Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[O:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1>CO.C(Cl)Cl>[O:22]1[C:26]2([CH2:31][CH2:30][N:29]([CH2:1][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]4[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CN3CCC4(CC3)OCCO4)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with 1,4-dioxa-8-aza-spiro[4,5]decane (71.6 mg, 0.50 mmol) as described in General Procedure X to afford Iz (51.0 mg, 44.7%) as a tan solid, tlc Rf=0.35 (10% MeOH/CH2Cl2-0.20% Et3N), m/z obs=424 (M+1).
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[CH2:4][CH2:3][CH2:2][C:1]2=[O:6])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=C1CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCN1c1cccc2cccnc12
Reaction time: 2 h

Procedure:
A mixture of γ-butyrolactone (9.5 g), technical grade 8-aminoquinoline (14.4 g), p-toluenesulphonic acid monohydrate (1.90 g) and mixed xylenes (15 ml) were refluxed with a Dean Stark trap prefilled with xylenes. After one hour γ-butyrolactone (9.0 g) was added and reflux was resumed for two hours. The residue obtained by concentration by vacuum distillation (≃15 mm Hg) of the reaction mixture was extracted with hot ethyl acetate (100 ml). The solid which formed upon cooling the ethyl acetate solution was recrystallized from acetone giving 1-(8-quinolyl)-2-pyrrolidinone, (m.p. 119°-123°), identical by tlc with the product of Example 1.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH2:25][CH2:26]2)=[CH:7][CH:8]=1
Reactant: NCC1CCN(CCCCCCCCCCCCO)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: OCCCCCCCCCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 32.5 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-(12-hydroxydodecyl)-piperidine (0.586 g, 2.0 mmol) according to procedure used for Example 2 to give 0.175 g of the title compound as an off-white solid (mp-110° C. (sinters) 166° C. (melts), Et2O).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)n1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)n1
Reaction time: 6 h

Procedure:
To a solution of 5-{4-[2-(6-methyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione (400 mg) in dioxane (60 ml) was added 5% palladium on carbon (1.2 g) and catalytic reduction was carried out at atmospheric pressure for 6 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was recrystallized from 70% ethanol to give 5-{4-[2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione as crystals. Yield: 218 mg (54.2%); m.p.: 156°-157° C.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:28].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC#N.O>[Cl:28][C:10]1[C:9]2[C:4](=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: COC(=O)c1cccc2c(=O)[nH]c(C)nc12
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cccc2c(Cl)nc(C)nc12
Temperature: 90 °C
Yield: 62 %

