Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH:23]=[C:22]([C:33]([F:36])([F:35])[F:34])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[CH:23]=[C:22]([C:33]([F:34])([F:35])[F:36])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.2 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.27 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.16 g, 49%). MS (ISP) 480.9 [(M+H)+]; mp 282° C.
Reaction SMILES: [CH2:1]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H].C(N1C[C@H]2[C@H](CCCC2)C1)CCCCCCCC>[C].[Rh].CC(O)C>[CH2:1]([N:10]1[CH2:11][C@H:12]2[C@@H:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCN1Cc2ccccc2C1
Reactant: [H][H]
Agent: [Rh]
Agent: CCCCCCCCCN1C[C@H]2CCCC[C@H]2C1
Solvent: CC(C)O
Product: CCCCCCCCCN1C[C@@H]2CCCC[C@H]2C1
Yield: 0.5 %

Procedure:
In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 265 g of N-nonylisoindoline, 735 g of 2-propanol and 26 g of 5% rhodium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 15 kg/cm2 and a temperature of 120° C. After a 5 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydro-N-nonylisoindoline is 98.0%. In addition, 0.5% of trans-hexahydro-N-nonylisoindoline is formed.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:6][CH:7]=1.Cl[C:16]1[N:17]=[N:18]C(C2C=CC(Cl)=CC=2)=CC=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:16]=[N:17][N:18]=3)[N:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: Clc1cccc(-c2ccc(Cl)nn2)c1
Product: Clc1cccc(-c2ccc3nncn3n2)c1

Procedure:
The procedure of Example 15 is repeated substituting an equimolecular amount of 3-chloro-6-(m-chlorophenyl)pyridazine for the 3-chloro-6-(p-chlorophenyl)pyridazine employed in that example. There is thus obtained the title compound in equally good yield; m.p. 175°-177° C.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@:13]12[C:19]([CH3:21])([CH3:20])[C@@:16]([CH3:22])([CH2:17][CH2:18]1)[C:15](=[O:23])[O:14]2)=[O:12])[CH2:2][CH2:3][CH3:4].[OH-:28].[K+].Cl>C(O)C.O>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([OH:28])[CH2:18][CH2:17][C@@:16]([CH3:22])([C:15]([OH:14])=[O:23])[C:19]1([CH3:20])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@]12CC[C@@](C)(C(=O)O1)C2(C)C
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(O)CC[C@@](C)(C(=O)O)C1(C)C
Temperature: 60 °C
Yield: 75.2 %

Procedure:
A mixture of the product from Example 102 (50.0 mg, 0.127 mmol) and potassium hydroxide (71.5 mg, 1.27 mmol) in ethanol (1 mL) and water (0.2 mL) was heated to 60° C. for 24 hours. After cooling to ambient temperature, 1N HCl (aq) was added to adjust the pH to −1. The mixture was extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated by rotary evaporator to give a white solid. Recrystallization of the solid from ethyl acetate afforded 39.2 mg (75%) of the title compound. 1H NMR (DMSO-d6) δ 0.79 (s, 3H), 0.92 (t, J=7.2 Hz, 3H), 1.07 (br s, 3H), 1.18 (br s, 3H), 1.27-1.40 (m, 3H), 1.50-1.63 (m, 3H), 1.68 (s, 9H), 1.85 (br s, 1H), 2.51-2.59 (m, 2H), 2.91 (br s, 2H), 9.07 (br s, 1H), 12.10 (br s, 1H). MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[NH:23][C:22]([CH:24]=O)=[C:21]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[CH:20]=1>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:24][C:22]2[NH:23][C:19]([CH3:18])=[CH:20][C:21]=2[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[O:27])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CCN(C)CC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-fluoro-phenyl)-3-[5-methyl-3-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (44.1 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:23]3[N:24]=[C:25]4[C:31]([CH:32]=[O:33])=[CH:30][N:29]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:26]4=[N:27][CH:28]=3)=[N:7][N:8]2[CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)=[CH:4][CH:3]=1.S(=O)(=O)([OH:44])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[C:19]([O:18][C:16]([N:14]1[CH2:13][CH:12]([CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([C:23]3[N:24]=[C:25]4[C:31]([C:32]([OH:44])=[O:33])=[CH:30][N:29]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:26]4=[N:27][CH:28]=3)=[N:7]2)[CH2:15]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(Cn2nc(-c3cnc4c(n3)c(C=O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)C1
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Cn2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of tert-butyl 3-((6-fluoro-3-(7-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (160 mg, 276 μmol) and sulfamic acid (161 mg, 1.65 mmol) in dioxane (5 mL) and water (2 mL), cooled to 0° C., was added a solution of sodium chlorite (32.4 mg, 358 μmol) and potassium dihydrogen phosphate (450 mg, 3.31 mmol) in water (3 mL) dropwise. The mixture was warmed to room temperature. After 2.5 h, the mixture was partitioned between ethyl acetate and water and the organic phase separated and washed with water then dried and concentrated in vacuo. A quantitative yield was assumed and the crude residue used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C[N-]C.CCOCC.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Agent: C[N-]C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(CCCOc2cccc3ccccc23)c2cccc(Br)c2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 7-bromo-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (2.39 g, prepared in a similar manner as described herein) in N,N-dimethylamide (20 mL) was added 1-(chloromethyl)-4-methoxybenzene (1.0 g) and Cs2CO3 (5.16 g). The mixture was stirred overnight at room temperature. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted with ether. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Concentration gave EXAMPLE 581A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([O:8][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[N:6][CH:7]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: CC(C)(C)OC(=O)Oc1cc(Br)c[nH]c1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Oc1cc(Br)cnc1OCc1c(F)cccc1F

