Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:16]([O:18]C)=[O:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@:20]12([OH:29])[N:27]([CH3:28])[C@@H:24]([CH2:25][CH2:26]1)[CH2:23][CH:22]=[CH:21]2.[Na].O>C(#N)C>[C@@:20]12([OH:29])[N:27]([CH3:28])[C@@H:24]([CH2:25][CH2:26]1)[CH2:23][CH:22]=[CH:21]2.[OH:1][C:2]1([C:16]([O-:18])=[O:17])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[O:9][C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: COC(=O)C1(O)c2ccccc2Oc2ccccc21
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: O=C([O-])C1(O)c2ccccc2Oc2ccccc21

Procedure:
13.65 g (0.053 mol) of methylester 3a, 8.35 g (0.06 mol) of tropenol and 0.2 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water with occasional agitation. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue is extracted with dichloromethane/water. Then the organic phase is washed with water, dried over magnesium sulfate, and the solvent is distilled off. The product is purified by recrystallization from diethyl ether/petroleum ether. Yield: 5.28 g of white crystals (27% of theoretical yield); melting point: 117° C.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][CH:9]=[C:10]([Cl:13])[C:11]=1[Cl:12])=[O:6])C.Cl>CC(C)=O.O>[Cl:12][C:11]1[C:10]([Cl:13])=[CH:9][S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(=O)c1scc(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C(=O)c1scc(Cl)c1Cl
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of yield (3,4-dichlorothiophen-2-yl)-oxo-acetic acid ethyl ester (0.42 g, 1.66 mmol) in acetone (10 ml), water (2 ml), and conc. HCl (10 ml) was stirred under reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature then was concentrated in vacuo to provide a crude oil. The crude oil was purified by preparative HPLC to provide pure (3,4-dichlorothiophen-2-yl)-oxo-acetic acid as a yellow solid (85 mg, 38%). MS (M−H)−: 222.80; 1H NMR (300 MHz, DMSO-d6) δ8.38 (1H, s). 13C NMR (75 MHz, CDCl3) δ173.14, 159.44, 136.57, 133.43, 128.97, 125.20.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18].CO.C(N(CC)CC)C>>[OH:18][CH2:17][CH:16]([N:15]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[CH2:19][OH:20]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1C(CO)CO

Procedure:
5-nitro-isochromen-1-one (4.2 g, 0.022 mol) and Serinol (2.0 g, 0.022 mol) were refluxed in methanol (40 mL, 1 mol) for 1 hour. TLC showed that all of the starting material was consumed. Triethylamine (5 mL, 0.04 mol) was added to the mixture and the reaction mixture was refluxed overnight. The volatiles were removed via rotovapor, and the residue was purified by flash column chromatography (40 g of silica gel, 0-50% EtOAc/Hexane), and gave a green yellow solid. MS m/z=264.7 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([CH2:11][O:12][CH3:13])[CH:3]=1.[CH3:14][N:15](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[CH3:13][O:12][CH2:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=1)[C:14]#[N:15]
Reactant: COCc1cc(Br)cc(COC)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: COCc1cc(C#N)cc(COC)c1
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of 1-bromo-3,5-bis-methoxymethyl-benzene (522 mg, 2.130 mmol) in dimethylformamide (5 mL) at room temperature was added zinc cyanide (150 mg, 1.278 mmol). The reaction mixture was degassed by passing argon through for I h before tetrakis(triphenylphosphine)palladium (148 mg, 0.128 mmol) was added. The reaction mixture was heated at 80° C. under argon for 12 h. The reaction mixture was taken up in toluene (30 mL) and washed with 10% ammonium hydroxide (2×40 mL), brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 3,5-bis-methoxymethyl-benzonitrile (320 g, 79%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[CH3:17]I>C(COC)OC>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1
Reactant: CI
Reactant: COC(=O)Cc1ccc(O[Si](C)(C)C)cc1
Solvent: COCCOC
Product: COC(=O)C(C)c1ccc(O)cc1
Temperature: -70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of methyl 2-(4'-trimethylsilyloxyphenyl)ethanoate (34.3 mmole) in dimethoxyethane (10 ml) was added dropwise to the reaction, the temperature rising to -30° C. before cooling to -70° C. This cold reaction mix was added dropwise to a solution of methyliodide (0.16 mole) in dimethoxyethane (20 ml) cooled to -70° C. The mixture was stirred at room temperature overnight before removing the solvent by evaporation. The residue was stirred with dilute HCl and extracted with dichloromethane, washed with saturated NaHCO3 solution, dried (MgSO4) and the product isolated by evaporation. Distillation of the crude product gave MHPP (yield 88%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([C:15]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.Cl>C(O)C.O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]([OH:14])[C:15]2([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(C(=O)c2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)C1(C(O)c2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.3 %

