])[CH3:34]
Reactant: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reactant: CC(C)O
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2OC(C)C)c1

Procedure:
The compound of step 1 of example 254 was reacted with 2-propanol in analogy to step 1 of example 1 and the obtained ester hydrolyzed in analogy to example 2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.Cl.[CH:14]12[O:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:15][CH:14]3[O:21][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1c(Cl)nc(Cl)nc1N1CC2CCC(C1)O2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,4,6-Trichloro-5-nitropyrimidine (45, 1.43 g, 6.26 mmoles) was dissolved in dichloromethane and cooled to 0° C. A solution of 8-oxa-3-azabicyclo[3.2.1]octane (2, 0.934 g, 6.26 mmoles) in dichloromethane and triethylamine (0.873 mL, 6.26 mmoles) was slowly added over 1 hour. The solution was allowed to stir at 0° C. for 2 hours, then warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was filtered, the filtrate was concentrated, dissolved in ethyl acetate, washed with 1N hydrochloric acid, saturated sodium bicarbonate, brine, dried, and concentrated to provide 3-(2,6-dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (46). Yield: 1.53 g (80%). HRMS; [M+H]+ Obs'd=305.0200, [M+H]+ Calc'd=305.0203.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].O>C(#N)C.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>[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:4][N:3]=2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cccc(-c2ccnc(Cl)c2)c1
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: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccnc(-c3ccc(C(C)C)cc3)c2)c1
Yield: 70 %

Procedure:
Part C. A solution of ethyl 3-(2-chloro-pyridin-4-yl)-benzoate (81 mg, 0.31 mmol), sodium carbonate (99 mg, 0.93 mmol) and 4-isopropylbenzeneboronic acid (60 mg) in acetonitrile-water (2 mL/0.5 mL) is treated with a catalytic quantity of tetrakis(triphenylphosphine)palladium, and heated to reflux for 24 h. The mixture is poured into water (60 mL), and this mixture is extracted with diethyl ether (3×60 mL). The extracts are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to afford ethyl 3-[2-(4-isopropyl-phenyl)-pyridin-4-yl]-benzoate (75 mg, 76%)
Reaction SMILES: FC1C=C([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)C=CC=1.CN(C(ON1N=N[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]1=2)=[N+](C)C)C.[B-](F)(F)(F)[F:34].CCN(C(C)C)C(C)C.BrC1C=C(C(N2CCNCC2CC)=O)OC=1Br>CN(C=O)C>[F:34][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:10]1([CH:13]=[O:15])[N:11]=[CH:12][NH:8][NH:9]1
Reactant: O=C(O)c1ncn(-c2cccc(F)c2)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: F[B-](F)(F)F
Agent: CCC1CNCCN1C(=O)c1cc(Br)c(Br)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=CC1(c2ccccc2F)N=CNN1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
50 mg (0.24 mmol) 1-(3-fluoro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid was stirred with 85 mg (0.27 mmol) TBTU and 0.10 mL (0.57 mmol) DIPEA in 1.5 mL DMF at RT. After 10 min, 89 mg (0.24 mmol) (4,5-dibromo-furan-2-yl)-(2-ethyl-piperazin-1-yl)-methanone was added and the mixture was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nc3c([N+](=O)[O-])cccc3o2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc3c(N)cccc3o2)CC1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 4-((4-nitrobenzo[d]oxazol-2-yl)methyl)piperazine-1-carboxylate (5.97 g, 16.6 mmol, 1.0 equiv) in MeOH (49 mL) was added Pd/C (10% Pd, wet, 2.99 g). The resulting suspension was fixed with a hydrogen balloon and sparged with hydrogen while stirring was maintained. After 1 h, the mixture was filtered through a pad of celite and concentrated in vacuo to provide the title compound as an off-white solid (5.0 g, 91%).
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO[C:16]1[C:20](OC)=[N:19][S:18](=[O:23])[N:17]=1.[NH3:24]>>[NH2:24][C:16]1[C:20]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]#[C:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:19][S:18](=[O:23])[N:17]=1
Reactant: N
Reactant: COC1=NS(=O)N=C1OC
Reactant: NCCCCC#CCN1CCCC1
Product: NC1=NS(=O)N=C1NCCCCC#CCN1CCCC1

Procedure:
In a manner similar to Example 1, reaction of 7-pyrrolidinohept-5-ynylamine and 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide followed by treatment with ammonia gives the title compound.
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].FC(F)(F)C(O[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O>N1C=CC=CC=1>[OH:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:9]
Reactant: O=C(O)c1ccnnc1O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccnnc1O
Yield: 84.7 %

