Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](N2CCCCC2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].C[O:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH2:32][CH2:33]Cl>>[CH2:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:33][CH2:32][O:31][C:24]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=3[C:22]([OH:21])=[O:35])[CH2:9][CH2:8]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(N2CCCCC2)c2cccnc21
Reactant: COC(=O)c1ccc(OC)cc1OCCCl
Product: CCCCn1cc(C2CCN(CCOc3cc(OC)ccc3C(=O)O)CC2)c2cccnc21
Yield: 35 %

Procedure:
This compound was prepared following the procedure described in example 4, part E and F starting with 2.5 g (9.1 mmol) of 1-butyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine and 3.3 g (13.6 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. After standard purification the overall yield was 35% (0.77 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]([NH2:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:6]=1[F:25])[CH:2]=[CH2:3].[C:26](O)(=O)C.C(N)=O.C(=O)(O)[O-].[Na+].O>CO>[CH2:1]([N:4]1[C:5]2[C:6]([F:25])=[C:7]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=3[F:24])[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[N:15]=[CH:26]1)[CH:2]=[CH2:3]
Reactant: C=CCNc1c(N)cc(C(=O)OC)c(Nc2ccc(I)cc2F)c1F
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: NC=O
Product: C=CCn1cnc2cc(C(=O)OC)c(Nc3ccc(I)cc3F)c(F)c21
Temperature: 25 °C

Procedure:
A stirred suspension of methyl 4-(allylamino)-5-amino-3-fluoro-2-(2-fluoro-4-iodophenylamino)benzoate (3.4 g, 7.4 mmoles)) and formamide acetate (3.8 g, 36.4 mmoles) in methanol (30 ml) is heated under reflux for 3 hours. The reaction mixture is cooled to room temperature and a saturated aqueous solution of sodium bicarbonate (30 ml) and water (30 ml) are added. The resulting precipitate is filtered and dried under vacuum to obtain the title compound.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[N:10]([O-])=[O:11].[Na+]>Cl.O>[N:10]([CH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1)=[O:11]
Reactant: C1CC[C@H]2CNC[C@H]2C1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NC1NC[C@@H]2CCCC[C@H]12
Yield: 54.6 %

Procedure:
cis-Octahydro-1H-isoindole (1.81 g, 14.5 mmol), which is the compound described in Tetrahedron, 55 (1999) 9439-9454, was dissolved in 1N hydrochloric acid (16 ml), and the mixture was stirred under ice-cooling, sodium nitrite (6.22 g, 90.1 mmol) dissolved in water (20 ml) was gradually added, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was extracted with diethyl ether, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. Me insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.22 g, yield 55%) as a bistered oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)O1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:30]([C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37](I)=[CH:38][N:39]=4)[CH:36]=3)=[CH:29][N:28]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:27]=2)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C)C=O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:30]([C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([C:9]5[CH:10]=[CH:11][C:12]([C:13]([NH2:15])=[O:14])=[CH:16][CH:17]=5)=[CH:38][N:39]=4)[CH:36]=3)=[CH:29][N:28]([C:41]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[N:27]=2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(I)n3c2)cc1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Yield: 43.2 %

