Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.CCOCC>C1(C)C=CC=CC=1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=NOC(c2ccc(C(F)(F)F)cc2)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
A solution of ethyl 5-[4-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-3-carboxylate (3.3 g) was stirred in toluene (15 ml), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (100 g) was then added in portions, followed by a portion of 3A molecular sieves, and the resulting mixture was stirred at 75° C. for 2 days. After cooling, ether was added and the mixture filtered through a layer anhydrous sodium sulfate. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography, to provide ethyl 5-[4-(trifluoromethyl)phenyl]isoxazole-3-carboxylate, a compound of formula (23).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]=[C:28]=[O:29])=[CH:26][C:21]=2[CH2:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][C:28](=[O:29])[O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]4)=[CH:26][C:21]=2[CH2:20][CH2:19]1
Reactant: O=C=Nc1ccc2c(c1)CCO2
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1ccc2c(c1)CCO2)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with 2,3-dihydro-1-benzofuran-5-ylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (9.0 mg, 13%) having the following characteristics.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.C([O:15][C:16](=O)[CH2:17][NH2:18])C>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:15])[CH2:17][N:18]=[C:9]([CH3:10])[C:3]=2[CH:4]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)c1cc(Br)ccc1N
Agent: Cl
Solvent: c1ccncc1
Product: CC1=NCC(=O)Nc2ccc(Br)cc21
Yield: 16.1 %

Procedure:
A mixture of 1-(2-amino-5-bromo-phenyl)-ethanone (8 g, 37 mmol) and glycine ethyl ester hydrogen chloride (6.7 g, 48 mmol) in pyridine was heated at reflux for 24 hrs under nitrogen. The reaction mixture was cooled, solvent removed, and residue was treated with a saturated aqueous ammonium chloride solution (200 mL). Ethyl acetate (300 mL) was added and organic layer was separated, dried (MgSO4), concentrated, and the residue purified on silica gel column (hexane:ethyl acetate/1:1) to give 7-bromo-5-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one as a brown solid (1.51 g, 16%). 1H NMR (DMSO-d6): δ 10.49 (s, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.66 (dd, J=8.7, 2.1 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 3.91 (s, 2H), 2.39 (s, 3H). MS (ESI) m/z 253/255 ([M+H]+); Anal. calcd for C10H9BrN2O: C, 47.46; H, 3.58; N, 11.07. Found: C, 47.58; H, 3.52; N, 10.95.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][N:8]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([CH2:26][CH2:27][NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].Cl>CO>[CH3:7][N:8]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([CH2:26][CH2:27][NH:28][C:29](=[O:37])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CCN(C)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(CCC(=O)O)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1

Procedure:
An aqueous 0.5N solution of K2CO3 (10 ml) is added to the product obtained in Step A (4 mmol) dissolved in methanol (10 ml). When the reaction has ceased, the solution is acidified to pH 6–7 using 1N hydrochloric acid solution. The reaction mixture is extracted with dichloromethane.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[P:5]([OH:8])([OH:7])[OH:6].P(Cl)(Cl)Cl>O1CCOCC1>[CH3:2][C:1]([P:5]([OH:8])([OH:7])=[O:6])([P:5]([OH:8])([OH:7])=[O:6])[OH:4]
Reactant: CC(=O)O
Reactant: OP(O)O
Solvent: C1COCCO1
Solvent: ClP(Cl)Cl
Product: CC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 92.5 °C
Yield: 5.2 %

