Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH:14](OC)=[O:15].[H-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[CH:14][OH:15])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1c(F)cccc1Cl
Reactant: COC=O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of methyl (2-chloro-6-fluorophenyl)acetate (5.20 g) and methyl formate (31.4 ml) in dry DMF (40 ml) was added dropwise to a stirred suspension of sodium hydride (1.23 g) in dry DMF (40 ml) at a temperature between 0° and 5° C. Vigorous evolution of gas was observed. The reaction mixture was stirred at room temperature for 3.5 hours, then poured into a mixture of ice and aqueous sodium carbonate, and washed with ether. The resulting aqueous mixture was acidified with concentrated hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated to give methyl 2-(2-chloro-6-fluorophenyl)-3-hydroxypropenoate (3.44 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1>CN(C=O)C.C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)sc1ncc(CO)n12
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)sc1ncc(C=O)n12
Yield: 95.6 %

Procedure:
A solution of 7-Methoxy-imidazo[2,1-b]benzothiazole-3-methanol (Formula M-2) (4.0 g) in DMF (25 mL) was diluted with toluene (200 mL) and the warm solution was treated with MnO2 (8.84 g). The suspension was azeotropically distilled for 4 hours, cooled to 50°, and filtered. The combined filtrate and toluene washes were concentrated and the concentrate was diluted with water. Precipitated 7-Methoxy-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3) (3.8 g) was filtered and recrystallized from acetonitrile to yield pure 7-Methoxy-imidazo [2,1-b]benzothiazole-3-carboxaldehyde (Formula M-3) (3.79 g), m.p. 168-169°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[OH-].[K+]>C(O)C.O>[Cl:26][C:4]1[CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Temperature: 40 °C
Yield: 88.3 %

Procedure:
To a solution of Example 7a (5.72 g, 15 mmol) in 60 mL ethanol/water (5/1) was added powdered KOH (2 g, 35 mmol). The resulting solution was heated at 40° C. for 2 hours. Most of the solvent was removed in vacuo, and the residue was diluted with ethyl acetate. A solid was filtered from the material and discarded. The organics were washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude material was triturated with dichloromethane and filtered, giving 3.5 g of the title compound as a white solid. MS (ESI+) m/z 263.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].Cl.[NH2:15][OH:16].[OH-].[K+]>CO>[NH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([NH:15][OH:16])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: NO
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N)ccc1C(=O)NO
Yield: 46.4 %

Procedure:
Methyl 2-methoxy-4-aminobenzoate (10 g, 55.25 mmol) and hydroxylamine hydrochloride (15.36 g, 221 mmol) were taken up in MeOH (80 ml) and a solution of KOH (15.4 g, 275 mmol) in MeOH (55 ml) was added carefully. The resultant mixture was stirred at reflux for 36 hrs. The volatiles were removed in vacuo The residue was taken up in 1M NaOH (50 ml) and washed with ethyl acetate (EtOAc, 50 ml). Concentrated HCl was added slowly until precipitation of a solid (pH was 10). The solid was filtered off, washed with H2O, then methyl-tert-butyl ether (MTBE) and dried under vacuum. 1H NMR showed the solid contained approx. 1/3 molar equivalent of ethyl acetate. The solid was taken up in 1M NaOH (100 ml) and the EtOAc was removed in vacuo. Concentrated HCl was added carefully until precipitation of a solid (pH was 8). The solid was collected by filtration, washed with H2O, then MTBE and dried under vacuum to give 4.67 g (47%) of the title compound as a dark red solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][NH2:18].Cl>C1(C)C=CC=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][N:18]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: NCc1cccs1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1cccs1
Yield: 91.2 %

