Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH:18](OC)[C:19](C)(C)C)[C:4](=[O:17])[C:5]1[C:10]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8](Br)=[CH:7][C:6]=1[Cl:16])C.[C:25](=O)=[O:26].CC(C)=O.[Li]CCCC.CN(C=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:16][C:6]1[CH:7]=[C:8]([CH:25]=[O:26])[CH:9]=[C:10]([Si:11]([CH3:12])([CH3:13])[CH3:14])[C:5]=1[C:4]([NH:3][CH2:18][CH3:19])=[O:17]
Reactant: O=C=O
Reactant: CCN(C(=O)c1c(Cl)cc(Br)cc1[Si](C)(C)C)C(OC)C(C)(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(Cl)cc(C=O)cc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of N-ethyl-N-(1-methoxy-2,2-dimethylpropyl)-2-chloro-4-bromo-6-(trimethylsilyl)benzamide (820 mg, 1.89 mmol) in THF (2 mL) was added dropwise to a dry-ice/acetone cooled solution of 2.5M n-BuLi in hexanes (1 mL, 2.5 mmol) in THF (2 mL). The resulting red solution was stirred at -78° C. for 15 min, then DMF (500 mL, 6.5 mmol) was added in a single portion. After 5 min, the reaction was poured into sat aq NaHCO3 and extracted with ether (2×). The combined organic extracts were dried (MgSO4) and concentrated, then a solution of this protected amide in acetone (5 mL) was charged with 6N HCl and stirred overnight at RT. The resulting mixture was poured into sat aq NaHCO3 and extracted with ether (2×), then the combined organic extracts were dried (MgSO4), concentrated, and purified by RC with 3:7 EtOAc/hexanes to give 220 mg of the title compound as a white solid, a 40% yield. m.p. 95-97° C.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][NH:21][CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C.CS(C)=O>O>[CH3:16][CH:17]1[NH:18][CH2:19][CH2:20][N:21]([C:2]2[CH:15]=[CH:14][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:22]1
Reactant: CC1CNCCN1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC1CN(c2ccc(C(=O)c3ccccc3)cc2)CCN1
Temperature: 100 °C
Yield: 92.8 %

Procedure:
To a 1 L two-neck flask was added 4-fluorobenzophenone (100 g) and 2-methyl piperazine (60 g), triethyl amine (160 mL) and dimethyl sulfoxide (200 mL). The flask was seated in oil bath. The oil bath was heated to 100° C. for 24 hours. The mixture was cooled to room temperature and then poured into water (300 mL). The mixture was extracted with chloroform (300 mL). The bottom layer was separated and washed with water (500 mL) and brine (300 mL). The final solution was condensed and the residue was filtered off a silica gel plug. The major fraction was condensed to afford yellow oily 4-(3-methylpiperazino)benzophenone (130 g).
Reaction SMILES: [NH2:1]/[C:2](/[CH:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][N:10]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:29][C:30](=O)[C:31]#[CH:32]>C(O)C>[CH2:7]([O:6][C:4]([C:3]1[C:2]([CH:9]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:12][CH2:11][N:10]2[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[N:1][C:31]([CH3:32])=[CH:30][CH:29]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)/C=C(\N)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: C#CC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc(C)nc1C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Yield: 59.6 %

Procedure:
To a solution of bis(1,1-dimethylethyl) 2-[(1Z)-1-amino-3-(ethyloxy)-3-oxo-1-propen-1-yl]-1,4-piperazinedicarboxylate (may be prepared as described in Intermediate 4; 7.4 g) in ethanol (300 mL), was added 3-butyn-2-one (3.15 g) and the reaction was heated to reflux for 20 hours. The reaction mixture was evaporated and then partitioned between 2× EtOAc and water. The combined organic phases were washed with brine, dried through a hydrophobic frit, and then evaporated to a brown oil (8.54 g), which was purified by silica column (SP4-40M) eluting with 0-40% ethyl acetate in isohexane over 12CV. The clean fractions were combined and evaporated to give the title compound as a yellow oil (4.96 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:6]([N+:15]([O-])=O)=[CH:5][CH:4]=1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:6]([NH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(N2CCOCC2)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1ccc(N)c(N2CCOCC2)n1