Procedure:
A suspension of methyl 2-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxylate (2.00 g; 9.17 mmol; 1.00 eq.) and benzyltriethylammonium chloride (4.18 g, 18.33 mmol) in dry CH3CN (5 mL) was treated with DIEA (1.75 mL, 10.1 mmol) and stirred as POCl3 (7.3 mL, 80.2 mmol) was slowly added to the flask. The contents were warmed to 90° C. for 30 min, cooled to ˜50° C., and slowly poured into a 2N NaOH (80 mL, 160 mmol) and water (80 mL) that was cooling in an acetone/dry-ice bath (ice formed in the flask). The off-red solid that precipitated was filtered, washed with 10% aqueous K2CO3 (15 mL), and dried under vacuum to afford 1 (1.35 g; 62% yield). LC-MS [236.8 (M+1)]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([O:9][CH:10]([F:12])[F:11])[CH:3]=1.C([O-])(=[O:15])C.[K+].OOS([O-])=O.[K+]>C1COCC1.CCOC(C)=O.O.C(OCC)C.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]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:15])=[C:4]([O:9][CH:10]([F:12])[F:11])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: FC(F)Oc1cc(Cl)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=S([O-])OO
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Oc1ccc(Cl)cc1OC(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-chloro-2-(difluoromethoxy)bromobenzene (Preparation 27, 200 mg, 0.63 mmol) in THF (6 mL) was added bis-neopentylglycolatodiboron (149 mg, 0.660 mmol), potassium acetate (191 mg, 1.88 mmol) and Pd(dppf)Cl2 (23 mg, 0.031 mmol). The reaction mixture was heated to reflux for 4 hours before cooling and diluting with EtOAc and water. The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in acetone (6 mL) and treated with a solution of oxone (1.64 g, 2.54 mmol) in water (6 mL). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with diethyl ether (10 mL) and water (5 mL). The organic layer was collected, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-15% diethyl ether in DCM to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N+:40]([O-:44])=[C:39]([CH3:45])[CH:38]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:42]=[C:41]([CH3:43])[N+:40]([O-:44])=[C:39]([CH3:45])[CH:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.092, m/z=479.1; 1H NMR (CDCl3) 1.38 (m, 1H), 1.56 (d, 3H), 1.71 (m, 1H), 1.95 (m, 2H), 2.19-2.31 (m, 3H), 2.58 (s, 3H), 2.61 (s, 3H), 2.95 (m, 1H), 3.58 (m, 1H), 5.71 (m, 1H), 7.05 (m, 4H), 7.21-7.32 (m, 4H), 7.38 (m, 2H).
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]2.[C:16]1([C:22]2(OC)[CH2:26][CH2:25][C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(OC)O2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2[N:2]([C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:12]=3[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]4)[C:24]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [NH3+]c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Reactant: COC1(c2ccccc2)CCC(OC)(c2ccccc2)O1
Agent: [Cl-]
Product: O=c1[nH]c2cc(Cl)c(-n3c(-c4ccccc4)ccc3-c3ccccc3)cc2[nH]c1=O

Procedure:
16.5 mmol of 6-ammonio-7-chloro-2,3(1H,4H)-quinoxalinedione chloride were reacted with 16.5 mmol of 2,5-diphenyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: CO[C:3](=O)[CH:4]=[CH:5][C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][C:8]=2[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)O[C:36](=O)[C:35]2[CH:34]=CC=CC1=2)=O.O>ClCCl>[C:20]([O:19][C:17](=[O:18])[NH:16][CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[S:10][C:6]([CH2:5][CH2:4][CH2:3][N:16]([CH2:34][CH2:35][CH3:36])[CH2:15][CH2:13][CH3:12])=[CH:7][C:8]=2[CH:14]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)C=Cc1cc2cc(CNC(=O)OC(C)(C)C)ccc2s1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCN(CCC)CCCc1cc2cc(CNC(=O)OC(C)(C)C)ccc2s1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 116.7 %

Procedure:
The compound (356.0 mg) obtained in Example 120-4 was dissolved in anhydrous dichloromethane (10 ml) and added with Dess-Martin periodinane (manufactured by Aldrich Corporation) (563.7 mg), followed by stirring at room temperature for 40 minutes. Then, the solution was added with water and extracted with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate). The purified product was dissolved in methanol (10 ml) and then added with di-n-propylamine (0.19 ml), trimethyl orthoformate (0.15 ml), and sodium cyanoborohydride (87.6 mg), followed by stirring at room temperature for 30 hours. The solution was added with water and then extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (241.9 mg) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.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:13][C:3]1[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: N#Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccccc2)c(F)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 48 h

Procedure:
5-Bromo-4-fluoro-2-nitrobenzonitrile (I-240) (9.1 g, 37.14 mmol) was dissolved in tetrahydrofuran (270 ml), and at room temperature, phenylboronic acid (9.06 g, 74.28 mmol), tripotassium phosphate (15.77 g, 74.28 mmol) and tetrakis(triphenylphosphine)palladium (2.15 g, 1.86 mmol) were added. After stirred under nitrogen atmosphere at 75° C. for 48 hours, this was cooled to room temperature. The insoluble matter was separated by filtration, the filtrate was concentrated under reduced pressure. The residue was fractionated with chloroform and aqueous saturated ammonium chloride solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[NH4+:18].[OH-]>>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH2:18])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: NC(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trans-4-trifluoromethylcyclohexanecarboxylic acid (0.5 g, 2.55 mmol) in thionyl chloride (3.70 mL, 51.0 mmol) was heated to 60° C. for 1 h, cooled to RT and concentrated to dryness. The material was co-evaporated with toluene (2×), dissolved in EtOAc (5 mL), treated with satd. NaHCO3 (5 mL) followed by NH4OH (˜13M, 0.588 mL, ˜7.65 mmol) and stirred at RT for 0.5 h. The layers were separated, the aqueous layer extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford trans-4-(trifluoromethyl)cyclohexanecarboxamide (380 mg, 76%) as a white solid.
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: COc1cc(CNc2nccc3cc(F)ccc23)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc(F)ccc12
Yield: 68.7 %

