Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH2:19][CH2:18][CH:17]([CH:20]=O)[CH2:16][CH2:15]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:20][CH:17]2[CH2:18][CH2:19][N:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH2:15][CH2:16]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: O=CC1CCN(c2ccccc2CN2CCOCC2)CC1
Product: c1ccc(N2CCC(CN3CCCC3)CC2)c(CN2CCOCC2)c1

Procedure:
Prepared from the product of Example 17 and pyrrolidine.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.P(Cl)(Cl)(Cl)=O.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C1C=CC=CC=1.CO>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:1]([O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13]1=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(CCOC(=O)c2ccccc2)C1=O
Reactant: Nc1ccccc1N1CCOCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: CN1CCN(CCOC(=O)c2ccccc2)C1=Nc1ccccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 133, 1-(2-benzoyloxyethyl)-3-methyl-2-imidazolidinone (8.8 g) in benzene (30 ml) was reacted with 4-(2-aminophenyl)morpholine (5.2 g) in benzene (20 ml) in the presence of phosphorus oxychloride (3.3 ml) for 35 hours at 80°-85° C. to yield an oil. The oil was dissolved in methanol (10 ml) and treated with fumaric acid (1.8 g). The solvent was removed by evaporation and the residue washed with ether and then dissolved in water. The aqueous solution was basified with aqueous sodium carbonate solution to pH 9-10 and extracted with ether to yield an oil which was purified by chromatography on an alumina column using dichloromethane as eluant. The purified base (0.8 g) in methanol (10 ml) was treated with fumaric acid (0.23 g) to give 4-((2-[1-(2-benzoyloxyethyl)-3-methyl-2-imidazolidinylideneamino]phenyl))morpholine monofumarate (m.p. 132°-133° C.) which was recrystallised from 1:2 mixture of methanol and ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:18][C:19](=[O:21])[CH3:20])=[CH:10]2)=[CH:5][CH:4]=1.COC1C=CC(I)=CC=1.[H][H]>C(O)C.[Ni].C(O)(=O)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:18][CH:19]([OH:21])[CH3:20])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(-n2cc(CC(C)=O)c3ccccc32)cc1
Agent: [Ni]
Agent: COc1ccc(I)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-n2cc(CC(C)O)c3ccccc32)cc1
Reaction time: 8 h

Procedure:
5.6 G (0.02 mole) of 1-(4-methoxyphenyl)-3-(2-oxopropyl)indole, prepared as described in example 1 but using 4-methoxyiodobenzene instead of iodobenzene are dissolved in 50 ml of anhydrous ethanol in a 200 ml autoclave. 2 g of Raney nickel are added. The autoclave is brought to a pressure of 50 kg of hydrogen and heat is applied at 100° for 8 hours at this pressure. The reaction medium is taken to dryness and the residue dissolved in normal acetic acid in the presence of diethyl ether. The organic phase is dried and the solvents are removed. The residue is then distilled.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:20]2[S:21][CH:22]=[CH:23][C:19]=2[CH3:18])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1ccsc1B(O)O
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccsc1-c1nc(C)c2c(C)nc3ccc(F)cc3n12
Yield: 100.2 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3-methyl-2-thienylboronic acid (178 mg, 1.25 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (78 mg, 100% yield). EIMS 312.0 [M+H]+.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(O)(=O)C.[N:21]([O-])=[O:22].[Na+]>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([N:21]=[O:22])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N2CCN(N=O)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 52.6 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 100 parts of acetic acid and 100 parts of water is added dropwise, during a 1.50 hours-period, a solution of 20.8 parts of sodium nitrite in 100 parts of water at a temperature between 0° and 5° C. Upon completion, stirring is continued for 30 minutes. The reaction mixture is diluted with water. The precipitated product is filtered off and crystallized from 2-propanol, yielding 22.5 parts of 1-(4-methoxyphenyl)-4-nitrosopiperazine, mp. 94.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]2[C:10]([C:11]=1[OH:12])=[C:9]([CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][CH2:19]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]2[C:10]([C:11]=1[O:12][CH2:17][O:18][CH3:19])=[C:9]([CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=2
Reactant: CCc1cccc2c(C=O)cc(Cl)c(O)c12
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc2c(C=O)cc(Cl)c(OCOC)c12