Procedure:
6.19 g (0.026 mol) of the product 4-(6-methoxy-3-nitropyrid-2-yl)morpholine synthesized according to the above procedure, 50 ml of ethanol, 20 ml of cyclohexene and 2 g of palladium-on-charcoal were placed in a fully equipped round-bottomed flask.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:21][C:16]3[CH:15]=[C:14]([C:12]4[O:13][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)=[N:10][N:11]=4)[CH:19]=[CH:18][C:17]=3[N:20]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(-c4nnc(Nc5cccc(Cl)c5)o4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[5-(3-chlorophenylamino)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine (210 mg, 0.7 mmol) and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (169 mg, 0.77 mmol) (from step D) in DMSO (2.5 mL) was added Yb(OTf)3 (86 mg, 0.14 mmol) and the mixture was stirred at RT for 72 h. The mixture was poured into water and the resulting precipitate was filtered and washed with water. The solid was purified by flash chromatography using 10% MeOH/CH2Cl2 as eluent to give the title compound as a tan solid. MS: m/z 502.0 (M+1). H1-NMR (DMSO-d6): δ ppm 12.91 (m, 0.6H), 10.93 (s, 0.3H), 10.48 (dd, 0.3H), 8.33 (s, 0.4H), 8.13 (s, 0.6H), 7.89-7.73 (M, 2.3H), 7.68 (d, 0.3H), 7.59 (d, 0.4H), 7.52 (m, 1H), 7.46-7.35 (m, 1H), 7.08 (s, 3H), 3.61 (s, 3H), 2.87 (t, 2H), 2.69 (t, 2H), 2.10 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15]OS(C)(=O)=O)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:21]([C:24]1[CH:28]=[N:27][NH:26][N:25]=1)([O-:23])=[O:22].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:3][C:4]1([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][N:26]3[N:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:28]=[N:27]3)[CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC1(c2ccnc(COS(C)(=O)=O)c2)OCCO1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccnc(Cn3ncc([N+](=O)[O-])n3)c2)OCCO1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl ester (315 mg, 1.15 mmol) in DMF (2.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (120 mg, 1.05 mmol) in DMF (2.0 mL) pre-treated for 30 min with DIPEA (0.36 mL, 2.10 mmol) and the reaction mixture was stirred for 48 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 1:4 hept-EA) gave the title compound as a pale yellow solid: TLC:rf (1:2 hept-EA)=0.24. LC-MS-conditions 02: tR=0.89 min, [M+H]+=292.27.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH3:17][O:16][C:14]([C:10]1[CH:9]=[C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH:2]2[O:1][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2O)c1
Reactant: BrCc1ccc2ccccc2c1
Product: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)c1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(3-methoxycarbonyl-phenyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(3-methoxycarbonyl-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate as a colourless oil; MS: 493 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=[O:12])[C:6]=2[CH:14]=1.Cl.[CH3:16]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH:7]([C:11]([O:13][CH3:16])=[O:12])[C:6]=2[CH:14]=1
Reactant: CO
Reactant: O=C(O)C1CCOc2ccc(F)cc21
Agent: Cl
Product: COC(=O)C1CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8.4 g of the 6-fluoro-2,3-dihydro-4H-benzopyran-4-carboxylic acid in 580 mL of methanol was perfused with HCl gas for 5 minutes. The resulting solution was stirred at room temperature overnight. The volatiles were evaporated and the residue dissolved in ether. The ether layer was washed with water then dried over Na2SO4, filtered and evaporated to give 8.7 g of crude product which was purified by chromatography on 300 g of silica gel eluting with CH2Cl2 to give 6.2 g of product as an oil. NMR (CDCl3) ppm (delta): 2.00-2.40 (m, 2H), 3.80 (s, 3H), 2.5 (t, 1H, J=4 Hz), 7.10-6.70 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[N:14][N:13]([CH2:32][CH3:33])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)cc4)c3c2cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(C#N)cc2)c2c3cc(OC)c(OC)cc3ncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 34000 %

Procedure:
4-(7,8-Dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (132 mg, 400 μmol) is dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (111 mg, 800 μmol) and ethyl iodide (37 μl, 440 μmol) is subsequently added. The reaction mixture is stirred at room temperature for 3 h. The mixture is subsequently poured into water (100 ml) and extracted twice with ethyl acetate (100 ml each time). The combined organic phases are washed once with water (50 ml), dried over Na2SO4, filtered with suction, and the filtrate obtained is evaporated to dryness in vacuo. The residue is chromatographed over flash silica gel (solvent gradient n-heptane/0-100% by vol. of ethyl acetate/ethanol 0-30% by vol.). After evaporation of the product fractions, the residue is dissolved in a little tetrahydrofuran, and 2-propanol (5 ml) is added, and the mixture is evaporated. The precipitate obtained is filtered off with suction and dried in a high vacuum, giving the title compound 4-(7,8-dimethoxy-3-ethyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (49 mg, 136 mmol) as a solid having a melting point of 227.4° C. MS: 359.0 (M+H+), TLC (HPTLC): Rf=0.51 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:14]=[CH:15][CH:16]=[C:3]12.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[NH2:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[NH:17][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]1[CH:14]=[CH:15][CH:16]=[C:3]1[C:2]2=[O:1])=[O:13]
Reactant: O=C(O)c1cccc2c1-n1cccc1C2=O
Reactant: Nc1ccncc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccncc1NC(=O)c1cccc2c1-n1cccc1C2=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 21.2 %