Procedure:
A solution of 1-(3,4,5-trimethoxybenzyl)amino-6-fluoro-isoquinoline (1.26 g, 3.68 mmol) in TFA (30 mL) is refluxed for 16 h. The solvent is evaporated under reduced pressure. Anhydrous MeOH (30 mL) is added to the residue. Solid K2CO3 is slowly added until pH>8. The suspension is filtered through a pad of Celite, and the solvent is evaporated under reduced pressure. The residue is dissolved in CH2Cl2 and filtered through a pad of Celite. The filter cake is rinsed with CH2Cl2, and the solvent is evaporated under reduced pressure. The residue is dried under vacuum to afford 0.41 g (69%) of 1-amino-6-fluoro-isoquinoline. LC/MS m/z=163 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH:8]=[CH:7]2)[CH:2]=[CH2:3].[C:17](O)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:17]([O:16][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:13][C:12]([CH3:14])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:15])[NH:10]2)(=[O:19])[CH3:18]
Reactant: C=CCc1cc(C)c2[nH]c(=O)ccc2c1O
Reactant: CC(=O)O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=CCc1cc(C)c2[nH]c(=O)ccc2c1OC(C)=O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of 6-allyl-5-hydroxy-8-methylcarbostyril (3.2 g, 14.9 mmol) in pyridine (50 ml), acetic acid (3.5 34.3 mmol) was added and stirred at room temperature for hour. The mixture was condensed and dissolved in chloroform. The resultant solution was washed with saturated aqueous sodium bicarbonate solution, aqueous 2N-HCl solution, and water, and dried and condensed. As a result, 3.5 g of 5-acetoxy-6-allyl-8-methylcarbostyril was obtained as colorless crystals (91.4%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.CO.[OH-].[Na+]>CCCCCC>[CH2:5]([OH:4])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=CCCCCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: CCCCC=CCCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A portion of the acetate is removed and converted to the corresponding alcohol as follows. 15.0 g (67 mmol) of the 5-decenyl acetate, 35 mL of methanol and 34 mL of 2 M sodium hydroxide were added to a 250 mL round-bottomed flask. This mixture was stirred for 3 hours at room temperature. After 3 hours the hydrolysis was complete, 10 mL of hexane was added and the solution was washed with 10 mL of 1 M HCl, 10 mL of NaHCO3 -saturated water and 10 mL of brine. The organic phase was dried with sodium sulfate, filtered and the hexane removed under reduced pressure to yield 9.4 g of 5-decenol. GC analysis showed the isometric ratio to be 80:20 E:Z.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:4][C@H:5]([C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]4)=[C:18]([O:28][CH3:29])[CH:17]=3)[S:13][CH:14]=2)[CH2:6][CH:7]([CH3:8])[CH3:9])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NS(=O)(=O)c3ccc(F)cc3)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 36 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 40 mg (0.2 mmol) 4-fluorobenzenesulfonylchloride. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 85 mg (80%) 4-fluoro-N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-benzenesulfonamide as a light yellow solid. MS ISP (m/e): 530.0 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.24 (s, 1H), 8.16 (d, 1H), 7.78-7.65 (m, 3H), 7.23-7.17 (m, 3H), 7.03 (s, 1H), 7.02 (d, 1H), 4.23 (q, 1H), 3.83 (s, 3H), 2.15 (s, 3H), 1.59 (m, 2H), 1.49 (m, 1H), 0.82 (d, 3H), 0.76 (d, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([C:23]([O:25]CC)=O)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].C([NH2:31])=O.C[O-].[Na+].CO>O.CN(C)C=O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([C:23](=[O:25])[NH2:31])[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: NC=O
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(-c2cccc(OC)c2)c2cccnc21
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCCCn1c(=O)c(C(N)=O)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 60 °C
Reaction time: 9 h
Yield: 89.6 %

