Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:34]=[CH:33][C:21]5[N:22]=[C:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)[CH2:4][CH2:3]1.S(C1C=CC2N=C(NC(=O)OC(C)(C)C)SC=2C=1)C#N.P([O-])(O)(O)=O.[K+].SCC(C(CS)O)O.[Cl:69]C1N2N=C(N3CCN(C)CC3)C=CC2=NN=1>O.C(O)C>[ClH:69].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:34]=[CH:33][C:21]5[N:22]=[C:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc3nnc(Cl)n3n2)CC1
Agent: CC(C)(C)OC(=O)Nc1nc2ccc(SC#N)cc2s1
Agent: CN1CCN(c2ccc3nnc(Sc4ccc5nc(NC(=O)OC(C)(C)C)sc5c4)n3n2)CC1
Agent: O=P([O-])(O)O
Solvent: O
Solvent: CCO
Product: Cl

Procedure:
The 1,1-dimethylethyl (6-{[6-(4-methylpiperazin-1-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate can be prepared according to the method described in Example 17a, but using 565 mg of 1,1-dimethylethyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate (prepared according to Example 2c), 16 cm3 of ethanol, 16 mg of potassium dihydrogen phosphate in 1.6 cm3 of water, 924 mg of DL-dithiothreitol and 505 mg of 3-chloro-6-(4-methylpiperazin-1-yl)[1,2,4]triazolo[4,3-b]pyridazine. 246 mg of 1,1-dimethylethyl (6-{[6-(4-methylpiperazin-1-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)carbamate hydrochloride are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CN>>[C:11]([C:10]1[C:9](=[O:14])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:19][N:18]([CH3:20])[CH:17]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)CC(=O)Cc1cccc(F)c1
Reactant: COC(OC)N(C)C
Agent: CN
Product: CC(=O)c1cn(C)cc(-c2cccc(F)c2)c1=O

Procedure:
A 1.5 g. portion of 1-(3-fluorophenyl)-2,4-pentanedione was reacted with 15 ml. of N,N-dimethylformamide dimethyl acetal, and then with 10 ml. of 40% aqueous methylamine as described in Example 4. The reaction mixture was then evaporated under vacuum to dryness, and the crude product was chromatographed on a silica gel column with ethyl acetate to obtain 1 g. of the desired product, which was identified by nmr analysis in CDCl3, showing peaks at δ8.1-8.2 (m, 1H, pyridine); 6.9-7.6 (m, 5H, phenyl and 1 pyridine); 3.80 (s, 3H, N--CH3); 2.83 (s, 3H, COCH3).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C>Br>[N+:11]([C:7]1[CH:6]=[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[N:15]=2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9])([O-:13])=[O:12]
Reactant: COc1cc(-c2ccnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: Br
Product: O=[N+]([O-])c1cc(-c2ccnc(-c3cccnc3C(F)(F)F)n2)cc(O)c1O
Temperature: 140 °C
Reaction time: 4 h

Procedure:
A suspension of 4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)pyrimidine (0.239 g, 0.59 mmol) in 48% hydrobromic acid (5 mL) was stirred at 140° C. for four hours and then allowed to cool to room temperature. The mixture was poured onto ice-water (100 mL) and the resulting filtrate was filtered off, washed with water and dried to give 3-nitro-5-(2-(2-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)benzene-1,2-diol, 0.201 g (90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.C([Li])CCC.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>C1COCC1.C1(C)C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[Br:18][C:19]([CH3:24])([CH3:23])[C:20]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[CH3:12])=[O:21]
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: CC(C)(Br)C(=O)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C)c(C(=O)C(C)(C)Br)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.6 %

