Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.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>[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1Br
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1ccccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a deoxygenated solution of o-bromophenol (10.0 g) in triethylamine (120 ml) may be added 1-dimethylamino-2-propyne (2.82 g), bis(triphenylphosphine)palladium(II) chloride (400 mg), and cuprous iodide (54 mg). The mixture may be stirred at room temperature under an atmosphere of argon for approximately 6 hours, heated briefly (ca. 10 minutes) to 60° C. The reaction mixture is then cooled, filtered through diatomaceous earth, and the solvent may be removed by evaporation in vacuo. The residue can then be dissolved in ethyl acetate, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent may be removed by evaporation in vacuo, and the residue may be purified by chromatography over silica gel (50% ethyl acetate in hexanes may be used as the eluant) to give the purified product.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:6][C:5]=2[NH:4][N:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl.O>C(O)C>[ClH:18].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:6][C:5]2[NH:4][N:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 174.5 %

Procedure:
A mixture of 3-methyl-6-(2-chlorophenyl)-4,5,6,7-tetrahydroindazol-4-one (0.22 g), aminoguanidine hydrochloride (0.098 g), concentrated hydrochloric acid (0.084 ml), water (0.084 ml) and ethanol (40 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The mixture was washed with diethylether and concentrated under reduced pressure, and the resulting crystals were recrystallized from water-ethanol to give 4-guanidinoimino-6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 21) (0.26 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17](=O)[CH3:18])[C:5]2[N:9]=[CH:8][N:7](C3CCCCO3)[C:6]=2[CH:16]=1.CC([O-])=O.[Na+].Cl.[NH2:26][OH:27]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:17](=[N:26][OH:27])[CH3:18])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:16]=1
Reactant: NO
Reactant: CC(=O)c1cc(F)cc2c1ncn2C1CCCCO1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1cc(F)cc2[nH]cnc12
Temperature: 80 °C
Yield: 89.6 %

Procedure:
A mixture of 1-(6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)ethanone (676 mg, 3.8 mmol), NaOAc (3.12 g, 38 mmol), and hydroxylamine hydrochloride (792 mg, 11.4 mmol) in MeOH (60 mL) was heated at 80° C. for 1 h. The reaction mixture was concentrated in vacuo. To the residue was added water (200 mL) and the resulting mixture was extracted with EOAc (50 mL×3). The combined extracts were concentrated in vacuo to afford 1-(6-fluoro-1H-benzo[d]imidazol-4-yl)ethanone oxime as a yellow solid (658 mg, 89.8%). MS (ESI): m/z=194.3 [M+1]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[O:14]1[CH2:15][CH2:16][N:11]([CH2:10][C@@H:9]([NH2:8])[CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:12][CH2:13]1
Reactant: CC(C)C[C@@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude N-tert-butoxycarbonyl-1-morpholino-2-(S)-amino-4-methylpentane (6.3 mmol) was dissolved in DCm (50 ml) and treated with excess trifluoroacetic acid (0.48 ml) at 0° C. The mixture was allowed to warm up to room temperature and was stirred for 3 h. The mixture was concentrated to dryness to give 1-morpholino-2-(S)-amino-4-methylpentane trifluoroacetate salt which was used immediately.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si](C)(C)C)[C:30](=O)[C@@:29]2([CH3:43])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)(C(C)(C)C)(C)C.F.C[C@@H]1[C@]2(OC[C@H](C)CC2)O[C@H]2C[C@@H]3[C@@](C)([C@@H]12)[C@H]([OH:66])C(=O)[C@H]1[C@H]3CC[C@@H]2[C@]1(C)CC[C@H](O)C2>C(#N)C>[CH3:20][C@@H:19]1[C@:21]2([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]2)[O:22][C@H:17]2[C:16](=[O:66])[C@@H:15]3[C@@:29]([CH3:43])([C@@H:18]12)[CH2:30][C@H:31]([OH:37])[C@H:32]1[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@:33]1([CH3:36])[CH2:34][CH2:35][C@H:9]([OH:8])[CH2:10]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O[Si](C)(C)C)C(=O)[C@]3(C)[C@H]1[C@@H]2C
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: F
Solvent: CC#N
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C(=O)[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@H]1[C@@H]2C