Procedure:
To a solution of 5-bromo-3-hydroxy-2(1H)-pyridinone (U.S. Pat. No. 3,471,506, 10.0 g, 52.6 mmol) in dioxane (30 mL) and H2O (15 mL) was added NaOH (2.1 g, 52.5 mol) dissolved in H2O (12.5 mL). To this mixture is added di-t-butyl-dicarbonate (12.5 g, 57.5 mmol), and the mixture is stirred at room temperature for 6 hours. At this time, the mixture is filtered, and the solid is washed with H2O (50 mL), and is dissolved in CH2Cl2 (100 mL). This organic solution is washed with brine, dried over MgSO4, and concentrated to yield 5-bromo-3-(t-butoxycarbonyloxy)-2(1H)pyridinone. A solution of 5-bromo-3-(t-butoxycarbonyloxy)-2(1H)-pyridinone (5.0 g, 17.2 mmol), AG2CO3 (4.74 g, 17.2 mmol) and α-bromo-2,6-difluorotoluene (3.56 g, 17.2 mmol) in toluene (60 mL) is heated to 42° for 24 hours in the dark. At this time the mixtut is filtered. The filtrate is concentrated in vacuo, and the residue is dissolved in EtOAc (150 mL) and washed with H2O (50 mL) and brine (50 mL), dried over MgSO4 and concentrates in vacuo. Chromatography (silica, 9:1 EtOAc/hexane) yields 5-bromo-3-(t-butoxycarbonyloxy)-2-(2,6-difluorobenzyloxy)-pyridine.
Reaction SMILES: CC1C(C)=CC=CC=1CCN.[CH3:12][NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18]C=CC=2)[C:16]=1[CH2:25]CC.Cl.[O:29]=[C:30]1[NH:39][C:38]2[N:37]=[CH:36][C:35](/[CH:40]=[CH:41]/[C:42](O)=[O:43])=[CH:34][C:33]=2[CH2:32][CH2:31]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:25][C:16]1[C:17]([CH3:18])=[CH:22][CH:23]=[CH:24][C:15]=1[CH2:14][N:13]([CH3:12])[C:42](=[O:43])/[CH:41]=[CH:40]/[C:35]1[CH:36]=[N:37][C:38]2[NH:39][C:30](=[O:29])[CH2:31][CH2:32][C:33]=2[CH:34]=1
Reactant: CCCc1c(CNC)ccc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cc1cccc(CCN)c1C
Agent: Cl
Product: Cc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c1C
Yield: 75 %

