Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:12]2[CH2:13][C:14]([O:16]CC)=[CH:15][C:11]=2[N:10]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[N:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:16]=[C:14]1[CH2:13][C:12]2[C:8]([C:6]([OH:7])=[O:5])=[N:9][N:10]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C:11]=2[CH2:15]1
Reactant: CCOC1=Cc2c(c(C(=O)OC(C)(C)C)nn2S(=O)(=O)c2ccc(C)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)O)c3c2CC(=O)C3)cc1

Procedure:
To a solution of the intermediate from step B above, (414 mg, 1.02 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL). After stirring the reaction at room temperature for 1.5 hours it was concentrated in vacuo and azeotroped with toluene (2×). This material was used in the next step without any further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:16]([CH3:18])[CH3:17].[CH:19](N1CCCCC1)=[O:20].Cl>CCCCCC.O1CCCC1>[CH:16]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH:13]([CH3:15])[CH3:14])[C:7]=1[CH:19]=[O:20])([CH3:18])[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1Br
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
6.8 ml of a 1.6M solution of butyllithium in hexane was added dropwise at -78° C. while stirring to a solution of 2.6 g of 2-bromo-1,3-diisopropylbenzene in 16 ml of tetrahydrofuran. The mixture was stirred at the same temperature for 30 minutes and thereafter treated with a solution of 1.3 g of N-formylpiperdine in 1.5 ml of tetrahydrofuran. Thereafter, the mixture was left to warm to room temperature over a period of 6 hours. The mixture was cooled to 0° C. and treated with 12 ml of 3N hydrochloric acid. The aqueous solution was extracted four times with diethyl ether and the combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was chromatographed on silica gel with dichloromethane as the eluent and yielded 1.07 g of 2,6-diisopropylbenzaldehyde as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14](SC)=[N:15][CH2:16][Si](C)(C)C)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[C:25]=1[Cl:37].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[N:9]1([C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH2:31][C:30]([C:28]4[CH:27]=[C:26]([Cl:36])[C:25]([Cl:37])=[C:24]([Cl:23])[CH:29]=4)([C:32]([F:35])([F:34])[F:33])[CH2:16][N:15]=3)=[CH:4][C:3]=2[C:1]#[N:2])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(-n2cncn2)c(C#N)c1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Temperature: -5 °C
Yield: 85 %

Procedure:
methyl 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbimidothioate (0.2 g) and 1,2,3-trichloro-5-[1-(trifluoromethyl)ethenyl]benzene (0.17 g) were dissolved in THF and cooled to −5° C. to be stirring. Additionally a solution of tetrabutylammonium fluoride (0.099 mL of 1.0 M in THF) in THF was added over 10 minutes under argon atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature and returned to room temperature gradually, and then stirred 4 hours. Water was added to the reaction liquor, and aqueous layer was extracted with ethyl acetate. The combined organic layers, were washed with a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 2-(1H-1,2,4-triazol-1-yl)-5-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzonitrile (0.25 g) at a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.C(Cl)(Cl)Cl>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Cc1ccccc1COc1cccnc1N
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1COc1cccnc1NC(=N)Cc1ccccc1
Yield: 9.5 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl phenylacetimidate hydrochloride (5.32 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, filtered to remove an insoluble white solid, and purified by flash chromatography (chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2)=O.[C:11]([CH2:13]C(O)=O)#[N:12].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:11]([CH2:13][CH:1]=[C:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2)#[N:12]
Reactant: N#CCC(=O)O
Reactant: CC1C2CCC(C2)C1C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC1C(=CCC#N)C2CCC1C2
Yield: 77 %

Procedure:
A stirred solution of 97 g (0.7 mol) of 2-formyl-3-methylbicyclo[2.2.1]heptane 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 87 g (77% yield) of 2-(2-cyanoethylidene)-3-methylbicyclo[2.2.1]heptane: b.p. 72°-85° C./1 mm; ir 2940, 2870, 2220, 1610, 1450, 1380, 830, 740; nmr 0.9-1.1 (3H, m), 1.2-2.8 (9H, m), 2.85-3.2 (2H, m), 4.8-5.4 (1H, m); ms 161.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[NH:18])[C:10]2[C:15]([CH3:16])=[C:14]([F:17])[CH:13]=[N:12][CH:11]=2)[CH:3]=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:18]=[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([F:17])[C:15]=3[CH3:16])[N:8]=[C:4]2[CH:3]=1
Reactant: Cc1c(F)cncc1C(=N)Nc1cc(Cl)ccn1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(F)cncc1-c1nc2cc(Cl)ccn2n1
Temperature: 150 °C