Procedure:
1.0 g of 3-chloro-5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde, 0.91 ml of chloromethyl methyl ether and 3.5 ml of N,N-diisopropylethylamine were dissolved in 10 ml of dichloromethane, and reacted at room temperature for 4 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.N#N.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:30]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:34][CH:33]=1)=[O:31]
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2cc(OC)ccc2c1
Agent: N#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OC)ccc2c1
Temperature: 0 °C

Procedure:
Dissolve 2,6-dimethoxynaphthalene (1.0 eq.) in CH2Cl2 (5 volume eq.) at ambient temperature in a dry round bottom flask equipped with stir bar, temperature probe and N2 line. Cool the solution to 0° C. with an ice bath, and add 4-(2-piperidin-1-yl-ethoxy)-benzoyl chloride (1.1 eq.). Add aluminum chloride (2.0 eq.). Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and CH2Cl2. Wash the aqueous layer with CH2Cl2 (20 mL). Combine the organic extracts and wash with brine and dry (Na2SO4). Recrystallize the crude product from methanol to give (2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[C:4]([N+:12]([O-])=O)[CH:3]=1.C(O)(=O)CCCCC(O)=O.[H][H]>[Ni].O>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([NH2:12])[CH:3]=1
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: O=C(O)CCCCC(=O)O
Solvent: O
Product: Nc1cc(N)c(N)c(Cl)c1
Reaction time: 2 h

Procedure:
109 Parts of finely ground 6-chloro-2,4-dinitro-aniline together with 73 parts of adipic acid, 10 parts of a commercial-type nickel catalyst (about 50% Ni on kieselguhr) and 500 parts by volume of water charged into a hydrogenation autoclave equipped with a double-acting, magnetically operated agitator. After the autoclave had been sealed, air was expelled from the free volume by passing nitrogen over it (for 15 minutes). Heating and agitator were then put to work, 120 atmsg. of hydrogen were forced in under pressure, and hydrogenation was effected. Hydrogen absorption started at about 60° C., and was complete within about 2 hours at a maximum temperature of 95° C. Evidence for 6-chloro-1,2,4-triamino-benzene obtained was provided by releasing the residual hydrogen, freeing the mixture from the catalyst by filtration through a pressure filter under a nitrogen pressure of 20 atmsg. and passing the filtrate into another stirrer-equipped vessel which contained 150 parts of urea. The mixture was then refluxed for 5 hours while maintaining the pH at 4 - 5 by adding a total of about 112 parts of sulfuric acid monohydrate. The ph was then adjusted to 6 by means of 54 parts of a 33% sodium hydroxide solution, and the mixture was cooled to room temperature. About 90 parts of a compound were obtained, which has a melting point of 341° C. and whose analytical data for C, H, Cl and N corresponded to the calculated values for the urea compound of the formula
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: CN(C)CCn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which have been described in example 19) with commercially available (2-chloro-ethyl)-dimethyl-amine as electrophile, the title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH3:22].C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH3:22])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Reaction time: 18 h
Yield: 53.3 %

Procedure:
A solution of the compound of Example 68, 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.67 mmol) in 30 mL of CH2Cl2 was treated with triethylamine (1.10 mL, 8.0 mmol). With vigorous stirring the solution was treated dropwise with benzoyl chloride (0.325 mL, 2.80 mmol). After 18 h, the reaction was treated with 50 mL water and 50 mL CHCl3 and the layers were separated. The aqueous portion was extracted with CHCl3 (3×30 mL). The combined organic portions were washed with brine, dried over Na2SO4, filtered and concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 574 mg of N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}benzamide as a white solid. mp=188-191° C.; 1H NMR (300 MHz, DMSO-d6) δ8.36 (t, J=5.4 Hz, 1 H), 8.04 (d, J=7.5 Hz, 1 H), 7.80-7.75 (m, 2 H), 7.62 (dd, J=1.1, 8.3 Hz, 1 H), 7.55-7.36 (m, 4 H), 7.18 (m, 1 H), 6.45 (s, 2 H), 4.70 (t, J=5.1 Hz, 2 H), 3.90 (t, J=5.1 Hz, 2 H), 3.49 (t, J=6.1 Hz, 2 H), 3.40-3.33 (m, 2 H), 2.93 (q, J=7.5 Hz, 2 H), 1.30 (t, J=7.4 Hz, 3 H); 13C NMR (75 MHz, DMSO-d6) δ166.7, 155.2, 152.0, 145.1, 134.8, 132.8, 131.4, 128.6, 127.5, 126.7, 126.6, 121.4, 120.5, 115.2, 69.4, 69.2, 45.4, 20.3, 12.1; MS m/z 404 (M+H)+; Anal. Calcd for C23H25N5O2: C, 68.47; H, 6.25; N, 17.36. Found: C, 68.27; H, 6.32; N, 17.28.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2([CH3:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:4][C:5]([O:8]C)=[CH:6][CH:7]=1.[I-].[Na+].[Si](Cl)(C)(C)C.OS([O-])(=O)=O.[Na+]>C(#N)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[N:4][C:3]=1[NH:10][CH2:11][C:12]1([CH3:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc(F)c(NCC2(C)CCOCC2)n1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(CNc2nc(O)ccc2F)CCOCC1
Temperature: 83 °C
Reaction time: 0.25 h