Procedure:
The title compound was synthesized from (3β,5α,11β,25R)-3-(t-butyidimethylsilyloxy)-11-(trimethylsilyloxy)spirostan-12-one was desilylated with hydrofluoric acid in acetonitrile according to the procedure described in J. Am. Chem. Soc., 1972, 94, 6190. The title compound must be carefully handled because it will rearrange to (3β,5α,12β,25R)-spirostan-3,12-diol-11-one if exposed to base.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[C:15]([O-])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.Cl>O>[C:15]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: N[C@H](CO)C(=O)O
Reactant: CCCCCCCCCCCCCC(=O)[O-]
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCC(=O)N[C@H](CO)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
D-serine 2.0 g (0.02 mol) and triethylamine 2.8 ml (0.02 mol) were dissolved in 60 ml of water. Myristate of 4-hydroxyphenyldimethylsulfomethyl sulfate (trade name: SANCELER My-DSP, manufactured by Sanshin Kagaku Kogyo Co., Ltd.) 9.52 g (0.02 mol) was added to the solution, and the mixture was stirred for 12 hours at room temperature. The solution reacted was adjusted to pH 2 or 3 with 1N-HCl and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-myristoyl-D-serine 3.8 g was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]2=[N:4][C:3]=1[C:14]([O:16]CC)=O.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][C:21]=1[CH3:28]>>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[N:4]=[C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:16])=[CH:22][C:21]=1[CH3:28]
Reactant: Cc1cc(CN)ccc1F
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC(=O)N3C)ccc1F
Yield: 61.6 %

Procedure:
Reaction of intermediate 13, ethyl 6-hydroxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.050 g, 0.197 mmol) with 4-fluoro-3-methylbenzylamine (0.10 g, 0.72 mmol) as described in the preparation of example 1 gave 0.042 g (61% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.21 (3H, d, J=1.5 Hz, CH3), 3.15 (3H, s, NCH3), 4.45 (2H, d, J=6.6 Hz, NCH2), 4.48 (2H, s, CH2), 7.05–7.25 (3H, m, aromatics), 9.45 (1H, broad t, NH), 12.29 (1H, s, OH). MS (ESI+) m/z 347 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7]([O:8][CH3:9])=[C:6]([CH:10]=[O:11])[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Product: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(Cl)c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-chlorobenzene boronic acid, gave 3′-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:14][O-:15].[Na+]>O1CCCC1>[CH3:14][O:15][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1C=C(Cl)C(=O)c2ccccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=CC(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
A solution of 2-chloro-1,4-naphthoquinone (10.3 g) in tetrahydrofuran (100 mL) was treated with a suspension of sodium methoxide (3.20 g) in tetrahydrofuran (25 mL) at room temperature. After stirring overnight, the mixture was evaporated, and the residue was taken up in ether. The organic layer was washed with brine, dried, filtered and evaporated. Chromatography over silica gel gave 2-methoxy-1,4-naphthoquinone, m.p. 182°-183° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:21]([NH:28][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccc(-c2cccc3ccccc23)c(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1c(CNCc2ccccc2)ccc(-c2cccc3ccccc23)c1Cl
Reaction time: 2 h

Procedure:
A solution of Example 5B (65 mg, 0.22 mmol) and benzylamine (0.024 mL, 0.22 mmol) in 1,2-dichloroethane (3 mL) at room temperature was treated with acetic acid (0.05 mL, 0.84 mmol), stirred for 2 hours, treated with sodium triacetoxyborohydride (64 mg, 0.31 mmol), stirred for 16 hours, and treated with saturated NaHCO3. The organic layer was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to ethyl acetate to provide the desired product. MS (ESI(+)) m/z 393 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ7.92 (d, 2H), 7.56-7.46 (m, 3H), 7.45-7.26 (m, 9H), 4.05 (s, 2H), 3.93 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C@@H:8]12[C:17](=O)[O:16][C:14](=[O:15])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2.CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14](=[O:15])[CH:9]3[CH:8]([CH2:13][CH2:12][CH2:11][CH2:10]3)[C:17]2=[O:16])=[CH:3][CH:4]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Nc1ccncc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: O=C1C2CCCCC2C(=O)N1c1ccncc1
Reaction time: 18 h

Procedure:
The starting material is prepared as follows: The mixture of 23.5 g of 4-aminopyridine, 38.5 g of cis-1,2-cyclohexanedicarboxylic acid anhydride and 400 ml of xylene is refluxed for 42 hours while stirring and separating the water formed. After the first half-hour, and after 18 hours, 1 ml of methane sulfonic acid is added to the mixture. It is filtered hot, the crystals formed after cooling are filtered off and recrystallized from isopropanol, to yield the 2-(4-pyridyl)-hexahydroisoindole-1,3-dione melting at 165°-168°.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](O)=[CH:3][C:2]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>CN1C(=O)CCC1>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[C:2]([OH:12])[CH:3]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Oc1cc(O)c2ccccc2n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CN1CCCC1=O
Product: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2ccccc2n1
Yield: 32 %