Procedure:
Acetic acid (50 g), phosphorous acid (240 gm) and 1,4-dioxane (1000 mL) was taken in a four necked round bottom flask fitted with an addition funnel, mechanical stirrer, condenser and thermometer pocket and allowed to stir at 90-95° C. Phosphorus trichloride (400 gm) was then added to the reaction mixture and allowed to heat at 90-95° C. The reaction mixture was cooled and distilled water (500 ml) was added to it. The reaction mixture was further heated to 90-95° C. It was then cooled and acetonitrile (1000 mL) was added to it. The solution was further cooled to 0-5° C. and stirred for 4-5 hrs. The precipitated solid was filtered, washed with acetonitrile and dried in vacuum oven to give 9 gm of product.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]3[C:14]4[C:19]([C:20]([C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[C:30]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)=[CH:29][CH:28]=5)=[C:21]5[C:26]=3[CH:25]=[CH:24][CH:23]=[CH:22]5)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>CN1CCCC1=O>[C:37]1([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([C:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:13]([C:9]4[CH:10]=[C:11]5[C:6]([CH:5]=[CH:4][C:3]([OH:2])=[CH:12]5)=[CH:7][CH:8]=4)=[C:14]4[C:19]=3[CH:18]=[CH:17][CH:16]=[CH:15]4)=[CH:28][CH:29]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc2ccc(-c3c4ccccc4c(-c4ccc(-c5ccccc5)c5ccccc45)c4ccccc34)cc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Oc1ccc2ccc(-c3c4ccccc4c(-c4ccc(-c5ccccc5)c5ccccc45)c4ccccc34)cc2c1
Temperature: 200 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Under the nitrogen atmosphere, 9-(7-methoxynaphthalen-2-yl)-10-(4-phenylnaphthalen-1-yl)anthracene (16.0 g) as the twentieth intermediate compound, pyridine hydrochloride (17.3 g) and N-methylpyrrolidone (30 ml) were added to a flask and stirred for 8 hours at 200° C. Once the heating is completed, the mixture was cooled to 100° C. or lower. Liquid separation was performed by adding water and toluene. The solvent was distilled off under reduced pressure and the resulting solid was purified by silica gel column chromatography (solvent: toluene) to give 7-(10-(4-phenylnaphthalen-1-yl)anthracen-9-yl)naphthalen-2-ol (15.5 g) as a twenty-first intermediate compound. The scheme is shown in the following “Reaction 33”.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[F:11].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:27]([C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[F:19])(=[O:29])=[O:28])[C:5]=1[F:11]
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To 3-amino-2-fluoro-benzoic acid methyl ester (72, 1.08 g, 6.4 mmol) in 40.64 mL of dichloromethane, pyridine (1.29 mL, 16 mmol) is added, followed by 2,5-difluorobenzenesulfonyl chloride (73, 3.391 g, 16 mmol). The reaction is stirred at room temperature overnight, then quenched with 1M aqueous hydrochloric acid. The organic layer is removed and the aqueous layer is extracted with dichloromethane. The organic layers are combined and washed with brine, then dried over sodium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (74, 0.956 g). MS (ESI) [M−H+]−=344.
Reaction SMILES: CN([CH:4]=[C:5]([C:9](=[O:12])[CH2:10][CH3:11])[C:6](=O)[CH3:7])C.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].C[O-].[Na+]>CO>[CH3:7][C:6]1[NH:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[CH:4][C:5]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: N#CCC(N)=O
Reactant: CCC(=O)C(=CN(C)C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)c1cc(C#N)c(=O)[nH]c1C
Reaction time: 3 h

Procedure:
A mixture containing 34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml of dimethylformamide dimethyl acetal was allowed to stand at rooom temperature overnight and then concentrated on a rotary evaporator at steam bath temperature to yield, as a liquid, 3-dimethylaminomethylene-2,4-hexanedione. A mixture containing said 3-dimethylaminomethylene-2,4-hexanedione, 300 ml of methanol 25.2 g of cyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirring for 3 hours and then concentrated in vacuo to remove the methanol. The residue was dissolved in 300 ml of warm water and filtered. The filtrate was acidified with acetic acid and the resulting precipitate was collected, washed with water, dried in vacuo at 90°-95° C. and recrystallized from dimethylformamide (75 ml) to yield 7.8 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile, m.p. 265°-268° C. with decomposition. The mother liquor was concentrated to dryness and digested with hot methanol and cooled. The separated solid was dried, 20.2 g, and recrystallized from dimethylformamide to yield 9.8 g of finely crystalline material, m.p. 259°-263° C. with decomposition. The NMR spectral data for this compound indicated it to be mostly said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridincarbonitrile. The resulting mother liquors were combined and concentrated on a rotary evaporator and the resulting residue was recrystallized from ethanol to yield 20.4 g of solid, m.p. 220°-226° C. The NMR spectral data for this solid indicated it to be a 5:4 mixture of said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)-3-pyridinecarbonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxo-3-pyridinecarbonitrile. Although preliminary attempts to separate the two compounds by fractional crystallization were unsuccessful, it is contemplated that the two compounds would be separable by other conventional separation techniques, e.g., chromatography.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].S(O)(O)(=O)=O.[NH2:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1.CCN(C(C)C)C(C)C.[CH3:33][C:34]1[C:35]([CH2:40][N:41]([CH2:48][C:49]2[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][N:50]=2)[CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[N:36][CH:37]=[CH:38][CH:39]=1>C(Cl)Cl.CN(C=O)C>[NH:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:1]([N:45]1[CH2:46][CH2:47][CH:42]([N:41]([CH2:48][C:49]2[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][N:50]=2)[CH2:40][C:35]2[C:34]([CH3:33])=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:43][CH2:44]1)=[O:2]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)Nc2ncc[nH]2)CC1
Temperature: 60 °C
Reaction time: 19 h
Yield: 17 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (0.0924 g, 0.57 mmol), 2-aminoimidazole sulfate (0.0687 g, 0.52 mmol), and DIPEA (0.36 mL, 2.08 mmol) in CH2Cl2 (6 mL) and DMF (6 mL) was stirred at room temperature for 4.5 hours. The mixture was concentrated to rid of CH2Cl2, and DIPEA (0.36 mL, 2.08 mmol) and COMPOUND 249 (0.1614 g, 0.52 mmol) were added. The mixture stirred at 60° C. for 19 hours, then concentrated. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 37.1 mg (16%) COMPOUND 345 as a white solid. 1H NMR (CDCl3) δ 1.66-1.70 (m, 2H), 1.93-1.97 (m, 2H), 2.08 (s, 6H), 2.72 (t, 3H, J=10.8 Hz), 3.82 (s, 4H), 4.32 (d, 2H, J=11.4 Hz), 6.70 (s, 2H), 7.07-7.09 (m, 2H), 7.36 (d, 2H, J=7.2 Hz), 8.34 (s, 2H). 13C NMR (CDCl3) 18.37, 27.61, 44.75, 54.96, 57.81, 122.81, 133.79, 138.43, 145.43, 146.30, 155.71, 157.54. ES-MS m/z 420.1 (M+H). Anal. Calcd. for C23H29N7O.0.3CH2Cl2: C, 62.89; H, 6.70; N, 22.03. Found: C, 62.84; H, 6.93; N, 21.82.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[OH:12])[CH:2]=[CH2:3].C(OO)(=[O:15])C.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[CH3:11][O:10][C:6]1[C:5]2[O:12][CH:2]([CH2:3][OH:15])[CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C=CCc1cccc(OC)c1O
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2c1OC(CO)C2
Temperature: 15 °C
Reaction time: 48 h
Yield: 16 %