Procedure:
In a 500 ml round-bottomed flask, a mixture of 730 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid obtained according to stage 2 of Example 1, 373 mg of 3,4-diaminopyridine, 721 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) and 508 mg of 1-hydroxybenzotriazole (HOBt) in 60 ml of dimethylformamide is stirred for 19 hours at ambient temperature. The reaction medium is evaporated to dryness under vacuum and the solid residue is taken up in 50 ml of water. The precipitate is filtered off and the solid is washed successively with 3 times 80 ml of water, 3 times 80 ml of a saturated solution of sodium bicarbonate and again with 3 times 80 ml of water. The solid is dissolved in methanol and the solvent is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (5% to 10% v/v) in dichloromethane and then a mixture of dichloromethane and 5N ammoniacal methanol (90/10 v/v). 220 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid (4-aminopyridin-3-yl)amide are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1(=O)[C:5]2=[CH:6][CH2:7][CH2:8][CH2:9][N:4]2[CH:3]=[N:2]1.[F:11][C:12]1[CH:19]=[C:18](I)[CH:17]=[C:16]([F:21])[C:13]=1[C:14]#[N:15]>>[F:11][C:12]1[CH:19]=[C:18]([CH:6]2[CH2:7][CH2:8][CH2:9][N:4]3[CH:3]=[N:2][CH:1]=[C:5]23)[CH:17]=[C:16]([F:21])[C:13]=1[C:14]#[N:15]
Reactant: O=C1N=CN2CCCC=C12
Reactant: N#Cc1c(F)cc(I)cc1F
Product: N#Cc1c(F)cc(C2CCCn3cncc32)cc1F

Procedure:
starting from 6,7-dihydro-5H-imidazo[1,5-a]pyridinone [426219-51-4] and 2,6-difluoro-4-iodobenzonitrile [141743-50-2]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:30]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][C:24]=3[N:23]([CH3:38])[C:22]=2[N:39]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:18]3[CH:19]=[CH:20][C:21]4[C:30]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][C:24]=5[N:23]([CH3:38])[C:22]=4[N:39]=3)[C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)nc31)CCNCC2
Temperature: 135 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
A suspension of 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (67 mg, 0.28 mmol), tert-butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (129 mg, 0.339 mmol), CuI (64 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg, 0.06 mmol) and Cs2CO3 (101 mg, 0.311 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2, and stirred at 135° C. for 16 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure afforded a tan solid. 2 N HCl in Et2O (100 mL) was added to a solution of the tan solid in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 15 h. The suspension was filtered, and the solid was washed with Et2O and freeze dried to afford 51 mg (36%) of the title compound as an off-white powder: 1H NMR (500 MHz, DMSO-d6) δ 9.17 (br s, 2H), 8.68 (s, 1H), 8.07-8.00 (m, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.20 (br d, J=6.0 Hz, 1H), 5.97 (br s, 1H), 5.25 (s, 2H), 3.73 (s, 3H), 3.44-3.21 (m, 6H), 3.19-3.11 (m, 2H); ESI MS m/z 436 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([N+:22]([O-])=O)[C:14]([F:21])=[C:15]([F:20])[C:16]=2[O:18][CH3:19])[C:11](=[O:25])[C:10]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Fe]>[NH2:22][C:13]1[C:14]([F:21])=[C:15]([F:20])[C:16]([O:18][CH3:19])=[C:17]2[C:12]=1[C:11](=[O:25])[C:10]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:9][N:8]2[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(Cc2ccccc2)c2c(OC)c(F)c(F)c(N)c2c1=O
Temperature: 90 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
A mixture of ethyl 1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (2.0 g, 4.78 mmol) and iron powder (2.67 g, 47.8 mmol) in AcOH (20 mL) was stirred e at 90° C. for 5 h. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The residue was diluted with water and basified with aq. NaOH. The mixture was filtrated over celite and washed with CH2Cl2. The resulting solution was extracted with CH2Cl2. The organic layer washed with water, brine, and then dried. The solvent was removed and the resulting solid washed with EtOH, dried to yield ethyl 5-amino-1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (1.12 g, 60%) as a yellow solid. M.p. 134-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13]([NH:15][NH:16]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:12][C:11](=[O:27])[CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36](=O)[CH3:37].[I-].[Na+]>COCCOC.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13]2[N:15]=[N:16][CH:35]=[C:36]([CH3:37])[C:12]=2[C:11](=[O:27])[CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)ccc3Cl)C2)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cc1cnnc2c1C(=O)CC(c1cc(Cl)ccc1Cl)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
To a mixture of 5-(2,5-dichlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (1.65 g), anhydrous potassium carbonate (0.696 g), methanol (10 ml) and 1,2-dimethoxyethane (8 ml) were added under ice-cooling 1-chloropropan-2-one (0.465 g) and sodium iodide (0.15 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added anhydrous potassium carbonate (0.64 g), and the mixture was stirred for 3 hours at 80° C. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate (70 ml) and water (30 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(2,5-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.253 g) as yellowish brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C.CO>CS(C)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][CH:16]([C:19](=[O:20])[NH2:21])[CH2:15][CH2:14]2)=[N:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: NC(=O)C1CCNCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(C(N)=O)CC2)nc1
Temperature: 95 °C