Procedure:
2,4-quinolinediol (10.0 g, 62.1 mmol) and 3,4-dichloroaniline (13.1 g, 80.7 mmol) were heated to 190° C. in 25 mL NMP for 48 h. After heating was discontinued, solids began to precipitate. These were collected, treated with 8.5 mL of HCl in isopropanol and sonicated in a 4:1 mixture of acetone:isopropanol. After 2.5 h of sonication, the solids were collected. The sonication cycle was repeated to afford 6.79 g of material (19.9 mmol, 32%). 1H NMR (300 MHz, DMSO): 12.7 (s,1 H), 9.34 (s, 1 H), 8.41 (d, 1 H, J=9 Hz), 7.71 (m, 3 H), 7.6 (d, 1 H, J=8.1 Hz), 7.44 (m, 2 H), 6.25 (s, 1 H), 6.08 (broad s, 1 H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25]>C(#N)C.CCOCC.[Cu]I>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C#CCCCCOCCCCCCBr
Reactant: Brc1ccc2ccccc2n1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCOCC
Product: BrCCCCCCOCCCCC#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
A mixture of 2-bromoquinoline (3.00 g), 6-[(6-bromohexyl)oxy]-1-hexyne (3.77 g), BTPC (90 mg), copper (I) iodide (11 mg) and dicyclohexyamine (2.79 g) in acetonitrile (35 ml) was stirred at room temperature under nitrogen for 20 h. The mixture was diluted with ether (90 ml), filtered and the filtrate evaporated in vacuo to give a brown oil. Purification by FCC eluting with hexane:ether (4:1→2:1) gave the title compound as a brown oil (4.25 g), t.l.c. (hexane:ether 2:1) Rf 0.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:6]=[CH:7][C:8]([OH:10])=[O:9].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9]
Reactant: COc1cc(C=CC(=O)O)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)O)ccc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
3-methoxy-4-hydroxy-cinnamic acid (8 g, 41.2 mmol) and imidazole (8.4 g, 123.6 mmol) were charged in a 500 mL round-bottom flask and dissolved in 30 mL of dimethylformamide. Tert-butyldimethylsilyl chloride (13.04 g, 86.5 mmol) was added thereto at 0° C., followed by stirring for 30 minutes. The reaction liquid was concentrated by distillation under reduced pressure and dichloromethane (200 mL) was added thereto, followed by washing with water.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1C=O.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[CH:27](OC)([O:30][CH3:31])[O:28][CH3:29]>ClCCl>[CH3:29][O:28][CH:27]([O:30][CH3:31])[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1]
Reactant: O=Cc1sccc1Br
Reactant: COC(OC)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: COC(OC)c1sccc1Br
Yield: 97 %

Procedure:
After dissolving 5.97 g of 3-bromothiophene-2-carboxaldehyde in 90 ml of dichloromethane, a mixture of 8.0 g of montmorillonite K-10 and 120 ml of trimethyl orthoformate was added while stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and then the solvent was distilled off under reduced pressure to obtain the title compound (7.21 g, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29].O>CN(C)C=O>[C:28]([O:27][CH2:26][CH2:25][O:8][C:4]1[C:3]([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCCBr
Reactant: Cn1nc(O)c(-c2ccc3c(c2)OCO3)c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
5-Amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-ol (Preparation 34) (11.39 g) was dissolved in dimethylformamide (40 ml), cesium carbonate (15.9 g) was added followed by 2-bromoethylacetate (8.16 g). The mixture was stirred at room temperature for 16 hours. The mixture was treated with water (750 ml) and extracted with ethyl acetate (2×250 ml). The organic fractions were combined washed with water (3×350 ml), brine (250 ml), dried over magnesium sulfate, filtered and evaporated. The crude product was purified on silica (300 g) eluting with ethyl acetate:hexane (3:1) to yield the title compound as a white solid (5.57 g).
Reaction SMILES: C[Si](C#C)(C)C.[CH3:7][O:8][C:9]1[CH:16]=[C:15]([C:17]#[C:18][Si](C)(C)C)[C:12]([CH:13]=O)=[CH:11][N:10]=1.[OH-].[NH4+:24]>C(O)C>[CH3:7][O:8][C:9]1[N:10]=[CH:11][C:12]2[C:15]([CH:16]=1)=[CH:17][CH:18]=[N:24][CH:13]=2
Reactant: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Reactant: [NH4+]
Agent: C#C[Si](C)(C)C
Agent: [OH-]
Solvent: CCO
Product: COc1cc2ccncc2cn1