Procedure:
222 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide prepared according to T. Ishiyama et al., J. Org. Chem., 60, 7508 (1995), 323 mg of 6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazolyl]-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 39), 200 mg tripotassium phosphate, 30 mg tetrakis(triphenylphosphine)palladium and 30 mL N,N-dimethylformamide were heated at 75° C. for 3 hours under nitrogen atmosphere. The solvent was removed, and the residue was purified by NH silica gel chromatography (hexane/ethyl acetate) to give 138 mg of the title compound (film).
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([N:13]([CH3:36])[C:14](=[O:35])[CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]2[NH:29][C:30](=[O:34])[CH:31]([CH2:32]O)[N:23]2[CH2:22]3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.CCN(C(C)C)C(C)C>O>[CH:7]1([N:13]([CH3:36])[C:14](=[O:35])[CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]2[NH:29][C:30](=[O:34])[C:31](=[CH2:32])[N:23]2[CH2:22]3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN(C(=O)CCCOc1ccc2c(c1)CN1C(=N2)NC(=O)C1CO)C1CCCCC1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=c1c(=O)[nH]c2n1Cc1cc(OCCCC(=O)N(C)C3CCCCC3)ccc1N=2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 500 ml of pyridine was added 5.14 g of N-cyclohexyl-N-methyl-4-(2-oxo-3-hydroxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutanamide to which was added 0.9 ml of mesyl chloride. This solution was cooled to about 0°-5° C., at which time 7.12 ml of DIPEA was added. This solution was stirred at room temperature for 3 hours. The pyridine was stripped under high vacuum at about 40° C. to give a suspension which was trituratured with water, centrifuged and crystals of the captioned compound collected by filtration: m.p. 176°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:12])=[C:5]([NH2:11])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=O)[C:16](OC)=[C:15]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[OH:13][C:14]1[C:15]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:16]2[C:17]([N:12]=[C:4]3[C:5](=[N:11]2)[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]3[O:2][CH3:1])=[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=12
Reactant: CCOC(=O)C1=C(OC)C(=O)c2ccccc2C1=O
Reactant: COc1ccc(OC)c(N)c1N
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccccc2c2nc3c(OC)ccc(OC)c3nc12
Yield: 92.6 %

Procedure:
In 50 ml of hot ethanol was dissolved 1.68 g of 3,6-dimethoxy-o-phenylenediamine. To this solution was gradually added 2.6 g of ethyl 1,4-dihydro-1,4-dioxo-3-methoxy-2-naphthoate under heating with stirring, and the mixture was refluxed for a further 2 hours. The reaction mixture was cooled and the precipitated solid was collected by filtration and recrystallized from benzene to give 3.50 g (92.6% yield) of ethyl 5-hydroxy-8,11-dimethoxybenzo[a]-phenazine-6-carboxylate as red needles, m.p. 290° C. (decomp.), Anal. Calcd.: (%) for C21H18N2O5 ; C, 66.66; H, 4.80; N, 7.40; Found: C, 66.46; H, 4.56; N, 7.53
Reaction SMILES: [OH-].[K+].N([CH2:5]NCNC(=O)OC(C)C)=O.[N+](=C)=[N-].[C:18]([OH:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)COCCO.O.CCOCC>[C:18]([O:26][CH3:5])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)OC(=O)NCNCN=O
Reactant: O=C(O)c1ccccc1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccccc1
Yield: 81 %

Procedure:
To a solution obtained by dissolving 4.2 g of potassium hydroxide in a mixed solvent of 15 ml of diethylene glycol (DEG) and 3 ml of water, 50 ml of ether was added. The temperature of a water bath was maintained at 45°-50° C. and when the ether began to be distilled out, a solution prepared by dissolving 8.8 g of isopropyl N-[(N-nitrosomethylamino)methyl]carbamate in 70 ml of ether was added dropwise thereto. The ether fraction rapidly changed to yellow. After adding dropwise for 15-20 minutes, ether was added dropwise in order to make the amount of ether in the flask constant. When about 70 ml of ether was added dropwise for 20 minutes, the distillate became colorless and the reaction was completed. To the distilled ether solution containing diazomethane, benzoic acid was added to produce methyl benzoate, and an excess of benzoic acid was back-titrated with 0.2 N NaOH. The amount of the diazomethane was 1.7 g (81% yield).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:23]2[CH2:26][C:25](=O)[CH2:24]2)=[CH:18][CH:17]=1.CC(C)([O-])C.[K+].CS(Cl)(=O)=O>O1CCCC1.C(OCC)C.O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[N:23]2[CH2:26][C:25](=[CH:1][S:2]([CH2:5][C:6]3[S:10][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=3)(=[O:4])=[O:3])[CH2:24]2)=[CH:29][CH:30]=1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)s1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)s1
Temperature: -70 °C
Yield: 15.3 %