Procedure:
Lead tetra acetate (0.15 g, 0.00034 mol) was added at RT to a solution of N-(4-chloropyridin-2-yl)-5-fluoro-4-methylnicotinimidamide (40-1; 0.09 g, 0.00034 mol) in toluene (10 mL) in a 40 mL microwave vial. The reaction mixture was heated to 150° C. for 1.5 h under microwave irradiation. It was then cooled to RT, diluted with water (20 mL), and extracted with ethyl acetate (2×30 mL). the combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was purified by Prep TLC to obtain the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.10-9.086 (d, J=8 Hz, 1H), 9.01 (s, 1H), 8.6 (s, 1H), 8.17 (s, 1H), 7.37-7.35 (d, J=8 Hz, 1H), 2.64 (s, 3H), MS (M+1): 263.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:5]([O:7]N1C(=O)CCC1=O)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:27][NH2:28].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:28][CH2:27][C:26]2[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:7])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCc2cc(OC)cc(OC)c2)cc1Cl
Yield: 72.6 %

Procedure:
A solution of 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 2.00 g, 6.4 mmol), 3,5-dimethoxybenzylamine (1.25 g, 7.5 mmol) and triethylamine (1.00 g, 9.9 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature overnight. The solvent was evaporated (<0.5 mm Hg, 40° C.), ethyl acetate (200 mL) was added, and the solution was allowed to stand over the weekend at room temperature. The white solid was filtered off and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (30-50% ethyl acetate/hexanes) to give 2-chloro-4-[[[(3,5-dimethoxyphenyl) methyl]amino]carbonyl]benzoic acid, methyl ester (1.69 g, 72%) as a white solid, mp 101-103° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl.[C:6]1([C@H:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20]2)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[OH:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C@@H:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH3:17])[CH2:20]2)=[CH:25][CH:26]=1
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)NCCO)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a mixed solution of 7.7 mg of 2-aminoethanol and 50 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (the compound obtained in Example 3.001) dissolved in 8 ml of dimethylformamide were added 22.2 mg of 1-hydroxybenzotriazole, 70 μl of triethylamine and 31.4 mg of EDC hydrochloride, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added to the residue, and the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH thin layer silica gel chromatography (chloroform:methanol=39:1) and thin layer silica gel chromatography (chloroform:methanol=9:1) to give 22.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide. (2) To a solution of 22.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide dissolved in 1 ml of methylene chloride was added dropwise 3 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred for a while. The reaction mixture was evaporated, and, to the residue was added tert-butanol to dissolve the same, and freeze-dried to obtain 25.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide hydrochloride (the following Table A3, Example 3.017).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[C:6]=1[OH:20])=[O:4].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([Br:21])[C:8]2[N:11]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:13][C:7]=2[C:6]=1[OH:20])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2nc(-c3ccccc3)oc2c1O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Yield: 61 %