Procedure:
To a solution of 0.974 g of methyl 1-(3-{[(t-butoxycarbonyl)amino]methyl}-4-methoxybenzoyl)-1-cyclopropanecarboxylate in 30 ml of ethanol and 10 ml of tetrahydrofuran was added 0.112 g of sodium borohydride, and the mixture was stirred at room temperature for 15 hours. 50 ml of water, 100 ml of ethyl acetate and 5 ml of hydrochloric acid (2N) were added, and the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, to give 0.483 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:32]/[OH:33])/[C:8]([NH:10][CH:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O-:29])=[O:28])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:35]([O:41][CH2:42][O:28][C:27]([C:14]1[N:13]2[C:30](=[O:31])[CH:11]([NH:10][C:8](=[O:9])/[C:7](/[C:5]3[N:6]=[C:2]([NH2:1])[S:3][CH:4]=3)=[N:32]\[OH:33])[C@H:12]2[S:17][CH2:16][C:15]=1[CH2:18][O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:29])(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(COC(=O)N4CCCC4)CS[C@H]23)cs1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(COC(=O)N2CCCC2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 28 %

Procedure:
The compound obtained in Example 13 and iodomethyl pivalate were reacted, whereby the title compound was obtained (yield: 28%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:29]([OH:32])CO)[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.O>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:29]=[O:32])[C:5]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(C(O)CO)cc(C)c32)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(C=O)cc(C)c32)cc1
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a suspension of (±)-1-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)ethane-1,2-diol (238 mg, 0.52 mmol) in THF (5 mL)/H2O (1 mL) was added NaIO4 (443 mg, 2.1 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1.25 h. The reaction mixture was diluted with EtOAc. The bi-layer was partitioned. The organic phase was washed with half satd. Na2S2O3, H2O and brine, dried over Na2SO4, and then filtered. Concentration of the filtrate gave the title compound with no need of any further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.02 (d, J=4.04 Hz, 1H), 7.68 (d, J=8.59 Hz, 2H), 7.55 (s, 1H), 7.43 (d, J=8.59 Hz, 2H), 7.20 (d, J=4.04 Hz, 1H), 5.27 (d, J=11.62 Hz, 1H), 5.09 (d, J=11.62 Hz, 1H), 4.69-4.76 (m, 1H), 3.68-3.81 (m, 1H), 3.37-3.51 (m, 1H), 2.52 (s, 3H), 2.36 (s, 3H), 1.53-1.70 (m, 2H), 1.32-1.53 (m, 4H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][N:24]=1>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:21][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:25][N:24]=1
Reactant: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2ccc(OCc3ccc(Cl)nc3)c(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution 0.07 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.50 g of 2-chloro-4-(3-trifluoromethylphenoxy)phenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.28 g of 2-chloro-5-chloromethylpyridine in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 2-chloro-5-[2-chloro-4-(3-trifluoromethylphenoxy)phenoxy]methylpyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:26]1>CN(C)C=O>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:38][CH2:39]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 20 °C
Yield: 33.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.9 g), triethylamine (4.5 cc) and 4-(1,2-benzisothiazole-3-yl)piperazine (6.6 g) in dimethylformamide (95 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (90 cc), 2-{2-[4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) is obtained, m.p. 162°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:29]=[CH2:30])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(NP1(N(CC)CC)N(C)CCCN1C)(C)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH:29]=[CH2:30])=[C:4]([NH:10][C@@H:11]([C:12]2[O:25][C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C@@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C=Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Agent: CCN(CC)[PH]1(NC(C)(C)C)N(C)CCCN1C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: C=Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reaction time: 1 h
Yield: 121.9 %