Procedure:
To an ice-cooled solution of 5-methoxy-2-methylindole (2.5 g, 15.5 mmol) in THF (30 mL) was added n-butyllithium (2.5M solution in hexanes: 6.25 mL, 16.28 mmol) in a dropwise manner. After 20 minutes, ZnCl2 (1M solution in ether; 15.5 mL, 1.0 eq.) was added and the resulting solution stirred at 0° C. for 2 hrs. The solvent was then removed and the residue dissolved in anhydrous toluene (30 mL) to which 2-bromoisobutyryl bromide (1.93 mL, 16.28 mmol) was added and the mixture stirred at ambient temperature for 24 hrs. The solution was partitioned between 1M HCl (100 mL) and EtOAc (100 mL), the organic phase separated, washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (0 to 25% EtOAc:hexanes) to afford 2.0 g of 2-bromo-1-(5-methoxy-2-methyl-1H-indol-3-yl)-2-methyl-propan-1-one as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.52 (1H, s), 7.97 (1H, d, J=2.2 Hz), 7.21 (1H, d, J=8.8 Hz), 6.87 (1H, dd, J=8.8, 2.2 Hz), 3.91 (3H, s), 2.67 (3H, s), 2.13 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:11][C:6]1[C:7]([CH2:8][CH2:9][O:10][S:13]([CH3:12])(=[O:15])=[O:14])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: OCCc1c(Cl)ncnc1Cl
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 2-(4,6-Dichloro-pyrimidin-5-yl)-ethanol (0.46 g, 2.4 mmol) in DCM (40 mL) and was added MsCl (0.50 g, 4.36 mmol), triethylamine (1 mL) and cat. amount of DMAP. After stirring at room temperature overnight, the solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to afford methanesulfonic acid 2-(4,6-dichloro-pyrimidin-5-yl)-ethyl ester (0.52 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 4.50 (t, J=6.4 Hz, 2H), 3.42 (t, J=6.8 Hz, 2H), 3.02 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:4].[O-:25]Cl=O.[Na+]>O1CCOCC1.O>[CH2:23]([O:22][C:20]([C:11]1[CH:12]([C:16]([F:19])([F:17])[F:18])[O:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]([OH:25])=[O:4])[CH:15]=2)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C=O)cc2OC1C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1=Cc2ccc(C(C)(C)C(=O)O)cc2OC1C(F)(F)F
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 7-(1,1-dimethyl-2-oxoethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (500 mg, 1.46 mmoles) in 20 mL of dioxane was added a solution of 80% NaClO2 (727 mg, (582 mg), 6.43 mmoles) in 5 mL of water. The resulting mixture was stirred in an oil bath at 90° C. for 1.5 h, and cooled. The mixture was partitioned between DCM and water, further extracted, and the combined organic extracts dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using 30% EtOAc—hexane—1% HOAc as eluent gave the title compound, 400 mg, as an oil.
Reaction SMILES: [CH2:1]1[C:12]2[C:4](=[C:5]([NH2:13])[C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(Cl)=[O:22].C(Cl)Cl>O1CCCC1.C1(C)C=CC=CC=1>[N:13]([C:5]1[C:4]2[CH2:3][CH2:2][CH2:1][C:12]=2[CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)=[C:21]=[O:22]
Reactant: Nc1c2c(cc3c1CCC3)CCC2
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C=Nc1c2c(cc3c1CCC3)CCC2
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.77 g (0.01 mole) of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine IX (Vejdelek et al. Coll. Czech Chem. Comm. 42: 3094 (1977) and 1.11 g (0.011 mole) of triethylamine in 25 mL of tetrahydrofuran was added 5.7 mL (0.011 mole) of a 1.93 M solution of phosgene in toluene. The reaction was stirred at room temperature for 15 min and at 70° C. for 15 min. The solvents were evaporated in vacuo. The residue was dissolved in hexane and purified on a plug of silica gel eluting with 10% CH2Cl2/hexane to give 1.79 g of non-labeled X (90%); mp 40-41° C. TLC:Hex/CH2Cl2::2/1 single-spot material Rƒ 0.70.1H-NMR (300 MHz CDCl3) δ: (2.13, t, 4H), (2.85, m, 8H), (6.93, s, 1H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([O:14][CH3:15])[CH:5]=1>C(O)(=O)C>[Br:1][C:9]1[C:4]([F:3])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([NH:10][C:11](=[O:13])[CH3:12])[CH:8]=1
Reactant: BrBr
Reactant: COc1cc(F)ccc1NC(C)=O
Solvent: CC(=O)O
Product: COc1cc(F)c(Br)cc1NC(C)=O
Reaction time: 3 h

Procedure:
Bromine (1.8 ml, 34 mmol) was added dropwise to a solution of the product of Step 1 (5.69 g, 31 mmol) in acetic acid (100 ml). After 18 hours at room temperature additional bromine (0.3 ml) was added and the solution stirred for a further 3 hours. The solution was partitioned between water and ethyl acetate and the layers separated. The organic phase was then washed with aqueous sodium thiosulfate solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound. MS (ES+) m/e 262/264 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:14]2([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([N:49]([CH2:66][CH2:67][C:68]1[N:69]=[CH:70][NH:71][CH:72]=1)[C:50](=[O:65])[NH:51][CH:52]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=1)[C:53](O)=[O:54])[CH3:48].C(N(C(C)C)CC)(C)C.[OH-].[Na+]>ClCCl.CN(C)C=O>[CH:8]1([C:14]2([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:16][N:17]([C:53](=[O:54])[CH:52]([NH:51][C:50]([N:49]([CH2:47][CH3:48])[CH2:66][CH2:67][C:68]3[N:69]=[CH:70][NH:71][CH:72]=3)=[O:65])[CH2:56][C:57]3[CH:58]=[CH:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=3)[CH2:18][CH2:19]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C1(C2CCCCC2)CCNCC1
Reactant: CCN(CCc1c[nH]cn1)C(=O)NC(Cc1ccc(OC)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)C(Cc2ccc(OC)cc2)NC(=O)N(CC)CCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.8 %

