Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.ClC1SC2C=CC([C:39]([F:42])([F:41])[F:40])=CC=2N=1>>[NH:23]1[CH2:22][CH2:21][CH:20]([N:18]2[CH:19]=[C:15]([C:13]3[CH:14]=[C:9]([C:7]4[S:8][C:4]5[CH:3]=[CH:2][C:28]([C:39]([F:42])([F:41])[F:40])=[CH:27][C:5]=5[N:6]=4)[C:10]([NH2:26])=[N:11][CH:12]=3)[CH:16]=[N:17]2)[CH2:25][CH2:24]1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: FC(F)(F)c1ccc2sc(Cl)nc2c1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(C(F)(F)F)ccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-5-trifluoromethyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.12-2.30 (m, 4H), 3.04-3.17 (m, 2H), 3.36-3.45 (m, 2H), 4.48-4.58 (m, 1H), 7.84 (dd, J=8.6, 1.2 Hz, 1H), 8.07 (s, 1H), 8.40-8.44 (m, 2H), 8.46 (d, J=8.4 Hz, 1H), 8.54 (s, 1H), 8.57 (d, J=2.2 Hz, 1H). MS (ES+): m/z=445.09 [MH+]. HPLC: tR=2.39 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[C:46]=1[Cl:55]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[C:46]=3[Cl:55])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1cccc(CBr)c1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccc(C(F)(F)F)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)b enzene and isolated as white solid. MS (m/e): 475.3 (MH+).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8](=[O:15])[N:9]2[CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[OH:29])([O-:22])=[O:21].[OH-].[K+]>CS(C)=O>[N+:17]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:25]1[CH:26]=[CH:27][C:28](=[O:29])[C:23]([N+:20]([O-:22])=[O:21])=[CH:24]1)[N:9]([CH2:12][CH2:13][CH3:14])[C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:19])=[O:18]
Reactant: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Reactant: O=[N+]([O-])c1cnccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(=O)c([N+](=O)[O-])c3)cc21
Yield: 91 %

Procedure:
First, 803 mg of 7-fluoro-6-nitro-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione, 700 mg of 3-nitro-4-hydroxypyridine, and 365 mg of potassium hydroxide were allowed to react at 130° C. for 4.5 hours in dry dimethylsulfoxide in the same way as in Example 9 to give 1.059 g of 6-nitro-7-(3-nitro-4-oxo-4H-pyridin-1-yl)-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [N:1]([O-])=O.[Na+].O.S(=O)(=O)(O)O.[CH3:11][S:12]([CH2:14][C:15]1[C:16](=[CH:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH2:17])=[O:13]>C(O)CC>[CH3:11][S:12]([C:14]1[C:15]2[C:16](=[CH:18][CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[NH:17][N:1]=1)=[O:13]
Reactant: O=N[O-]
Reactant: CS(=O)Cc1cc(C(F)(F)F)ccc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: CS(=O)c1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cooled (ice/water) solution of 3.7 g. of sodium nitrite predissolved in 20 ml. of water is slowly added 50 ml. of 3N sulfuric acid. To the resulting cooled (ice/water) solution is added dropwise, over a period of 30 minutes, a solution of 12.0 g. of a α-methylsulfinyl-4-trifluoromethyl-o-toluidine predissolved in 200 ml. of 1-propanol, while the temperature is maintained below 10° C. After the reaction mixture is stirred with cooling for an additional 90 minutes, it is allowed to stand overnight at room temperature. The reaction mixture is then nearly concentrated to dryness under vacuum and taken up in 100 ml. of chloroform and 60 ml. of a 15% sodium hydroxide solution. After separation of the phases, the aqueous phase is acidified with concentrated hydrochloric acid and the resulting precipitate filtered off. The acidified aqueous phase is washed three times with chloroform and the combined chloroform extracts are dried over potassium carbonate to a solid. Recrystallization of the crude product from chloroform/hexane yields 3-methylsulfinyl-5-trifluoromethyl indazole, m.p. 168°-170° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.C(O)(=O)C>I>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(-c2cc3ccccc3cn2)cc1
Agent: I
Solvent: CC(=O)O
Product: Oc1ccc(-c2cc3ccccc3cn2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
2-(4-Methoxyphenylethynyl)benzaldehyde (2.06 g, 8.73 mmol) and t-butylamine (3.83 g, 52.4 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and the organic layer was dried over anhydrous Na2SO4, concentrated to give the imine (2.4 g, 94%) which was used in the next step without further purification. To a solution of this imine (2.39 g, 8.2 mmol) in 100 mL anhydrous DMF was added (0.156 g, 0.82 mmol) copper(I) iodide and flushed with nitrogen. The reaction mixture was heated at 100° C. for 4 h. The mixture was cooled to room temperature, and diluted with ether (200 mL). The organic layer was washed with saturated aqueous ammonium chloride (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound as a dark coloured solid. Purification by column chromatography (SilicaGel 230-400 mesh; 10% ethylacetate in hexanes as eluent) afforded 3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%) as a white solid. The 3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30 mL hydroiodic acid and 12 mL of acetic acid was added. The reaction mixture was stirred at 110° C. for 2 h, then cooled to room temperature. The precipitate formed was filtered off, washed with acetic acid (2×5 mL) and dried under vacuum to give a yellow solid. The crude compound was purified by triturating with 5% methanol in ether to give 4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. MS (ES) m/z: 222.89 (M+1), 221.86 (M); Mp. 218-219° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Clc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-chlorobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 336.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.58 (s, 1H); 8.45 (d, J=5.3 Hz, 1H); 8.01 (br s, 1H); 7.86 (m, 1H); 7.28 (m, 6H); 6.87 (d, J=5.3 Hz, 1H); 5.80 (br s, 1H); 4.74 (d, J=5.9 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>COCCOC>[C:31]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:36]=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1cccc(C#N)c1
Yield: 24.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-cyano-phenylboronic acid (38 mg, 0.26 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (13 mg, 25%). LC-MS m/e 412.21 (M+H+)
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCCO3)c2n1
Yield: 92.5 %