Procedure:
To 3-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine in acetonitrile (12 mL) was added sodium iodide (4.24 g, 28.3 mmol) and slowly TMS-Cl (3.62 mL, 28.3 mmol). The mixture was heated to reflux (oil bath: 83° C.) for 4 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc and saturated aqueous NaHCO3 solution. The mixture was vigorously stirred for 15 min and acidified with 0.5N aqueous NaHSO4 solution and stirring was continued for 5 min. The mixture was neutralized with saturated aqueous NaHCO3 solution. The separated aqueous phase was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, 25 min, EtOAc/heptane=5/95 for 2 min, 5/95 to 50/50 over 18 min, then 50/50] providing 5-fluoro-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-ol as colorless highly viscous oil. Yield: 420 mg. LCMS (m/z): 241.1 [M+H]+; Retention time=0.55 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:6][N:5]([CH2:4][C:3]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=2[Cl:1])[C:15](=[O:14])[CH:16]=1
Reactant: NNCc1ccc(F)cc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(F)cc2Cl)[nH]1
Reaction time: 8 h

Procedure:
53.8 g of 2-chloro-4-fluorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 49.2 g of β-aminoβ-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 250 ml of ethanol, in the course of which the temperature rose from 22° to 32° C. After standing overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 192°, 25 g (34%).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:38])=[O:5])(=[O:13])=[O:14])=[C:16]([O:25][CH2:26][CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[CH:17]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ccccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ccccc23)c1

Procedure:
A solution of 3-[4-acetylamino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (110 mg) in methylene chloride (6 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature for 4 hours. The solvent was evaporated. The residue was triturated with ether and the resulting amorphous solid (58 mg) was collected by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3=[N:13][C:14]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[CH2:31](O)[CH3:32]>>[CH2:31]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([C:14]2[N:13]=[C:11]3[N:10]([CH:15]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[S:12]3)=[CH:17][CH:18]=1)[CH3:32]
Reactant: O=C(O)c1ccc(-c2cn3nc(-c4ccc(O)cc4)sc3n2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(O)cc4)sc3n2)cc1
Temperature: 80 °C
Reaction time: 9 h

Procedure:
To a suspension of 4-[2-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (4.0 g) in ethanol (50 ml) was added sulfuric acid (1.0 ml) and the mixture was stirred at 80° C. for 9 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration, washed with water, acetonitrile and diisopropyl ether and dried to give 4-[2-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester (2.09 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[CH:19]=[C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]4=[CH:16][C:15]=3[N:14]([CH2:25][C:26]3[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[C:13]2=[O:35])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:32][C:31]([F:34])([F:33])[C:28]1[O:27][C:26]([CH2:25][N:14]2[C:15]3[CH:16]=[C:17]4[O:24][CH2:23][CH2:22][O:21][C:18]4=[CH:19][C:20]=3[C:12]3([C:3]4=[CH:4][C:5]5[O:10][CH2:9][CH2:8][O:7][C:6]=5[CH:11]=[C:2]4[O:1][CH2:36]3)[C:13]2=[O:35])=[CH:30][CH:29]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc3c(cc2N1Cc1ccc(C(F)(F)F)o1)OCCO3
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C12COc1cc4c(cc12)OCCO4)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one was obtained (76%) as a colorless solid: mp 176-178° C.; 1H NMR (300 MHz, CDCl3) δ 6.75-6.67 (m, 2H), 6.49-6.43 (m, 2H), 6.37-6.31 (m, 1H), 6.22-6.16 (m, 1H), 4.87 (ABq, 2H), 4.69 (ABq, 2H), 4.26-4.04 (m, 8H); 13C NMR (75 MHz, CDCl3 δ 177.2, 155.0, 152.0, 151.9, 144.6, 144.0, 140.1, 138.3, 135.2, 124.3, 120.9, 113.7, 112.6, 112.6, 111.5, 109.1, 99.3, 98.9, 80.0, 64.6, 64.5, 64.0, 63.9, 57.8, 37.0; MS (ES+) m/z 501.9 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].[NH2:17][C:18]1[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21]>>[CH2:1]([O:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([NH:17][C:18]1[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:21])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: CCCCOc1cc(OC)ccc1C(=O)O
Product: CCCCOc1cc(OC)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(OC)cc1
Yield: 25.2 %