Procedure:
To a solution of commercially available phthalic anhydride 1 (500 mg, 3.38 mmol) in toluene (30 mL) at room temperature was added thiophene-2-methylamine (463 mg, 4.1 mmol) and the resulting reaction mixture was allowed to stir at reflux for 2 hours. The reaction mixture was poured onto 1N HCl and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 750 mg of 11 as a pale yellow solid (812 mg theoretical, 91% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:24]([O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O-])=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:33]([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]1[CH3:20])(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])=[O:36]
Reactant: C[Si](C)(C)CCOC(=O)CCCCCCCCC(=O)[O-]
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC(=O)CCCCCCCCC(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
To a solution of the compound 1 (334 mg, 1 mmol), 60 (303 mg, 1.00 mmol) and N,N-dimethylaminopyridine (122 mg, 1 mmol) in methylene chloride (5 mL) was added 1,3-dicyclohexylcarbodiimide (206 mg, 1.08 mmol) under ice-cooling. The reaction mixture was stirred at room temperature for 18 hours. The precipitated insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluate: hexane - ethyl acetate (1:1)) to give the compound 64 (580 mg, 94%) as oil. Rf 0.27 (1:1 EtOAc-hexane).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:41])[C:5]2[N:6]=[CH:7][N:8]([C:39]=2[N:40]=1)[C@@H:9]1[O:38][C@H:28]([CH2:29][O:30][Si](CC)(CC)CC)[C@@H:19]([O:20][Si](CC)(CC)CC)[C@H:10]1[O:11][Si](CC)(CC)CC.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][OH:51])=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][O:51][C:2]2[N:3]=[C:4]([NH2:41])[C:5]3[N:6]=[CH:7][N:8]([C:39]=3[N:40]=2)[C@@H:9]2[O:38][C@H:28]([CH2:29][OH:30])[C@@H:19]([OH:20])[C@H:10]2[OH:11])=[CH:45][CH:44]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: CC[Si](CC)(CC)OC[C@H]1O[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](CC)(CC)CC)[C@@H]1O[Si](CC)(CC)CC
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C

Procedure:
To a 250-mL, three-neck round bottom flask was added 2-chloro-2′,3′,5′-tri-O-(triethylsilyl)adenosine (5.0 g, 7.8 mmol, Example 4) and 2-(4-chlorophenyl)ethanol (15 mL). The mixture was flushed with nitrogen for 5–10 minutes, then heated to 50° C. To this mixture was added sodium hydride (1.56 g, 39 mmol, as a 60% dispersion in mineral oil) at such a rate as to avoid excessive gas evolution. The reaction was maintained at 50° C. for 20 hours, at which time HPLC indicated complete conversion to the fully deprotected, alkylated product. The reaction was then cooled to room temperature, carefully quenched with water (40 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (120 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford a clear oil. This material was purified by passing through a plug of silica gel, eluting with CH2Cl2, 3% methanol in CH2Cl2, and 10% methanol in CH2Cl2. Those fractions containing products were combined and evaporated to dryness, affording the desired product as a white solid. 680 mg (21%).m.p.: 114–120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])/[CH:10]=[CH:12]/[N:13]([CH3:15])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(F)cc1F
Product: CN(C)/C=C/C(=O)c1ccc(F)cc1F
Yield: 82 %

Procedure:
The title compound was prepared in 82% yield from 1-(2,4-difluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.90 (3H, s), 3.11(3H, s), 5.59-5.62 (1H, m), 6.77-6.83 (1H, m), 6.88-6.93 (m, 1H), 7.75-7.83 (2H, m).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[S:3]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].Cl.CN(C)CCCN=C=NCC.CN(C)C=O>O>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])[CH:10]=[CH:11][C:12]=1[O:18][CH3:19]
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)O
Reactant: NCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 19.8 %

Procedure:
5-[(2,4-Dioxothiazolidin-5-yl)methyl]-2-methoxybenzoic acid (282 mg, 1.00 mmol), 2-picolylamine (114 mg, 1.05 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol) and N,N-dimethylformamide (5 mL) were mixed and stirred for 5.5 hours at room temperature, which was then allowed to stand overnight. After water was added to the reaction mixture, this was made acidic and extracted with ethyl acetate. The extracted solution was dried and then concentrated. The residue was recrystallized from acetonitrile to obtain 73.7 mg (20%) of the title compound as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([NH:17][CH:18]2[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]2=[O:25])[N:3]=1.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:5]=[C:4]([NH:17][CH:18]3[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]3=[O:25])[N:3]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(Nc3ccc(OC)cc3)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reaction time: 18.5 h
Yield: 57.1 %