Procedure:
According to the procedure of Example 1 (a), except substituting 2,3-dimethylbenzylmethyl amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.368 g, 75%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.68-10.64 (m, 1H), 8.38-8.32 (m, 1H), 8.10-7.99 (m, 1H), 7.57-7.50 (m, 1H), 7.29-7.04 (m, 3H), 6.94-6.77 (m, 1H), 4.82-4.65 (m, 2H), 3.06-2.85 (m, 5H), 2.57-2.48 (m 2H), 2.28-2.14 (m, 6H); MS (APCI) m/e 350 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:34])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20](Br)[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][C:36]1(C)C(C)(C)OB(C=C)O1.C(Cl)Cl.[F-].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([CH3:34])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:35]=[CH2:36])[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=Cc1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Temperature: 90 °C
Yield: 124 %

Procedure:
1-{5-[7-Bromo-2-(3-ethyl-ureido)-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid ethyl ester (50 mg), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (28 mg), PdCl2(dppf).DCM (4 mg), potassium fluoride (16 mg), 1,4-dioxane (1.5 mL) and water (0.5 mL) were combined in a 0.5-2 mL microwave vial, degassed and heated in a pre-heated oil bath at 90° C. overnight. The mixture was cooled to rt, diluted with water and extracted into EtOAc (4×10 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Biotage Si chromatography, 12 g Grace cartridge, 4-5% MeOH in DCM. The relevant fractions were combined to give a solid (56 mg) which was purified again by Biotage Si chromatography, 12 g Grace cartridge, 2% MeOH in DCM isocratic. The relevant fractions were combined to give the desired product as a light orange solid (27 mg, 60%). m/z: 495 [M+H]+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[NH:20][C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][C:24]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:31][CH:30]=2)=[CH:23][CH:22]=4)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:45]([N:20]1[C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=3)=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[C:24]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:31][CH:30]=1)[CH:25]=2)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCOc1ccc(-c2ccc3[nH]c4ccc(-c5ccc(OCCCCCCCC)cc5)cc4c3c2)cc1
Reactant: CCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc3c(c2)c2cc(-c4ccc(OCCCCCCCC)cc4)ccc2n3CCCCCCCC)cc1
Yield: 26.7 %

Procedure:
3,6-bis(4-(octyloxy)phenyl)-carbazole (4.2 g, 7.29 mmol), 1-bromooctane (4.25 g, 22.0 mmol) and tetrabutylammoniumhydrogensulphate (0.64 g, 1.88 mmol) was dissolved in toluene and mixed with NaOH 50% aqueous solution (5.5 ml). The reaction was quenched after 4 h, extracted three times with ether, and the combined organic phases was washed with water, evaporated, and purified using column chromatography with a 5/2 petroleum ether/toluene mixture as mobile phase. The product was obtained as colourless oil which crystallized to give 9-octyl-3,6-bis(4-(octyloxy)phenyl)-carbazole (1.34 g, 1.95 mmol) as white crystals. 1H NMR(C2D2Cl4, δ): 0.7-0.9 (m, 9H), 1.15-1.45 (m, 30H), 1.758 (m, 4H), 1.848 (m, 2H), 3.957 (t, 4H), 4.251 (t, 2H), 6.951 (d, 4H), 7.389 (d, 2H), 7.61 (m, 6H) 8.23 (s, 2H) MS MALDI-TOF (m/z): 687.461
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[NH4+:47]>>[NH2:47][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCC(N)=O
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCC(N)=O