Procedure:
To a solution of N′-((2R,3S)-2-(3-chloro-4-cyano-2-vinylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (0.79 g, 1.86 mmol) in anhydrous THF (200 mL) at room temperature was added 2-tert-butylamino-2-diethylamino-1,3-dimethyl perhydro-1,3,2-diazaphosphorine on polystyrene (3 mmol base/g) (2.54 g, 5.59 mmol) followed by para-toluene sulfonyl chloride (p-TSCl) (355 mg, 1.86 mmol) and the mixture was stirred for 1 h. The mixture was filtered under suction, the residue then washed with acetone (300 mL) followed by methanol (300 mL) and then concentrated to furnish a yellow oil (0.92 g). Purification by flash column chromatography [EtOAc-hexanes (3:2) as eluent] afforded the title compound as a white crystalline solid (86 mg, 11%). 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.20 (d, J=9 Hz, 2H), 7.99 (d, J=9 Hz, 2H), 7.56 (d, J=9 Hz, 1H), 6.90 (d, J=9 Hz, 1H), 6.83 (dd, J=12 and 18 Hz), 6.22 (d, J=9 Hz, 1H), 5.94 (dd, J=2 and 12 Hz) 5.84 (dd, J=2 and 18 Hz), 5.19 (d, J=9 Hz, 1H), 4.68-4.60 (m, 1H) and 1.20 (d, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:23])([CH3:22])[C:12](OCC3C=CC=CC=3)=[O:13])[NH:8]2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:23])([CH3:22])[CH2:12][OH:13])[NH:8]2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(C)(C(=O)OCc1ccccc1)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(CO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate (18.0 g, 0.05 mol) in CH2Cl2 (100 mL) was added DIBAL-H (12 mL) at −78° C. The mixture was stirred for 1 h at that temperature and was warmed to room temperature. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (10.0 g, 77%). 1H NMR (300 MHz, CDCl3) 9.37 (s, 1H), 8.32 (d, J=7.2 Hz, 1H), 7.11 (d, J=11.7 Hz, 1H), 6.36 (s, 1H), 3.73 (d, J=5.1 Hz 2H), 1.97 (t, J=5.1 Hz, 1H), 1.39 (s, 6H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][C:14]1[N:19]=[N:18][C:17]([O:20][C:21]2[C:26]3[C@@H:27]4[C@H:32]([CH2:33][CH2:34][C:25]=3[CH:24]=[CH:23][CH:22]=2)[NH:31][CH2:30][CH2:29][CH2:28]4)=[CH:16][CH:15]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:31]3[C@@H:32]4[C@@H:27]([C:26]5[C:21]([O:20][C:17]6[N:18]=[N:19][C:14]([CH3:13])=[CH:15][CH:16]=6)=[CH:22][CH:23]=[CH:24][C:25]=5[CH2:34][CH2:33]4)[CH2:28][CH2:29][CH2:30]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1ccc(Oc2cccc3c2[C@H]2CCCN[C@H]2CC3)nn1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: Cc1ccc(Oc2cccc3c2[C@H]2CCCN(C(=O)c4ccc5[nH]cnc5c4)[C@H]2CC3)nn1
Yield: 17 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-10-(6-methyl-pyridazin-3-yloxy)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 17% of theory; LC (method 1): tR=2.39 min; Mass spectrum (ESI+): m/z=440 [M+H]+.
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][CH2:7]I.[CH:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13]>>[OH:3][CH2:4][CH2:5][O:6][CH2:7][C:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13]
Reactant: C[Si](C)(C)OCCOCI
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Product: O=[N+]([O-])C(COCCO)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
In the next step, the iodomethyl 2-(trimethylsilyloxy)ethyl ether is reacted with nitroform to produce 2,2,2-trinitroethyl 2-hydroxyethyl ether:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=[O:12].[CH3:16][CH:17](C(O)=O)C(O)=O.Cl>C(N(CC)CC)C>[O:12]=[C:11]([C:3]1[C:2]([C:14]([OH:13])=[O:15])=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][CH3:17]
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Reactant: CC(C(=O)O)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC(=O)c1cc2ccccc2cc1C(=O)O
Yield: 56.3 %