Procedure:
A suspension of 5-[4-chloro-6-(4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-3-methyl-imidazolidine-2,4-dione (Example 1.10, Part A) (50 mg, 0.14 mmol), p-methoxyaniline (25 mg, 0.21 mmol) and potassium carbonate (48 mg, 0.34 mmol) in anhydrous DMF (5 mL) was stirred under a nitrogen atmosphere for 18.5 h. The reaction mixture was diluted with water and the crude product was extracted with ethyl acetate. The organic layer was dried and evaporated, and the crude product was purified by column chromatography (silica; dichloromethane:ethyl acetate starting with a solvent ratio of 10:1 and increasing the polarity to dichloromethane:methanol, 10:1) to afford the product as a pale yellow solid (36 mg, 58%). δH (300 MHz, (CD3)2CO) 8.14 (br s, 2H, NH), 7.60 (br s, 4H, ArH (ortho to NH attach)), 7.43 (br s, 1H, NH), 6.91 (d, J 8.7 Hz, 1H, NH), 6.85 (d, J 9.0 Hz, 4H, ArH (ortho to O attach)), 5.91 (d, J 7.8 Hz, 1H, CH), 3.77 (s, 6H, OCH3), 2.86 (br s, 2.0H, NCH3), 2.73 (br s, 1.0H, NCH3). Mass spectrum (ESI) m/z 451 (37%, MH+).
Reaction SMILES: CS(C)=O.C[O:6][C:7]1[CH:16]=[C:15]2[C:10](C(Cl)=CC=N2)=[CH:9][C:8]=1C(N)=O.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](NC1CC1)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:31])[O:6][C:7]1[CH:16]=[CH:15][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Reactant: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc(O)cc1Cl)Oc1ccccc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 142.4 %

Procedure:
To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:20])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]2.[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26](O)=O)#[N:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:21]([C:23]1[CH:24]=[C:25]([C:26]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]4)[N:20]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:34])[CH3:35])#[N:22]
Reactant: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Temperature: 25 °C
Yield: 50 %

Procedure:
Ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D52) (265 mg, 0.96 mmol), 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (197 mg, 0.96 mmol), EDAC (203 mg) and HOBt (142 mg) were stirred in DMF (5 ml) at 80° C. for 2 hours. Stirred at room temperature over the weekend, then heated at 80° C. for a further 4 hours. The reaction mixture was cooled and then partitioned between EtOAc and sodium bicarbonate. The organic layer was separated, washed with brine, dried and evaporated to dryness in vacuo. The crude material was purified by flash chromatography to afford the title compound (214 mg) as a white solid. MS (ES): C24H23N5O4 requires 445; found (MH+) 446.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][S-:11].[Na+]>C(O)C>[F:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([S:11][CH3:10])=[N:3][CH:4]=1
Reactant: C[S-]
Reactant: Nc1nc(Cl)ncc1F
Agent: [Na+]
Solvent: CCO
Product: CSc1ncc(F)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 2-chloro-5-fluoropyrimidin-4-amine (15.50 grams (g), 105 millimoles (mmol)) in ethyl alcohol (EtOH; 420 milliliters (mL)) was added sodium thiomethoxide (NaSCH3; 9.20 g, 131 mmol), and the resulting turbid mixture was warmed to reflux and stirred for 3 hours (h). The reaction mixture was cooled to room temperature, the solvent evaporated, and the residue partitioned between ethyl acetate (EtOAc; 250 mL) and water (H2O; 250 mL). The phases were separated, and the aqueous phase was extracted with additional EtOAc (100 mL). The organic phases were combined, dried over sodium sulfate (Na2SO4), filtered, and concentrated to an off-white solid. The solid was purified by flash chromatography (330 g silica gel (SiO2); 0→30% EtOAc/hexanes) to give 5-fluoro-2-methylsulfanylpyrimidin-4-ylamine (16.38 g, 98%) as a white solid: mp 114-115° C.; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=3.0 Hz, 1H), 5.29 (s, 2H), 2.50 (s, 3H); CIMS m/z 159 ([M]+).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[CH2:18]([CH:20]([CH2:26][CH3:27])[C:21](=O)[CH2:22][C:23]#[N:24])[CH3:19]>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[C:22]([C:23]#[N:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Reactant: CCC(CC)C(=O)CC#N
Product: CCC(CC)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C#N