Procedure:
Methyl 5-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methylsulfonylmethyl)thien-2-yl-carboxylate may be obtained in the following manner: 5.15 g of methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate are added, at room temperature under an argon atmosphere, to a solution of 6.12 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 200 cm3 of tetrahydrofuran and then the suspension obtained is cooled to −70° C. There are successively added 2.47 g of potassium tert-butoxide, and then after 1 hour 30 min at this temperature a solution of 1.7 cm3 of methylsulfonylchloride in 8 cm3 of ethyl ether over 2 minutes. The reaction medium is maintained for 1 hour at −70° C. and then the temperature is allowed to rise to around 20° C. before pouring in 80 cm3 of distilled water. The tetrahydrofuran is expelled under reduced pressure and the aqueous residue obtained is extracted with 500 cm3 of dichloromethane. The mixture is separated after settling, the organic phase is washed with 3 times 80 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 1.6 g of methyl 5-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methylsulfonylmethyl)thien-2-ylcarboxylate are obtained in the form of a cream-colored foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[C:41]([NH2:42])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[C:41]([NH2:42])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1N
Yield: 49.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.280 mmol) was coupled with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (Intermediate 60) (86 mg, 0.34 mmol) using sodium carbonate (89 mg, 0.84 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in DME/water (10/1 mL) to afford 80 mg (49.2% yield) after purification by column (Silica gel 6/120) using 4/1/5 EtOAc/methanol/hexane as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]2[S:22][C:23]([S:26](Cl)(=[O:28])=[O:27])=[C:24]([CH3:25])[C:20]=2[CH:19]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][S:26]([C:23]2[S:22][C:21]3[CH:30]=[CH:31][C:18]([Cl:17])=[CH:19][C:20]=3[C:24]=2[CH3:25])(=[O:28])=[O:27])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1
Reactant: COc1cc(N)ccc1N1CCN(C)CC1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)ccc1N1CCN(C)CC1
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A solution of 3-methoxy-4-(4-methylpiperazin-1-yl)phenylamine (D35) (50 mg, 0.23 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (64 mg, 0.23 mmol) in dichloromethane (2 ml) was allowed to stand at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with potassium carbonate (aq), which was back-extracted with further dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated under reduced pressure to give a crude product, which was purified by chromatography on silica gel, eluting with methanol and dichloromethane. This gave the title compound (E128) as an off-white solid (36 mg, 34%) MH+=466.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]([CH3:14])C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5]CN.[CH:15]([N:18](C(C)C)CC)(C)C.Cl.[O:25]=[C:26]1[NH:35][C:34]2[N:33]=[CH:32][C:31](/[CH:36]=[CH:37]/[C:38]([OH:40])=O)=[CH:30][C:29]=2[CH2:28][CH2:27]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:11][CH2:12][CH3:14])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][N:18]([CH3:15])[C:38](=[O:40])/[CH:37]=[CH:36]/[C:31]1[CH:32]=[N:33][C:34]2[NH:35][C:26](=[O:25])[CH2:27][CH2:28][C:29]=2[CH:30]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Oc1c(Cl)cccc1CCN
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(Cl)cccc1CN(C)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reaction time: 18 h
Yield: 21.7 %