Procedure:
124 g of 2-allyl-6-methoxyphenol, dissolved in 80 ml of acetic acid, are added to a mixture, cooled to 15° C., containing 160 ml of 32% strength peracetic acid in acetic acid and 2.4 g of sodium acetate. The mixture is left at room temperature for 48 hours and then hydrolyzed with 2 l of water containing 400 g of sodium carbonate. The mixture is extracted with ethyl ether and the organic phase is washed with sodium hydroxide. It is dried, the ether is evaporated off and the residue is distilled at 110° C. and at 0.02 mmHg to obtain 7-methoxy-2,3-dihydro-2-benzofuranylmethanol.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].C(O)C.[Cl-].[NH4+]>[Fe].O>[CH3:1][N:2]([CH3:23])[C:3]([CH:5]1[CH2:6][CH2:7][N:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)C1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
1-(4-Nitro-benzenesulfonyl)-piperidine-4-carboxylic acid dimethylamide (0.17 g, 0.49 mmol) was suspended in a 5:1 mixture of ethanol and water (3 ml). To this solution was added iron powder (0.08 g, 0.98 mmol) followed by saturated ammonium chloride solution (0.1 ml) and the mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.15 g, 100% yield) as a yellow solid. Tr=1.71 min, m/z (ES+) (M+H)+ 312.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[Br:19].[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].O>C(#N)C>[Br:19][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:11]=1[CH:10]1[NH:9][C:37](=[O:38])[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[C:21]2[CH2:22][CH2:23][C:24](=[O:25])[C:20]1=2)[C:15]#[N:16]
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCC2=O)c(Br)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)c(Br)c1
Temperature: 25 °C