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(3-chloro-phenyl)-methanone (prepared as described in example 91 step A) and 4-ethyl-3-oxo-hexanenitrile (prepared as described in example 101 step A). Light yellow oil. MS (ESI): 369.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:40])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:40])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][C:36]([F:38])([F:39])[F:37])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCC(F)(F)F)c1
Yield: 74 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10.0 mmol, 4.8 eq) of sodium hydroxide and methyl 3-[3′-(3-heptyl-1-methylureido)-2-(4,4,4-trifluorobutoxy)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 252 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(4,4,4-trifluorobutoxy)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=78° C.). Yield=74% over the two steps
Reaction SMILES: C([O:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[CH:11]=[CH:10][CH:9]=2)(=O)C.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]=[C:25]=[O:26])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1COCC1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][NH:24][C:25]([NH:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:5]([OH:4])[N:6]=[CH:7]3)=[O:26])=[CH:21][CH:22]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: CC(=O)Oc1cc2c(N)cccc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Br)cc1)Nc1cccc2cnc(O)cc12
Reaction time: 1 h

Procedure:
5-Amino-3-isoquinolinyl acetate in toluene:THF (5:1, 5 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (105 mg). After stirring for 1 hour, the mixture was concentrated under reduced pressure and the residue dissolved in MeOH (20 mL) and treated with K2CO3 (4 eq) and stirred for 16 hours. The mixture was concentrated under reduced pressure and partitioned between CH2Cl2 and water. The aqueous phase was separated and the pH was adjusted to approximately 6 with HCl. The acidified solution was filtered, and the filter cake was dried. The solid was purified by reverse-phase chromatography (using TFA as eluent) to provide the title compound. MS (ESI+) m/z 374, 372 (M+H)+; MS (ESI−) m/z 372, 370 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 4.33 (d, J 5.8, 2H), 7.06 (m, 1H), 7.29 (m, 3H), 7.57 (m, 3H), 8.07 (d, J 7.8, 1H), 8.48 (s, 1H), 8.80 (s, 1H), 8.87 (s, 1H); Anal. Calcd for C17H14BrN3O2+0.2 TFA: C, 53.08; H, 3.42; N, 10.43. Found: C, 52.91; H, 3.62; N, 10.43.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[F:16][C:17]([F:37])([F:36])[C:18]1[C:27]([C:28](Cl)=[O:29])=[C:26]([OH:31])[C:25]2[C:20](=[C:21]([C:32]([F:35])([F:34])[F:33])[CH:22]=[CH:23][CH:24]=2)[N:19]=1>C(OCC)(=O)C.[OH-].[Na+]>[F:36][C:17]([F:16])([F:37])[C:18]1[C:27]([C:28]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)=[O:29])=[C:26]([OH:31])[C:25]2[C:20](=[C:21]([C:32]([F:35])([F:33])[F:34])[CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Cl)c1)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A solution of 4.083 g of m-chloroaniline, 9.71 g of triethylamine and 65 ml of ethyl acetate was poured over 15 minutes at 8° C.-10° C. into a solution of 11.96 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride in 130 ml of ethyl acetate with violent stirring and the temperature was allowed to return to room temperature. The mixture was refluxed for one hour and was cooled and vacuum filtered. The filtrate was washed with water, was dried and evaporated to dryness at 40° C. under reduced pressure to obtain 17.14 g of a triethylamine salt. The residue was dissolved in 2 N sodium hydroxide solution which was then heated to reflux and cooled to room temperature. The mixture was vacuum filtered and the recovered product was dissolved in water. The solution was adjusted to a pH of 1 by addition of 20% hydrochloric acid and the mixture was vacuum filtered. The recovered product was crystallized from benzene to obtain 7.599 g of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(3-chlorophenyl)-3-quinolinecarboxamide melting at 152° C.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 8.86 g) in tetrahydrofuran (170 mL) was added a solution of EXAMPLE 341B (30.52 g) in tetrahydrofuran (100 mL). This mixture was stirred for 30 minutes and benzyl bromide (24 mL) was added. After stirring for 72 hours, the reaction was quenched with saturated ammonium chloride solution (400 mL) and diluted with ether (500 mL). The layers were separated and the aqueous layer was extracted with ether (2×150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel eluting with a 0, 10, 15, 75% ethyl acetate in hexanes step gradient to provide the title compound.