Procedure:
A mixture of 2,3-naphthalenedicarboxylic anhydride (35.5 g), methylmalonic acid (25 g) and triethylamine (250 ml) was stirred and refluxed for 8 hr. The cooled reaction mixture was poured onto 10% hydrochloric acid (2 liter) and the aqueous slurry was extracted with chloroform (1.5 liter). The dried (magnesium sulphate) extract was evaporated to dryness to give an oil which was recrystallised from light petroleum (b.p. 60°-80°)/chloroform to give 3-(1'-oxopropyl)naphthalene-2-carboxylic acid (23 g, m.p. 147°).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].C(N(CC)CC)C>CN(C)C=O>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A suspension of 4.6 g (20 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 2.36 ml (30 mmol) of ethyl isocyanate, and 70 ml of dimethylformamide is stirred at room temperature and 2.8 ml (20 mmol) of triethylamine is added. The resulting solution is allowed to stand overnight at room temperature and another 2.36 ml (20 mmol) of ethyl isocyanate is added. After 6 hrs the dimethylformamide is evaporated under high vacuum and the residue is treated with 100 ml of water. The solid is filtered and dried to give 1.5 g of 2-[4-(N-ethylcarbamoylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid. The filtrate is acidified to pH 2.5 with hydrochloric acid and another 3.10 g of acid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([C:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24](O)=[O:25])=[CH:21][CH:22]=4)[NH:17][CH:16]=3)=[O:14])=[C:11]([CH3:27])[O:10][N:9]=2)=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.O[N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=CC=2N=N1.CCN(CC)CC.C1(N)CC1>CN(C=O)C>[CH:45]1([CH2:44][NH:40][C:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:15]([C:13]([C:12]4[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[N:9][O:10][C:11]=4[CH3:27])=[O:14])=[CH:16][NH:17]3)=[CH:22][CH:21]=2)=[O:25])[CH2:47][CH2:46]1
Reactant: On1nnc2ccccc21
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c2cc(C(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c2cc(C(=O)NCC3CC3)ccc12
Yield: 71.9 %

Procedure:
A solution of 62 mg (0.17 mmol) 3-[3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-1H-indole-6-carboxylic acid, 41 mg (0.21 mmol) N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide, 23 mg (0.17 mmol) 1-hydroxy benzotriazole, 59 uL (0.43 mmol) Et3N and 0.26 mmol cyclopropylamine in DMF (1 mL) was reacted at room temperature overnight. After evaporation the mixture was subjected to preparative HPLC purification on reversed phase eluting with an acetonitrile/water (0.05% NEt3) gradient to afford 51 mg of the title compound in 72% yield as a white solid. (m/e): 418.1 (MH+; 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:13][OH:14]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[N:13]/[OH:14])/[CH2:6][CH2:5]2
Reactant: NO
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl
Solvent: CCO
Product: O/N=C1\CCc2cc(Br)ccc21
Yield: 88.5 %

Procedure:
5-bromo-2,3-dihydro-1H-inden-1-one (25 g, 118 mmol) and hydroxylamine hydrochloride (12.35 g, 178 mmol) were heated in Ethanol (150 mL) for 5 hours with stirring. The solvent was evaporated in vacuo and remaining solid partitioned between H2O and EtOAc. The organic layer was separated and washed with brine (2×), dried on Na2SO4 and solvent evaporated in vacuo to afford the title compound as a light brown solid (23.6 g, 87%). MS (ESI): m/z [M+H]+ 227.0
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.C(Cl)(Cl)Cl.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>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL) CHCl3 (40 mL) in a dry flask, under nitrogen. TEA (8.14 mL<58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5% HCl (2×40 mL), dried over anhydrous MgSO4 and concentrated to a brown paste (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluting with 10% EtOAc/hexane (1 L) followed by 15% EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91%) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H1: 249.0947, found 249.0947.