Procedure:
A solution of 2-butyloxy-8-methoxy-9-[2-(tetrahydro-2H-pyran-2-yl)ethyl]-9H-purin-6-amine (88 mg) in methanol (2 mL) was treated with 4N HCl in 1,4-dioxane (1 mL) for 1 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting white solid was filtered, washed with water and dried to give the title compound (78.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:26]([Mg]Br)[CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:26][CH3:27]
Reactant: CC[Mg]Br
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Under an argon atmosphere, 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (140 mg) was dissolved in tetrahydrofuran (2 ml), and the solution was then cooled to −78° C. A 0.96 M tetrahydrofuran solution (0.7 ml) of ethylmagnesium bromide was added dropwise thereto, and the mixture was stirred at −78° C. for one hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (74.5 mg, yield 49%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:15][CH2:16][CH2:17][OH:18])[C@H:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH:8]1[CH2:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH2:13]1)[CH2:15][CH2:16][CH2:17][O:18][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCCO)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CCC(N(CCCOc2ccccc2)C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 51.5 %

Procedure:
(3-Hydroxy-propyl)-(trans-4-methyl-cyclohexyl)-carbamic acid tert-butyl ester (1.5 g, 5.53 mmol) and phenol (0.52 g, 5.53 mmol) in dry THF (15 mL) was added DEAD (1.06 g, 6.08 mmol) and resin bound triphenyl phosphine (polystyrene, 2% cross linking, loading=3 mmol/g, 2.76 g). The reaction mixture was gently stirred for 18 h before the resin was filtered off and washed with THF (2×15 mL). The fitrate was concentrated in vacuo and the resulting residue was purified (SiO2, 0-20% EtOAc in heptane) to give 0.99 g of (4-methyl-cyclohexyl)-(3-phenoxy-propyl)-carbamic acid tert-butyl ester. This was dissolved in DCMTFA ((3:1), 16 mL) and the mixture was stirred for 18 h before the solvent was removed in vacuo to give 0.75 g of the TFA salt of (4-methyl-cyclohexyl)-(3-phenoxy-propyl)-amine.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:25][CH2:26][CH3:27])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:7]1[CH2:25][CH2:26][CH3:27])=[O:41]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCCc1[nH]c2cc(C(=O)OCc3ccccc3)ccc2c1C(=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)OCc3ccccc3)cc2n1C(=O)c1ccccc1Cl
Temperature: 20 °C
Yield: 115.4 %

Procedure:
To a stirred mixture of benzyl 3-isobutyryl-2-propylindole-6-carboxylate (207 mg) and diisopropylethylamine (295 mg) in dichloromethane (6 ml) were added 2-chlorobenzoyl chloride (299 mg) and 4-dimethylaminopyridine (12 mg) at 0° C. The reaction mixture was refluxed for 15 hours. The reaction mixture was cooled to 20° C. and washed with 1N hydrochloric acid, water, saturated sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:10) to give benzyl 1-(2-chlorobenzoyl)-3-isobutyryl-2-propylindole-6-carboxylate (330 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Br:1][C:2]1[N:3]=[C:4]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][CH:6]=1
Reactant: C1COCCN1
Reactant: O=Cc1nc(Br)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Brc1csc(CN2CCOCC2)n1
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) was added morpholine (130 ul, 1.5 mmol) and 3 drops of AcOH. The mixture was stirred for 12 hr and then Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hr. the mixture was quenched with Sat. NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was separated and concentrated to give 200 mg of 4-[(4-bromo-1,3-thiazol-2-yl)methyl]morpholine (76%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.C([Li])CCC.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C(OC)(C)(C)C>[CH:13]1([CH2:12][O:11][C:3]2[CH:4]=[C:5]([F:10])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH2:15][CH2:14]1
Reactant: COc1cc(Br)c(OCC2CC2)cc1F
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1F
Reaction time: 1 h