Procedure:
A suspension of 7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (3.57 g, 13.2 mmol; example 1d), N-bromosuccinimide (2.47 g, 13.9 mmol), and benzoyl peroxide (320 mg, 1.32 mmol) in 43 mL of benzene was heated at reflux temperature for 5 hours. The reaction mixture was washed successively with saturated sodium bicarbonate, brine, saturated ammonium chloride solution, and brine. The organic solution was dried, filtered, and concentrated. The residue was purified by flash chromatography eluting from silica gel with a gradient of 0-25% methanol in methylene chloride to give 2.81 g of the title compound as a light yellow solid. MS: (+) m/z 348.9, 350.9 (M+1, 79Br/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([OH:28])=O)[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:5]2=[CH:4][CH:3]=1.Cl.CN.C[CH2:41][N:42]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:25][C:26]([NH:42][CH3:41])=[O:28])[CH:11]3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(F)cc1C1CC(=O)N(CC(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1C(=O)CC(c2cc(F)ccc2C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-hydroxycarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (70 mg, 0.13 mmol) prepared in example 146d, Methylamine hydrochloride (11 mg, 0.16 mmol), EDC.HCl (31 mg, 0.16 mmol), HOBt (22 mg, 0.16 mmol) and DIPEA (69 mg, 0.533 mmol) in DMF (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-1′-(methylamino-carbonyl-methyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (29 mg as a white solid.
Reaction SMILES: O.[NH2:2]N.[CH2:4]([O:11][C:12]1[C:13]([CH:27]=O)=[C:14]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:15]([N:17](CC)CC)=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH2:4]([O:11][C:12]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:14]2[C:13]=1[CH:27]=[N:2][NH:17][C:15]2=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1C=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(=O)[nH]ncc2c1OCc1ccccc1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Glacial acetic acid (285 ml) at 10-20° C. was dropwise added with hydrazine monohydrate (10.16 ml, 209 mmoles) and added with 3-benzyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide (14.27 g, 41.8 mmoles), prepared as described in example 56. The mixture was left to stand for 2 hours, then evaporated, dissolved in CH2Cl2, washed with water, anhydrified over Na2SO4, brought to dryness, and the crude was triturated in petrolatum/ethyl ether 2:1 (150 ml) and filtered to give 11.3 g of the title compound (yield: 96%).
Reaction SMILES: O.C([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)C.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])c2ncccc2c1O

Procedure:
The water washings of the crude 5-ethoxy-6-methoxy-8-nitroquinoline were acidified with acetic acid and basified with sodium bicarbonate to give 0.44 g of 5-hydroxy-6-methoxy-8-nitroquinoline.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([CH:14]=[O:15])[CH:3]=1.[Na].OO.Cl([O-])=[O:20].[Na+]>C(#N)C.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([OH:20])=[O:15])[CH:3]=1
Reactant: COc1c(C=O)cc(F)c2ccccc12
Reactant: [O-][Cl+][O-]
Agent: OO
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: COc1c(C(=O)O)cc(F)c2ccccc12
Reaction time: 2.5 h
Yield: 93.7 %

Procedure:
9.3 g of 4-fluoro-1-methoxynaphthalene-2-carbaldehyde were dissolved in 100 ml of acetonitrile. 2.1 g sodium dihydrogenphsophate monohydrate in 10 ml of water were added, followed by the addition of 9.5 ml hydrogen peroxide (30%). 8.9 g sodium chlorite, dissolved in 20 ml water were added dropwise while maintaining an internal temperature between 5° C. and 15° C. The reaction was then allowed to come to room temp over 2.5 h. The precipitated solid was filtered with suction, and the solid was washed with water, and dried in vacuo at 40° C. to yield 9.4 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid. The filtrate was treated with 60 ml of cold 10% aqueous sodium bisulfite solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was washed with 0.2 N NaOH twice. The washes were acidified with 6 N HCl to pH 3, whereupon crystallization occurred. The precipitating product was filtered, washed with water and dried in vacuo at 40° C. to yield a second batch of 1.0 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][CH:13]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:15](=[O:27])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][CH:13]2[CH2:17][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:15](=[O:27])[CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: COc1ccc(CN2CC(N)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CN2CC(Nc3ccc(Cl)cc3[N+](=O)[O-])CC2=O)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A mixture of 4-chloro-1-fluoro-2-nitrobenzene (9.2 g, 52.4 mmol), 4-amino-1-(4-methoxybenzyl)pyrrolidin-2-one (11.5 g, 52.4 mmol) and K2CO3 (14.5 g, 105 mmol) in 300 mL of anhydrous CH3CN was heated with stirring at 50° C. for 16 hours. The reaction mixture was filtered and the filter cake was dissolved with H2O (400 mL), and extracted with EtOAc (200 mL×4). The organic layers and the filtrate was combined and concentrated in vacuo to 50 mL. The precipitate was collected by filtration and washed with 10 mL of PE to afford 4-[(4-chloro-2-nitrophenyl)amino]-1-(4-methoxybenzyl)pyrrolidin-2-one as an orange solid (15.8 g, yield: 80.2%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.[NH2:32][C:33]1[N:38]=[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][NH:48][C:49](=[O:54])[C:50]([F:53])([F:52])[F:51])=[CH:43][CH:42]=2)[C:36]([N:55]=[O:56])=[C:35]([NH2:57])[N:34]=1.Cl>C1COCC1>[NH2:32][C:33]1[N:38]=[C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][NH:48][C:49](=[O:54])[C:50]([F:52])([F:53])[F:51])=[CH:45][CH:46]=2)[C:36]([N:55]=[O:56])=[C:35]([NH:57][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[N:34]=1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: Nc1nc(N)c(N=O)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)Nc1nc(N)nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c1N=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
Under an argon atmosphere 4-(tert-butoxycarbonylamino)-butyric acid (1.58 g, 8 mmol) is dissolved in 20 mL dry THF and cooled to 0° C. Diisopropyl ethylamine (1.18 g, 9 mmol) is added, the mixture cooled to −20° C., and chloroformic acid isobutylester (1.15 g, 8 mmol) added. The mixture is stirred at this temperature for 5 min, and nitroso-pyrimidine 38 (Example 21, 2.64 g, 7 mmol) dissolved in 20 mL dry THF is added via a syringe. The reaction mixture is allowed to warm to room temperature, heated to 55° C. and stirred at this temperature over night. After cooling to room temperature, the mixture is poured into 100 mL of 1 N HCl and the product extracted with ethyl acetate (300 mL). The combined organic phases are washed with water and brine, subsequently dried over MgSO4 and the solvent evaporated. The residue is adsorbed on SiO2 and purified by flash column chromatography (cyclohexane/ethyl acetate 1:2 to 1:10) to yield the title compound as a blue solid (1.96 g, 3.53 mmol, 50.4%). From the crude material, an analytical sample is recrystallized from ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.ClC1C2C=C(N(C)C)N=CC=2N=CN=1.N>C(O)C.ClCCl>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Fc1ccccc1CBr
Agent: CN(C)c1cc2c(Cl)ncnc2cn1
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc(OCc2ccccc2F)cc1