Procedure:
66 mg (0.19 mmol) of ethyl 4-cyclohexylpiperidine-4-carboxylate trifluoroacetate are diluted in 3 mL of dichloromethane and 3 mL of dimethylformamide, and 67 mg (0.21 mmol) of TBTU and 75 mg (0.21 mmol) of 2-{3-ethyl-3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionic acid and 0.06 mL (0.38 mmol) of diisopropylethylamine are added. After 2 hours of stirring at room temperature, aqueous 1N NaOH solution is added and the organic products are extracted with dichloromethane. The organic phase is dried and then evaporated. The crude product obtained is chromatographed on silica gel (eluent: 95/5 dichloromethane/methanol). 34 mg of ethyl 4-cyclohexyl-1-[2-{3-ethyl-3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]piperidine-4-carboxylate in the form of a yellow oil are obtained in a yield of 30%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[NH4+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Cc1cc(N)ncc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
5-chloro-4-methylpyridin-2-amine (30 g, 210 mmol) was dissolved in concentrated sulfuric acid (150 mL), and the solution was cooled to −10° C. Nitric acid (36 mL, 806 mmol) was added dropwise. The reaction mixture was stirred at 55° C. for 3 hours. The reaction mixture was poured into an ice/water mixture, and the pH was adjusted to 8 by addition of concentrated aqueous ammonium hydroxide (22%). The resulting suspension was filtered, and the solids were washed with water and dried under vacuum to provide the title compound (23 g, 123 mmol, 58.3% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH2:37]>C1COCC1.CCOC(C)=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:37][CH3:36])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 40 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (492 mg, 0.97 mmol) in THF (1 ml) was treated with a solution of 2M methylamine in THF (7 ml, 14.4 mmol) and stirred at 40° C. in a sealed vessel for 75 minutes. The reaction mixture was allowed to cool to room temperature and dissolved in EtOAc (100 ml) which was washed with sat. NaHCO3 (100 ml) solution followed by brine. The organic extract was dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford the title compound as a colourless oil (337 mg, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:41]5[CH:40]=[C:39]([F:42])[CH:38]=[CH:37][C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cc(F)ccc1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cc(F)ccc5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-5-fluoro-phenylboronic acid.
Reaction SMILES: S([O-])([O-])=O.C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+:53].[Na+:54].[Na+].[Na+].[C:57]1([C:76]([OH:78])=[O:77])[C:66]2[C:65]([C:67]([OH:69])=[O:68])=[CH:64][CH:63]=[C:62]([C:70]([OH:72])=[O:71])[C:61]=2[C:60]([C:73]([OH:75])=[O:74])=[CH:59][CH:58]=1>>[Na:53][Na:54].[C:57]1([C:76]([OH:78])=[O:77])[C:66]2[C:65]([C:67]([OH:69])=[O:68])=[CH:64][CH:63]=[C:62]([C:70]([OH:72])=[O:71])[C:61]=2[C:60]([C:73]([OH:75])=[O:74])=[CH:59][CH:58]=1
Reactant: [Na+]
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: O=C(O)c1ccc(C(=O)O)c2c(C(=O)O)ccc(C(=O)O)c12
Agent: O=S([O-])[O-]
Product: [Na][Na]