Procedure:
Preferably the 1,2,3,4-tetrahydro-2,7-naphthyridine intermediate (VIIb) can be synthesised as shown in Schemes 3 and 4. In Route B, commercially available 6-methoxynicotinaldehyde is treated successively with the lithium salt of N,N,N′-trimethylethylenediamine, then n-BuLi in hexanes and finally iodine to afford the 4-iodo-6-methoxynicotinaldehyde (cf. Tetrahedron Lett. 1993, 34(39), 6173-6176). The iodo compound is coupled with trimethylsilylacetylene under usual Sonagashira-Hagihara conditions (Synthesis 1980, 627-630) and the resulting 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde is condensed with ammonium hydroxide in ethanol to give 3-methoxy-2,7-naphthyridine (Synthesis 1999, 2, 306-311). Regioselective catalytical reduction (cf. Eur. J. Med. Chem. Ther. 1996, 31(11), 875-888) affords 6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine. Demethylation and N-protection with BOC-anhydride and finally treatment of the resulting tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate with triflic anhydride in a two-phase system gives (VIIb).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][OH:8].[H-].[Na+].[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[NH:13]1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN1CCC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1CON1C=CC=C(Cl)N1
Temperature: 0 °C
Yield: 41.7 %

Procedure:
(R)-1-Methyl-2-pyrrolidinemethanol (300 mg, 2.61 mmol) was dissolved in anhydrous THF and cooled to 0° C. with stirring. NaH (80% dispersion in mineral oil, 0.082 g, 2.9 mmol) was added and the mixture was slowly warmed to room temperature with stirring. After 30 minutes a THF solution of 3,6-dichloropyridazine (0.41 g, 2.74 mmol) was added to the mixture via syringe. The reaction was stirred for 48 hours. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and then with brine. The organic layer was dried over MgSO4. The resulting crude material was purified by flash chromatography (10% MeOH/CHCl3) to give 0.25 g (42% yield) of the title compound as a cream colored solid. MS (DCI/NH3) m/e 228 (M+H)+. [α]25D =+32° (c=1, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])=[O:5].N1C=CC=CC=1.[F:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1>[F:28][CH2:29][C:30]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:31]
Reactant: O=C(Cl)CF
Reactant: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 91.2 %

Procedure:
3.3 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-4-chloroaniline and 1.6 g of pyridine are dissolved in 60 ml of tetrahydrofuran, and 1.93 g of fluoroacetyl chloride are added dropwise thereto under ice-cooling and stirring. The mixture is stirred for 30 minutes under ice-cooling and further stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure to remove tetrahydrofuran. Water is added to the residue and crystalline precipitates are collected therefrom. The crystals are recrystallized from a mixture of dimethylformamide and ethanol (1:3). 3.6 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-chloroaniline are obtained as colorless needles.
Reaction SMILES: C([O:8][C@H:9]([CH3:44])[C:10]([NH:12][C:13]1[CH:18]=[C:17]([O:19][C:20]2[C:25]([F:26])=[CH:24][C:23]([NH:27][C:28]([C:30]3([C:33]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)=[O:34])[CH2:32][CH2:31]3)=[O:29])=[C:22]([F:43])[CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:11])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:43][C:22]1[CH:21]=[C:20]([O:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10](=[O:11])[C@H:9]([OH:8])[CH3:44])[CH:18]=2)[C:25]([F:26])=[CH:24][C:23]=1[NH:27][C:28]([C:30]1([C:33]([NH:35][C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[O:34])[CH2:32][CH2:31]1)=[O:29]
Reactant: C[C@@H](OCc1ccccc1)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 12 h
Yield: 11.7 %

Procedure:
To a solution of (R)—N-(4-((2-(2-(benzyloxy)propanamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.331 mmol) in methanol (20 mL) was added Pd(OH)2 (50 mg). The mixture was then hydrogenated (1 atm) for 12 h. The reaction mixture was filtered, concentrated and purified by HPLC chromatography to give (R)—N-(2,5-difluoro-4-((2-(2-hydroxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (20 mg, 11.7% yield). 1H NMR (400 MHz, CD3OD): δ 8.23-8.18 (m, 2H), 7.69 (s, 1H), 7.54-7.50 (m, 2H), 7.31-7.28 (m, 1H), 7.09-7.05 (m, 2H), 6.86-6.84 (m, 1H), 4.28-4.23 (q, J=6.8 Hz, 1H), 1.76-1.67 (m, 4H), 1.39 (d, J=6.8 Hz, 3H); MS (ESI); m/z 515.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][N:9]2[C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:27][NH2:28].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:28][OH:27])[CH2:7][CH2:8][N:9]2[C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(C(=O)c2ccc(Cl)cc2Cl)c2cc(Cl)ccc21
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(c1ccc(Cl)cc1Cl)N1CCC(=NO)c2ccc(Cl)cc21
Yield: 87.7 %

Procedure:
To a mixture of 7-chloro-1-(2,4-dichlorobenzo-yl)-2,3-dihydro-4(1H)-quinolinone (17.5 g), obtained in example 5, and ethanol (250 ml) were added hydroxyl amine hydrochloride (7 g) and pyridine (8.5 g), and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into 1000 ml of water, and precipitated crystals were separated by filtration, washed, dried and recrystallized with ethanol to obtain 7-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime (yield 16 g) as white crystal.