Procedure:
A stirred solution of 1-bromo-2-cyclopropylmethoxy-4-fluoro-5-methoxy-benzene from example A19 (27.51 g; 0.10 mol) in dry tert-butylmethylether (500 mL) is cooled to −20° C. before addition of n-butyl lithium (1.6 M in hexane; 68.8 mL; 0.11 mol) via syringe. After complete addition stirring is continued for one hour. Neat 2-iso-propoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane is added via syringe into the reaction mixture at −40° C. After 30 min the reaction is quenched with 1M citric acid (200 mL) at 0° C. and stirred for one hour at ambient temperature. The organic layer is separated. The aqueous layer is extracted with tert-butylmethylether (100 mL). The combined organic layers are washed with brine (200 mL) dried over MgSO4 and filtered through a plug of neutral alumina containing 5 wt % of water. The product is completely eluted with several small portions of tert-butylmethylether. The solvent is removed under reduced pressure. The crude is purified by short path distillation at 3×10−3 mbar (160° C.) to give the title compound as a colorless oil that solidifies at ambient temperature. Yield: 22.65 g.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1N[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[C:20]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Product: CC(=O)c1ccccc1NC(=O)C1CCCCC1
Yield: 90 %

Procedure:
This compound was prepared following the procedure described for compound 26A of example 26, except that 2-acetylaniline was used in place of 2-trifluoromethylaniline. Yield: 90%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.S(=O)(=O)(O)O.O.[CH3:21]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-Hydroxy-2-(trifluoromethyl)benzoic acid (30.0 g) was dissolved in methanol (600 ml), thereto was added dropwise conc. sulfuric acid (10 ml). Then, the mixture was refluxed with stirring for 20 hours. The mixture was cooled to room temperature, and to the reaction mixture was added water (200 ml), and methanol was removed by evaporation, and the resultant was extracted twice with ethyl acetate (300 ml). The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (32.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:57][C:58]1[NH:59][C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=1>C(Cl)Cl>[NH:59]1[C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=[C:58]1[NH:57][C:14](=[O:15])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Reactant: Nc1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1C#N
Yield: 95 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 26, 100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzimidazole (62 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25° C. for 3 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) to afford N-(1H-benzimidazol-2-yl)-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (129 mg, 95%) as a yellow solid: mp 148-152° C.; EI-HRMS m/e calcd for C23H24N4O3S (M+) 436.1569, found 436.1573.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:34]5[CH2:35][CH2:36][CH:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)C1CCNC1
Product: CS(=O)(=O)C1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)C1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (45 mg) was coupled to 3-(methylsulfonyl)pyrrolidine via General Procedure B. The product was purified via reverse phase HPLC to give 26.1 mg of 168. MS (Q1) 513.1 (M)+.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]=[CH2:8])(=[O:3])[CH3:2].[C:9]([NH2:13])(=[O:12])[CH:10]=[CH2:11].ClCCl>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O>[C:9]([CH:10]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][CH2:8][CH2:11]1)(=[O:12])[NH2:13]
Reactant: C=CC=COC(C)=O
Reactant: C=CC(N)=O
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)OC1C=CCCC1C(N)=O
Temperature: 110 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
1-Acetoxy-1,3-butadiene (20.79 g, 0.185 mol) was dissolved in toluene (21 mL). To this was added acrylamide (11.98 g, 0.168 mol) and hydroquinone (0.111 g). The colourless solution was heated at 110° C. for 116 h under argon. More 1-acetoxy-1,3-butadiene (5.67 g, 0.051 mol) was then added, and heating continued for a further 24 h. The solution was cooled then dichloromethane added. This solution was purified by Biotage 75 chromatography twice on silica (2×400 g) to give the title compound as a viscous oil (21.76 g, 71%), which solidified on standing;
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9](=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[F:27][C:28]([F:43])([F:42])[S:29]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[NH:32][S:29]([C:28]([F:43])([F:27])[F:42])(=[O:31])=[O:30])=[CH:16][CH:17]=2)[C:9](=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)C(F)(F)F
Reactant: CCCCc1cccc(=O)n1Cc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1cccc(=O)n1Cc1ccc(NC(=O)c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
A mixture of 2.56 g of 6-butyl-1-p-aminobenzyl-1,2-dihydro-2-oxopyridine, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 ml of CH2Cl2 is cooled to 5° and a solution of 2.88 g of o-trifluoromethanesulfonamidobenzoyl chloride in 20 ml of CH2Cl2 is added dropwise. The mixture is stirred for a further 16 hours at 20°, evaporated and worked up in conventional manner to give 6-butyl-1-[4-(o-trifluoromethanesulfonamidobenzamido)benzyl]-1,2-dihydro-2-oxopyridine.