Procedure:
4-(2-Fluorobenzyloxy)aniline was prepared from 4-nitrophenol (Aldrich) and 2-fluorobenzylbromide (Aldrich) according to Procedure D. This was reacted with 4-chloro-6-(N,N-dimethylamino)pyrido[3,4-d]pyrimidine according to Procedure A to give the product; tlc (dichloromethane:ethanol:aq.ammonia, 100:8:1) Rf 0.48; m/z (M+1)+390.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1>CCOC(C)=O>[Cl:14][C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1ncccc1-c1ccnc(NCCCN2CCOCC2)n1
Temperature: 80 °C

Procedure:
To 2-chloro-4-(2-chloropyridin-3-yl)pyrimidine (100 mg, 0.44 mmol) and potassium carbonate (122 mg, 0.88 mmol) was added DMSO (1.0 mL) and 3-morpholinopropan-1-amine (77 mg, 0.53 mmol). The resulting mixture was heated for 15 hours at 80° C. The cooled reaction was diluted with EtOAc and extracted with water. The organic layer was dried over sodium sulfate, filtered and concentrated to yield the title compound as a yellow oil. MS m/z=334 [M+H]+. Calc'd for C16H20ClN5O: 333.84.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:33])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:33][CH:25]([CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: NCC(O)CN1CCOCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.4 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (74 mg, 0.48 mmol) to precipitate 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (65 mg, 36%). The mother liquid was evaporated to dryness and the residue was purified by flash chromatography to give additional 2N (70 mg, 39%). 1H NMR (DMSO-d6) δ 2.28 (m, 1H), 2.32 (m, 1H), 2.40 (m, 4H), 2.40, 2.42 (2×s, 6H, 2×CH3), 3.15 (s, 1H), 3.31 (m, 1H), 3.55 (m, 4H), 3.78 (m, 1H), 4.73 (brs, 1H, OH), 6.82 (dd, J=4.5, 8.4 Hz, 1H), 6.90 (td, 2J=2.8, 3J=10.0 Hz, 1H), 7.53 (m, 1H), 7.70 (s, 1H), 7.74 (dd, J=2.0, 9.6 Hz, 1H) (aromatic and vinyl), 10.87 (s, 1H, CONH), 13.66 (s, 1H, NH). LC-MS (m/z) 441.4 (M−1).