Procedure:
3-Hydroxypyridazine-4-carboxylic acid (1.40 g) was dissolved in pyridine (20 ml) at 40° C, and p-nitrophenyl trifluoroacetate (2.82 g) was dropwise added thereto. The resultant mixture was stirred at 40° to 50° C for 1 hour and concentrated under reduced pressure to dryness. The residue was washed with chloroform and acetone in order and dried to give the objective compound (2.21 g). M.P. 233° C (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][NH:22][CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][N:22]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1c(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)cnn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Nc2ncc(Cl)c(NC3CC4CN(C(=O)CC#N)CC4C3)n2)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5-chloro-N2-(1,5-dimethyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (58.4 mg, 0.17 mmol) and 2-cyanoacetic acid (23.1 mg, 0.27 mmol) in mixture of DCM (8 mL) and DMF (2 mL) were added HATU (109.8 mg, 0.29 mmol) and Et3N (45.7 mg, 0.45 mmol). The reaction mixture was stirred at rt for 1 h, quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/50) to give the title compound as a beige solid (46.5 mg, 66.7%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl>O1CCOCC1>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of 1-Boc-4-(6-chloro-naphthalen-2-ylsulfonyl)piperazine (2.8 g, 6.8 mmol) in dioxane (50 mL) was added 4 M HCl in dioxane (5 mL, 40 mmol). After stirring overnight at room temperature, the solvent was evaporated in vacuo, and the residue was dissolved in water. The aqueous phase was and made basic with 5 N NaOH and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, then dried over sodium sulfate and evaporated to 2.1 g (100%) solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][NH:15][C:14]1=[O:23].C(N(CC)CC)C.CN(C)C=O>O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:20]2[CH2:19][CH2:18][C:17]3([O:13][C:14](=[O:23])[NH:15][CH2:16]3)[CH2:22][CH2:21]2)=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C1NCC2(CCNCC2)O1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1NCC2(CCN(CCc3c[nH]c4ccccc34)CC2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
A mixture of 3.94 g of 3-(2-bromoethyl)indole, 2.74 g of 1-oxa-3,8-diazaspiro[4.5]decan-2-one, 2 g of triethylamine and 10 ml N,N-dimethylformamide is stirred at 50° for 16 hours. The mixture is cooled to room temperature and 150 ml of water is added with stirring The aqueous layer is decanted from the residue which adheres to the walls of the flask. The residue is washed with 100 ml water following by 100 ml diethyl ether. The residue is dissolved in a minimum amount of 10% (v/v) methanol-dichloromethane and the resulting solution is filtered through 25 g silica gel with 150 ml of 10% (v/v) methanol-dichloromethane. Evaporation of the filtrate followed by crystallization with diethyl ether affords 2.35 g of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 183°-186° (d).
Reaction SMILES: [CH:1]1[CH:20]=[CH:19][C:17](=[O:18])/[C:3](=[CH:4]/[NH:5][CH2:6][CH2:7][NH:8]/[CH:9]=[C:10]2/[CH:11]=[CH:12][CH:13]=[CH:14][C:15]/2=[O:16])/[CH:2]=1.[Zn:21](CC)CC>C1COCC1>[CH:12]1[CH:13]=[CH:14][C:15](=[O:16])/[C:10](=[CH:9]/[NH:8][CH2:7][CH2:6][NH:5]/[CH:4]=[C:3]2/[CH:2]=[CH:1][CH:20]=[CH:19][C:17]/2=[O:18])/[CH:11]=1.[Zn:21]
Reactant: CC[Zn]CC
Agent: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Solvent: C1CCOC1
Product: [Zn]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
THF was added to a mixture of Salen and Et2Zn via a syringe under argon. The reaction mixture was stirred at 25° C. for 24 hours. The crude product was isolated from the concentrated reaction mixture by removal of the solvent under reduced pressure. A pure product Salen-Zn was obtained after recrystallization using THF and water.
Reaction SMILES: [F:1]C(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][C:10]=1F.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C([Si](C)(C)[O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([NH2:79])=[C:75]([O:80][CH3:81])[CH:74]=1)(C)(C)C>ClCCl>[OH:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([NH:79][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[C:14]([F:1])[C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:75]([O:80][CH3:81])[CH:74]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCO)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3c2ccc(Cl)c3F)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 43.7 %