Procedure:
Triethylamine (0.43 mL, 3.0 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(tri-fluoromethyl)phenylamino)cyclopent-1-enyl)methyl)-3-bromobenzonitrile hydrochloride (intermediate 20, 5.90 g, 12.1 mmol) and 1,1′-carbonyldiimidazole (2.46 g, 15.2 mmol) in acetonitrile (60 mL), and the mixture is stirred at room temperature over night. Water (700 mL) is added and the precipitate is filtered, washed with water and dried. Yield: 5.45 g. ESI a) mass spectrum: [(79Br)-M+H]+=476, [(81Br)-M+H]+=478; Retention time HPLC: 1.10 min (X011_S01).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCCC2)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (73%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:23][CH:24]=1)(=[O:4])=[O:5]
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3CCNCC3)n2)cc1
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(OCc2csc(C3CCN(c4ncccn4)CC3)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of 4-[4-(4-methylsulfonyl-phenoxymethyl)-thiazole-2-yl]-piperidine hydrochloride (100 mg, 0.24 mmol), 2-chloropyrimidine (30 mg, 1.1 eq.) and diisopropylethylamine (122 mg, 4 eq.) in i-PrOH (5 mL) was heated at 90° C. for 1.5 hours. The solvent was removed in vacuo. The residue was purified on silica gel (60% EtOAc in hexanes) to afford the desired product. 1H NMR (CDCl3): δ 8.32 (2H, d, J=4.8 Hz), 7.88 (2H, d, J=8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J=8.8 Hz), 6.49 (1H, t, J=4.8 Hz), 5.24 (2H, s), 4.89 (2H, m), 3.32 (1H, m), 3.06 (2H, m), 3.04 (3H, s), 2.22 (2H, m), 1.81 (2H, m).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH3:17])[C:4]=1[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].C(S)C.Cl>CN(C)C=O.O>[OH:2][C:3]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:8]=[C:7]([CH3:17])[C:4]=1[C:5]#[N:6]
Reactant: COc1cc(N2CCOCC2)cc(C)c1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCS
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOCC2)cc(O)c1C#N
Temperature: 90 °C
Yield: 48.5 %

Procedure:
To a solution of 2-methoxy-6-methyl-4-morpholin-4-yl-benzonitrile (0.9 g, 3.88 mmol) in dimethylformamide (15 ml) are added potassium carbonate (2.1 g, 15.5 mmol) and ethanethiol (2.3 ml, 31.0 mmol) and the resulting mixture is heated at 90° C. for 16 h. The reaction mixture is poured onto cold water (50 ml), acidified with 2M hydrochloric acid to pH 3 and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by flash column chromatography (silica gel, 30% ethyl acetate/hexane) affording 2-hydroxy-6-methyl-4-morpholin-4-yl-benzonitrile (0.41 g, 1.88 mmol, 48%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29](OC)[C:28]=2[F:37])[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.BrC1N=C(C(O)C2C(F)=C([N:98]3[CH2:102][CH2:101][CH2:100][C:99]3=[O:103])C=C(CC)C=2)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.BrC1N=C(C(Cl)C2C=C(CC)C=C(OC)C=2F)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>>[Br:1][C:2]1[N:3]=[C:4]([CH:26]([NH:38][C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[C:45]([N:49]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:57]([O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[O:58])=[N:44][CH:43]=[CH:42]3)[C:27]2[CH:32]=[C:31]([CH2:33][CH3:34])[CH:30]=[C:29]([N:98]3[CH2:102][CH2:101][CH2:100][C:99]3=[O:103])[C:28]=2[F:37])[N:5]([C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1
Reactant: CCc1cc(OC)c(F)c(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCc1cc(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(N2CCCC2=O)c1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Agent: CCc1cc(OC)c(F)c(C(Cl)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(N2CCCC2=O)c1

Procedure:
According to the procedure for the preparation of Intermediate 206.4, Intermediate 398.3 (65 mg, 0.104 mmol) was converted to the chloro intermediate, then displaced with di-tert-butyl (6-aminoisoquinolin-1-yl)imidodicarbonate (rt for 14 h) to afford after flash chromatography (0 to 100% EtOAc/hexanes gradient) 53.3 mg of Intermediate 398.4 as a colorless solid. LCMS (2 min gradient) RT=2.14 min, 723.1 (M+(H−Tr)+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH3:13])[CH:10]=[C:11](I)[C:3]=12.[N:14]1([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH3:13])[CH:10]=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)[CH:20]=3)[C:3]=12
Reactant: Cc1cc(Cl)c2c(I)cn(C)c2n1
Reactant: OB(O)c1cccc(N2CCCC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)c2c(-c3cccc(N4CCCC4)c3)cn(C)c2n1
Temperature: 65 °C
Yield: 25.4 %

Procedure:
A mixture of 4-chloro-3-iodo-1,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (D13) (500 mg, 1.631 mmol), (3-(pyrrolidin-1-yl)phenyl)boronic acid (374 mg, 1.957 mmol), bis(triphenylphosphine)palladium(II) chloride (114 mg, 0.163 mmol) and sodium carbonate (2M aq. solution) (8 mL, 16.00 mmol) was heated at 65° C. for 1 hour. The mixture was transferred to a separatory funnel with ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL×3). The organics were combined, dried over magnesium sulfate and concentrated. The crude was purified over normal phase chromatography eluting with ethyl acetate and cyclohexane (0-30%) to give the title compound (135 mg). LCMS (A): m/z (M+H)+ 326, C19H20ClN3 requires 325 (acidic).