Procedure:
5-[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanamide (2.25 g, 6.89 mmol) was treated with mCPBA (2.77 g, 12.0 mmol), ammonium hydroxide (40 mL), and benzenesulfonyl chloride (1.71 mL, 13.4 mmol) according to the method described in Part D of Example 36. The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 90:10 to 85:15). The resulting product was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 0.752 g of 5-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanamide as a tan solid, mp 198-200° C.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[C:13]2[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=3)[S:18][C:12]=2[N:11]([CH3:39])[C:10]1=[O:40])=O.[Li+].[OH-].O>C1COCC1.O.C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:16]2[C:13]3[C:14](=[O:15])[N:9]([CH2:8][CH2:7][CH2:6][OH:5])[C:10](=[O:40])[N:11]([CH3:39])[C:12]=3[S:18][C:17]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:28])([F:29])[F:30])[CH:21]=2)=[CH:33][CH:34]=1
Reactant: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cccc(OC(F)(F)F)c3)sc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenoxy)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (25 mg, 0.039 mmol) in THF (4 mL) and water (4 mL) was added LiOH/H2O (3.29 mg, 0.079 mmol). The reaction was stirred at RT for 15 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-3-(3-hydroxypropyl)-1-methyl-6-(3-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 47.1% yield) as a white solid. 1H NMR (DMSO-d6) δ: 7.49 (t, J=8.3 Hz, 1H), 7.21 (dd, J=18.8, 8.6 Hz, 4H), 7.17-7.07 (m, 2H), 7.03 (s, 1H), 4.50 (t, J=5.1 Hz, 1H), 4.10 (s, 2H), 3.99-3.86 (m, 2H), 3.51-3.42 (m, 2H), 3.41 (s, 3H), 1.69 (s, 2H). LCMS: MH+ 541 and TR=3.317 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)(=[O:15])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.O.[Sn](Cl)Cl>>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)(=[O:15])=[O:14]
Reactant: Cc1ccc2cccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])c2n1
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1ccc2cccc(NS(=O)(=O)c3ccccc3N)c2n1
Yield: 47.2 %

Procedure:
In a similar fashion using route 15 general procedure 29, N-(2-methyl-quinolin-8-yl)-2-nitro-benzenesulfonamide (Intermediate 149) (423 mg, 1.23 mmol) and tin (II) chloride dihydrate (701 mg, 3.70 mmol) gave the title compound (182 mg, 47%) after purification by column chromatography with DCM/MeOH (99:1-95:5) gradient elution.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7]/[C:8](=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)/[CH:9]([CH3:13])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].C([O-])(=O)C.[K+].O>CCCCCCC>[C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]1[C:9]([CH3:13])=[C:10]([O:12][C:23](=[O:25])[CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=2)[CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)O)/C(=C\c1ccc(F)cc1)CC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCCC
Product: CC(=O)Oc1c(C)c(CC(=O)OC(C)(C)C)cc2ccc(F)cc12
Temperature: 85 °C
Reaction time: 10 h
Yield: 69 %

Procedure:
The above prepared 3-[1-(4-fluoro-phenyl)-meth-(Z)-ylidene]-2-methyl-pentanedioic acid 5-tert-butyl ester (38.3 g, 124.2 mmol) was dissolved in acetic anhydride (96.00 mL, 995.3 mmol). To this solution was added potassium acetate (18.66 g, 186.3 mmol), and the reaction mixture was stirred at 85±2° C. for 10 hours, when HPLC analysis showed completed reaction. The reaction mixture was then cooled to room temperature and diluted with 96 mL of heptane. To this solution, 270 mL of water was added over 1 hour, while maintaining the internal temperature at ˜23° C. The mixture was then cooled to 0-5° C., and stirred for 2 hours. The solid formed was filtered, and then washed with water (2×40 mL), heptane (2×40 mL), and then dried under vacuum to furnish 28.5 g of a yellow solid, which was used in the next step without further purification.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl.C([O-])(O)=O.[Na+]>CCO>[OH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)COc1cccc(OCCCOC2CCCCO2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)COc1cccc(OCCCO)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a solution of ethyl {3-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]phenoxy}acetate (3.54 g. crude) in EtOH (34.5 mL) was added 1M HCl aqueous solution (20.4 mL) at ambient temperature. The mixture was stirred for an hour at ambient temperature. The reaction mixture was neutralized with saturated NaHCO3 aqueous solution and evaporated in vacuo. The resulting residue was dissolved in EtOAc (50 mL) and washed with brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (n-hexane:EtOAc=2:1-1:1) to give ethyl [3-(3-hydroxypropoxy)phenoxy]acetate (2.1 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([C:22]#[N:23])=[CH:18][NH:17][C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:29])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([C:22]#[N:23])=[CH:18][N:17]([CH3:29])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]cc(C#N)c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c(C#N)cn(C)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-3-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 8.00 ppm (s, 1H), 7.83 ppm (d, 1H), 7.38 ppm (d, 1H), 5.25 ppm (m, 1H), 3.55 ppm (s, 3H), 1.37 ppm (2xd, 6H),