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 174 (0.2 g, 0.3 mmol) in dichloromethane (3 mL) was added diisopropylethylamine (0.2 g, 1.7 mmol), diphenylphosphinic chloride (Aldrich) (0.16 g, 0.67 mmol) respectively. The mixture was stirred at room temperature for 8 min, then 40[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-methoxy-phenylamine prepared in Example 132 (0.15 g, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was dissolved into tetrahydrofuran (3 mL), and an aqueous solution (1N) of HCl (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (0-50% of EtOAc in CH2Cl2) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-amide as a yellow solid (85 mg, 39%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:31]=[C:32]=[O:33])[CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)Cl.CO>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:32]([NH:31][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:33])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CCCCCN=C=O
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCNC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
A solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 4 mL of acetonitrile was stirred at 20° C. 156 μL (4 molar equivalents) of pentyl isocyanate in 3 mL acetonitrile were added. The mixture was magnetically stirred at 20° C. during 18 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95:5 ratio) to provide 37 mg (yield: 28%) of the desired product (formula below) as an orange powder
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][S:14]([C:17]2[C:18]3[C:19]4[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[C:20]=4[CH:27]=[CH:28][CH:29]=3)(=[O:16])=[O:15])(F)[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[NH:30]1C2C3C(=CC=CC=3[C:31]1=O)C=CC=2.ClS(O)(=O)=[O:45]>O>[C:31]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:13][S:14]([C:17]2[C:18]3[C:19]4[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[C:20]=4[CH:27]=[CH:28][CH:29]=3)(=[O:16])=[O:15])([OH:45])[CH3:11])=[CH:6][CH:5]=1)#[N:30]
Reactant: O=S(=O)(O)Cl
Reactant: CC(F)(NS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2cccc3cccc1c23
Solvent: O
Product: CC(O)(NS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2)c1ccc(C#N)cc1
Temperature: 60 °C

Procedure:
MATERIALS AND METHODS: All chemicals and reagents were used as received from the supplier. TLC's were run on EMD Silica Gel 60 F254 coated plates. Melting points were determined using a Fisher-Johns melting point apparatus and are uncorrected. 1H-NMR spectra were run on a Bruker Advance WB 300 MHz instrument, using TMS as an internal standard. 1-Hydroxy-1-(4-cyanophenyl)bromoethane (1). Sodium borohydride reduction of 4-cyano-α-bromoacetophenone produced hydroxy compound (1). 6-Chlorosulfonylbenz[cd]indol-2(1H)-one (2). Benz[cd]indol-2(1H)-one (2.523 g; 14.9 mmoles) was added slowly to 5.1 ml of chlorosulfonic acid while keeping the temperature below 15° C. The reaction mixture was heated to 60° C. and held there until no more HCL gas evolved. Then, the reaction mixture was poured into 125 ml of cold water. The resulting solid suspension was extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with water, saturated sodium bicarbonate, saturated brine, then dried with sodium sulfate. The solvent was removed and the residue was recrystallized from chloroform/ethyl acetate. The yield of the sulfonamide compound was 1.620 g (41%). A Beilstein test confirmed the presence of the chlorine atom. Melting point was 194-197° C. (dec) 1H-NMR (d6DMSO) δ 6.86 (d, 1H, Ar), 7.79 (m, 2H, Ar), 7.98 (d, 1H, Ar), 8.72 (d, 1H, Ar), 10.83 (s, 1H, NH). 6-{N-[1-(4-cyanophenyl)-1-hydroxyethyl]sulfamoyl}benz[cd]indol-2-(1H)-one (3). 1-Hydroxy-1-(4-cyanophenyl)bromoethane (1), 4-chlorosulfonylbenz [cd]indol-2(1H)-one (4), and triethylamine were dissolved in anhydrous dimethylformamide with stirring. The reaction was heated at 100° C. for 20 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate washed with 0.5 N HCl, water, followed by saturated brine. The ethyl acetate layer was dried with sodium sulfate, the solvent was removed and the residue recrystallized to give compound (3). 6-{N-[1-(4-carboxyphenyl)-1-hydroxyethyl]sulfamoyl}benz[cd]indol-2(1H)-one (4). Hydrolysis of 6-{N-[1-(4-cyanophenyl)-1-hydroxyethyl]sulfamoyl}benz[cd]indol-2-(1H)-one (3) gave the carboxylic derivative (4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[C:7]([N+:11]([O-])=O)[CH:8]=[CH:9][CH:10]=1)[OH:6]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5](=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[OH:6]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1O

Procedure:
Methyl-3-nitrosalicylat (4.93 grams, 25 mmol) dissolved in 50 mL of methanol was placed in a Parr bottle together with 200 mg of 10% Pd/C and hydrogenated at room temperature at 45 psi for 2 hours. The reaction was then filtered through celite, concentrated to dryness and the product dried in vacuo. Yield 4.17 gram (99% light green needles, M+168, single spot on TLC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3OCCO[C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.ClC1N=C(Cl)C(F)=CN=1.NC1C=C(C=CC=1)[CH2:33][OH:34]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:33][OH:34])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cccc(CO)c1
Agent: Fc1cnc(Cl)nc1Cl
Product: OCc1cccc(Nc2nc(Cl)ncc2F)c1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-aminobenzylalcohol were reacted to yield 2-chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.45 (bs, 1H), 7.96 (d, 1H, J=2.9 Hz), 7.65 (d, 1H, J=8.2 Hz), 7.34 (s, 1H), 7.31 (t, 1H, J=8.2 Hz), 7.07 (d, 1H, J=8.2), 4.52 (s, 2H)); 19F NMR (CDCl3): −44394 (s, 1F); LCMS: ret. time: 20.29 min.; purity: 100%; MS (m/e): 254 (MH+).