Procedure:
Ethyl-6-chloronicotinate (1.86 g, 10 mmol) and piperidine-4-carboxamide (1.54 g, 12 mmol) are dissolved in DMSO (7 ml). N,N-Diisopropylethylamine (2.1 ml, 12 mmol) is added and the reaction mixture is heated at 95° C. for 3 hours. Methanol (8 ml) is added as the reaction mixture cools to give a precipitate. The solid is collected, washed with water followed by diethyl ether, and dried in vacuo at 45° C. to yield the title compound as a white solid. MS (ES+) m/e 278 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([NH2:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([NH2:13])=[O:12]
Reactant: NC(=O)CBr
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 3-chlorophenol (2.57 g, 20.0 mmol), 2-bromoacetamide (2.76 g, 20.0 mmol) and K2CO3 (5.53 g, 40.0 mmol) in acetone (40 mL) was stirred at 70° C. overnight. The mixture was then cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (3.22 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Cl[C:25]1[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[N:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cc1ccc(Cl)nn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3ccc(C)nn3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 3-chloro-6-methyl-pyridazine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:3]=1.[NH2:14][CH2:15][CH2:16][NH2:17]>>[CH3:13][C:8]1([C:4]2[CH:3]=[C:2]([NH:14][CH2:15][CH2:16][NH2:17])[CH:7]=[CH:6][N:5]=2)[O:12][CH2:11][CH2:10][O:9]1
Reactant: CC1(c2cc(Cl)ccn2)OCCO1
Reactant: NCCN
Product: CC1(c2cc(NCCN)ccn2)OCCO1
Temperature: 180 °C
Yield: 95.2 %

Procedure:
4-Chloro-2-(2-methyl-1,3-dioxolan-2-yl)pyridine (500 mg, 2.5 mmol) was mixed with 1,2-diaminoethane (1.09 ml, 26.2 mmol) and stirred in a closed vessel at 180° C. with microwave heating for 30 minutes in two batches. The mixture was evaporated to dryness, the solid residue was washed with acetone. The washing solution was evaporated to dryness and this solid residue was washed with acetonitrile. The solid residues were combined and dried under reduced pressure to yield 531 mg of a solid (2.38 mmol, 95%). MS (APCI) m/z=224.1 [M+H]+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(=O)([O-])O.[K+].[CH2:15]([NH2:18])[CH2:16][CH3:17]>CC(C)=O.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:18][CH2:15][CH2:16][CH3:17])[N:7]=1
Reactant: CCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cyanuric chloride (1) (36.9 g, 0.2 mole) was dissolved in acetone (600 ml) and cooled in an ice/acetone bath. Potassium hydrogen carbonate (25.03 g, 0.25 mole) was dissolved in water (150 ml) with propylamine (11.82 g, 0.2 mole) and added dropwise to the solution of (1) while maintaining the temperature below 0° C. The mixture was stirred for 1 hour at 0° C. and then stirred for 1 hour at room temperature. The acetone was evaporated off under reduced pressure and the residue (300 ml) was poured into water (11). The resulting white solid was filtered, washed with water and dried under vacuum.