Procedure:
Using the procedure described in Example 102, Part A, 2-butoxy-4-methoxybenzoic acid (0.54 mmol) and 2-amino-N-(4-methoxyphenyl)benzamide (0.54 mmol) yielded 61 mg (25%) of the title compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([S:40]([N:30]2[CH2:31][CH2:32][CH:27]([N:12]3[C:13]4[C:22]5[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=5[N:16]=[CH:15][C:14]=4[C:25](=[O:26])[N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=4)[C:11]3=[O:33])[CH2:28][CH2:29]2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(S(=O)(=O)c4ccccc4)CC3)c12

Procedure:
1-(1-Benzenesulfonyl-piperidin-4-yl)-3-(3-chloro-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (51 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and benzenesulfonyl chloride. LCMS: m/z 577 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([CH2:19][Cl:20])[NH:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>CC(C)=O>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:6]([NH:5][CH:4]([C:3]([OH:21])=[O:2])[CH2:19][Cl:20])=[O:18])=[CH:13][CH:12]=1)[CH:16]=[CH2:17]
Reactant: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccc(CC(=O)NC(CCl)C(=O)O)cc1
Temperature: 40 °C
Yield: 94.2 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-(DL)-alanine methyl ester (2.0 g) was suspended in acetone (20 ml). Aqueous sodium hydroxide (1M, 8.0 ml) was added and the mixture was gently warmed to effect solution, and then heated at 40° C. for 20 min. After the solution has been cooled, the pH was adjusted to 2-3 using dilute hydrochloric acid (3M) and the product was extracted with ethyl acetate (40 ml). The extract was dried (anhydrous sodium sulphate). The solvent was evaporated at reduced pressure to leave a solid residue (1.8 g); it had m.p. 120°-124° C. After recrystallisation from ethyl acetate/light petroleum (b.p. 60°-80° C.) the above-named product, (1.6 g), m.p. 123°-124° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.CN(C)[CH2:16][CH2:17]O.C([Zn]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.C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:16][CH3:17])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: CN(C)CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[Zn]CC
Solvent: C1CCOC1
Product: CCc1nc(C(=O)OC)cc(Cl)c1Cl

Procedure:
A 100 mL three-neck flask equipped with a reflux condenser and nitrogen inlet was charged with methyl 4,5,6-trichloropicolinate (2.40 g, 9.98 mmol). Anhydrous THF (50 mL) was added followed by N,N-dimethylethanolamine (0.20 g). The reaction mixture was sparged with nitrogen for 15 min Solid Pd(PPh3)2Cl2 (140 mg, 0.2 mmol) was added. The reaction mixture was stirred under nitrogen for 20 min Diethylzinc (1M solution in hexanes; 10 mL, 10 mmol) was added in 2 mL portions. When starting material was no longer observed through analysis by GC, the reaction mixture was quenched with water and extracted into EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to a white solid (2.34 g). Analysis by GC-MS showed the solid contained 11% starting methyl 4,5,6-trichloropicolinate. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H, pyridine H), 4.01 (s, 3H, CO2Me), 3.10 (q, J=8 Hz, 2H, CH2), 1.33 (t, J=8 Hz, 3H, CH2CH3); 13C{1H} NMR (101 MHz, CDCl3) δ 164.4, 162.8, 145.4, 143.3, 132.9, 124.5 (C3), 53.1 (CO2Me), 30.0 (CH2), 12.3 (CH2CH3).