Procedure:
The process as claimed in claim 9, wherein, after the oxidation has ended, the reaction mixture is subjected to a heat treatment at a temperature of between 90° and 100° C. under the autogenous pressure of 1 to 5 bar which is established, in the presence of sulfite, the resulting suspension of the tetrasodium salt of naphthalene-1,4,5,8-tetracarboxylic acid is cooled, after the reaction vessel has been let down, to a temperature of 20° to 30° C. the pH is then adjusted to 4.5 to 5 by acidification, the resulting disodium salt of naphthalene-1,4,5,8-tetracarboxylic acid is isolated, this salt is converted into the tetrasodium salt of naphthalene-1,4,5,8-tetracarboxylic acid in an aqueous alkali metal hydroxide solution and, optionally after removal of insoluble impurities, naphthalene-1,4,5,8-tetracarboxylic acid 1,8-monoanhydride is precipitated by acidification to a pH of less than 1 at a temperature of 80° to 100° C.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:29][N:15]1[C:16](=[O:27])[C:17]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[C:13]([C:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]4[CH:2]=2)[C:14]1=[O:28]
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A mixture of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione (0.1 g, 0.27 mmol) in 4.5 ml of dimethylformamide was treated with potassium carbonate (0.038 g, 0.27 mmol) and stirred for 1 h at rt. Methyl iodide was added (0.034 ml, 0.55 mmol) and the solution was stirred overnight at room temperature. The mixture was treated with cold water and stirred. Crystals were collected by filtration, washed with water and dried under vacuum to give 0.098 g (95%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([CH3:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([OH:18])=[C:10](C(OCC)=O)[C:9]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:7][C:8]2([CH3:25])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([OH:18])=[CH:10][C:9]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(CC2CCCCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC1(CC2CCCCC2)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A solution of Example 41D (4.56 g, 13.3 mmol) in 1,4-dioxane (30 mL) was treated with aqueous 1N hydrochloric acid solution (30 mL) and refluxed for 3 hours. The mixture was cooled to 25° C. and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated in hot hexane and filtered. The precipitate was dried to give the title compound (2.72 g, 76%). 1H NMR (300 MHz, CDCl3): δ ppm 0.85 (m, 6H) 1.43 (m, 8H) 2.03 (m, 2H) 3.80 (m, 1H) 6.05 (m, 0.5H) 7.51 (m, 3-H) 8.06 (m, 0.5H) 8.13 (m, 0.5H). MS (ESI−) m/z 269 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].ClC(Cl)Cl.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(C(=O)CC2CCN(Cc3ccccc3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(CC(=O)c2cccc(C)c2)CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
To a stirred mixture of 20.9 parts of 1-(3-methylphenyl)-2-[1-(phenylmethyl)-4-piperidinyl]ethanone, 0.75 parts of sodium carbonate and 150 parts of trichloromethane are added dropwise 8.1 parts of ethyl chloroformate. Upon completion, stirring is continued overnight at room temperature. Water is added to the reaction mixture and the layers are separated. The aqueous phase is extracted with trichloromethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 18 parts (91%) of ethyl 4-[2-(3-methylphenyl)-2-oxoethyl]-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[C:10](=[O:11])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1.S(=O)(=O)(O)O>C1COCC1>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[C:10](=[O:11])[CH2:9][CH:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: CNc1nc(Cl)nc2c1C(=O)CC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1C(=O)CC2c1ccccc1

Procedure:
A solution of 2-chloro-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one (Preparation AN) (7 mg) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (7 mg) in THF (0.2 mL) and sulfuric acid (4 mg) was heated at 85° C. for 12 h. THF was removed in vacuo, and the residue was purified by reverse phase preparative to give the title compound (as its TFA salt) as a yellowish oil (9 mg). LC-MS (M+H)+=461.12. 1H NMR (500 MHz, CD3OD) δ ppm 7.80 (m), 7.1-7.4 (m), 4.50 (1H, m), 3.25 (1H, m), 2.56 (1H, m), 3.50 (3H, s), and 3.19 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([O:18]C)=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Br)cc2c1cnn2C1CCCC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylate (3 g, 9.28 mmol) in ethanol (30 mL), aqueous NaOH solution (0.56 g in 3 mL water, 13.93 mmol) was added and reaction stirred at 60° C. for 4 h. On completion, ethanol was removed under reduced pressure and residue acidified with 1N HCl to pH 6. The resulting precipitate was filtered, washed with water and dried to 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid (2.3 g, 80.4%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CO.O.[Fe]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)c(F)c1Nc1ccccc1
Yield: 99.4 %

Procedure:
(2,3-Difluoro-6-nitro-phenyl)-phenylamine (4.2 g, 16.9 mmol), iron powder (3.8 g, 67.6 mmol), and ammonium chloride (5.2 g, 101.4 mmol) in methanol (60 mL) and water (15 mL) were heated at 90° C. for 3 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a red solid (3.7 g, 100%). 1H NMR 400 MHz δ (CDCl3): 7.25-7.16 (2H, m), 6.94-6.82 (2H, m), 6.70-6.64 (2H, m), 6.47 (1H, ddd, J=12.0, 6.1, 3.0 Hz), 5.23 (1H, br s), 3.71 (2H, br s).