Procedure:
A mixture of 1-butyl-3-ethoxycarbonyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine (45.0 g, 120 mmol), formamide (15.5 ml, 390 mmol) and dimethylformamide (120 ml) was dissolved at 60° C., and thereto was added a 25% solution of sodium methoxide in methanol (108 ml, 390 mmol), and the mixture was stirred at 60° C. for 9 hours. The mixture was cooled to 0° C., and thereto was added water (1.2 liter), and the mixture was stirred for 15 minutes. The precipitated solid was collected by filtration, washed with ethanol, and dried to give the title compound (37.8 g, yield; 87%) as white powder.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:21]2[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=2[F:15])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1cccc(F)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(Cl)cc2)c(F)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
Aluminium trichloride (144 g, 1.08 mol) was added to a cooled (0° C.) solution of nitrobenzene (450 mL). A solution of 4-chlorobenzoyl chloride (128.5 mL, 1 mol) in nitrobenzene (200 mL) was slowly added. 3-Fluoroanisole (108.5 mL, 0.95 mol) was slowly added. The reaction mixture was stirred overnight at 20° C., partitioned between ice water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The warm solution was poured onto cyclohexane. The solid was filtered, washed with cyclohexane and dried in vacuo, affording the title compound (104.5 g, 41%) as an off-white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:24]>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][CH:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:24])=[O:2])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: N
Solvent: CO
Product: NC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
To 2-(4-Chloro-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester (750 mg) is added 10 mL of a 1.0 M solution of ammonia in methanol. The reaction is heated for 48 h at 65° C., cooled to room temperature, and the solvent removed. The resultant solid is first triturated with ethyl acetate, filtered, and then triturated with methylene chloride to provide the title compound. 1HNMR (400 MHz, CD3OD) 2.70 (dd, 1H, J=14.0 Hz and 9.6 Hz), 3.01 (dd, 1H, J=14.0 Hz and 5.4 Hz), 3.95 (dd, 1H, J=9.0 Hz and 5.0 Hz), 7.05-7.15 (m, 5H), 7.32-7.36 (m, 2H), and 7.53-7.56 (m, 2H). MS 339.1 m/z (M+1).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[O:10]=[C:11]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[S:23][C:24]([C:32]([NH2:34])=O)=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]=2[CH:13]=[CH:12]1.O>CN(C=O)C>[O:10]=[C:11]1[N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:15]2[S:23][C:24]([C:32]#[N:34])=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]=2[CH:13]=[CH:12]1
Reactant: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reaction time: 26 h
Yield: 71.1 %

Procedure:
A mixture of cyanuric chloride (28 mg, 0.15 mmol) and the compound of Example 75 (52 mg, 0.15 mmol) in DMF (1.5 mL) was heated at 110° for 18 h. Two further portions of cyanuric chloride (14 mg, 0.075 mmol) were added and heating continued for a further 26 h. Water was added and the precipitate filtered off, washed with water and dried. The crude product was purified by column chromatography on silica (1% THF in DCM) to give the title compound as a white solid (35 mg, 71%). δH (DMSO-d6) 7.78 (1H, d, J 9.6 Hz), 7.71–7.67 (1H, m), 7.66–7.64 (1H, m), 7.64–7.59 (7H, m), 7.59–7.58 (1H, m), 6.67 (1H, d, J 9.6 Hz). LCMS (ES+) RT 3.65 minutes, 329 (M+H)+.