Procedure:
A stirring solution of (3-chloro-2-isopropoxybenzyl)methylamine (0.229 g, 1.07 mmol) and diisopropylethylamine (0.51 mL, 2.9 mmol) in DMF (20 mL) under N2 was treated sequentially with (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (0.250 g, 0.980 mmol), 1-hydroxybenzotriazole hydrate (0.144 g, 1.07 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.205 g, 1.07 mmol). After stirring for 18 h, the reaction mixture was diluted with H2O (30 mL). The resulting solids were collected by filtration and washed with Et2O (100 mL), suspended in MeOH (30 mL) and sonicated for 30 minutes. The solids were then collected by filtration, washed with MeOH and dried to yield the title compound (0.085 g, 21%) as a white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.67-10.64 (m, 1H), 8.37-8.32 (m, 1H), 8.09-7.91 (m, 1H), 7.53-7.48 (m, 1H), 7.42-7.37 (m, 1H), 7.28-7.02 (m, 3H), 4.83-4.68 (m, 2H), 4.53-4.45 (m, 1H), 2.94-2.85 (m, 5H), 2.56-2.49 (m, 2H), 1.33-1.28 (m, 6H); MS (ESI) m/e 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([OH:21])=[CH:13][CH:12]=1.[K].[O-]CCCC>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH2:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c2ccccc12
Agent: CCCC[O-]
Agent: Cl
Agent: [K]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ccc(Oc2ccnc(Cl)c2)c2ccccc12
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To a stirred solution of 2-chloro-4-fluoropyridine (1.26 g, 9.58 mmol) and 4-amino-1-naphthol hydrochloride (2a) (750 mg, 3.83 mmol) in NMP (40 mL), at −20° C., was added potassium tart-butoxide (1.290 g, 11.50 mmol). The reaction mixture was allowed to warm to RT and after 2.5 hr the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL then 2×80 mL). The combined organic extracts were washed with brine (150 mL), dried and evaporated in vacuo. The crude product was subjected to SCX capture and release and the solvent was removed in vacuo to give the title compound (72) (1.02 g, 92%) as a brown solid: m/z 271 (M+H)+ (ES+).
Reaction SMILES: CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:14]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:14]=1)[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2cc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A DMF (4 mL) solution containing Na2CO3 (60 mg, 0.57 mmol), 4-chloro-2-fluoro-1-nitrobenzene (100 mg, 0.57 mmol) and methyl 4-hydroxybenzoate (87 mg, 0.57 mmol) was stirred at room temperature for 8 hours. HPLC analysis indicated ca. 85% product. The reaction solution was stirred for an additional 2 hours at 40° C. The solution was then diluted with ethyl acetate and washed with 1N NaOH. The organic phase was washed with water (3×), brine and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 8.11 (d, J=8.1 Hz, 2H); 8.01 (d, J=8.2 Hz, 1H); 7.31-7.27 (m, 1H); 7.11-7.07 (m, 3H); 3.95 (s, 3H). LCMS1 3.66 min. (M+H)=308.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: N
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 378) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (0.090 g 21%). mp 180–183° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.49 (m, 5H), 7.36 (m, 2H), 7.53 (m, 2H), 7.62–7.73 (m, 4H), 7.98 (m, 3H). MS (DCI/NH3) m/z 416 (M+H)+, 433 (M+NH4)+. Anal. calc. for C21H22FN3O3S: C, 60.71; H, 5.34; N, 10.11. Found: C, 60.37, H, 5.36, N, 9.84.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15]C)=[O:14].[OH-].[K+].CO.Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: COc1ccc2ccccc2c1C(=O)O
Temperature: 0 °C
Yield: 67.8 %

Procedure:
A solution of 21.6 g of the compound of Step A above in 48 ml of Claisen's alkali solution (solution of 21 g of KOH in 15 ml of water, made up to 60 ml with methanol) is heated at reflux for 4 hours. The reaction mixture is then diluted with 50 ml of water and poured into 75 ml of 15.5% hydrochloric acid solution cooled to 0° C. with stirring. The white precipitate formed is then filtered off over a Buchner funnel and then washed with water and dried under a phosphoric vacuum. The dry residue obtained is dissolved in a solution of ethanol and water (80:20, v/v) at boiling. After cooling to 0° C., 13.7 g of the expected product are obtained.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[Cl:23][C:24]1[C:33]([CH:34]=O)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[ClH:23].[Cl:23][C:24]1[C:33]([CH2:34][NH:1][CH2:2][C@@H:3]2[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:22])[CH2:4]2)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: O=C1COc2cc(Cl)c(CNC[C@H]3CN(CCn4c(=O)ccc5ncc(F)cc54)C[C@H]3O)nc2N1
Reaction time: 18 h
Yield: 43 %

Procedure:
1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (118 mg, 0.386 mmol) and 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c)) (90 mg, 0.425 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 18 h then sodium triacetoxyborohydride (257 mg, 1.16 mmol) was added and stirred for 1 h. The reaction mixture was concentrated and purified to obtain the free base of the title compound as a pale yellow oil (83 mg; 43%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:19])=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:19][C:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: CCOC(=O)C=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(C(=O)Cl)cc1
Yield: 78.8 %

Procedure:
14.8 g (67 mmols) of ethyl 4-carboxycinnamate, 9.57 g (80 mmols) of thionyl chloride, 100 ml of toluene and 0.18 ml of N,N-dimethylformamide are boiled under reflux for 30 minutes. The reaction mixture is evaporated and the crude product is recrystallised from n-hexane. 12.6 g (79% of theory) of ethyl 4-chloroformylcinnamate are obtained in the form of white crystals; melting point 76.8° C.