Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][O:19][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=4)=[CH:18][N:17]=3)[CH2:22][CH2:23]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)nc2)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)nc1
Temperature: 80 °C
Yield: 66.3 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-[(4-piperidinylmethyl)oxy]pyridine dihydrochloride (Example 71, Step 1, 0.16 g, 0.38 mmol), 2-chloro-5-ethylpyrimidine (0.1 mL, 0.76 mmol) and K2CO3 (0.26 g, 1.91 mmol) in CH3CN (3 mL) was degassed, purged with N2 and heated at 80° C. overnight. After more CH3CN (2 mL) was added, the reaction mixture was heated at 80° C. for two days. The mixture was allowed to cool to ambient temperature, water was added and the mixture was extracted with EtOAc. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light yellow solid. The crude product was purified by chromatography on a silica gel column eluted with 2:5 EtOAc/CH2Cl2 to give 0.114 g (66%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.5 Hz), 8.20 (bs, 2H), 8.01 (d, 2H, J=8.3 Hz), 7.82 (dd, 1H, Ja=8.7 Hz, Jb=2.6 Hz), 7.70 (d, 2H, J=8.3 Hz), 6.85 (d, 1H, J=8.5 Hz), 4.81 (bs, 2H), 4.24 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 3.05-2.85 (m, 2H), 2.55-2.40 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (ESI), m/z 453 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:19]=[CH:20][N:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=34)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:19]=[CH:20][N:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=34)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(F)cc(F)c34)nc12
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3ncn4cc(F)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
In a round-bottomed flask, 2-(6,8-difluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (134 mg, 0.25 mmol) was dissolved in dichloromethane (1.2 ml) and trifluoroacetic acid (0.75 ml, 9.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1.2 ml) and ethylenediamine (1.0 ml, 14.8 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 74 mg (78%) of 2-(6,8-difluoro-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a yellow powder. MS: (M+H)+=387; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.14 (br. s., 1H), 9.03 (s, 1H), 8.70 (d, J=1.9 Hz, 1H), 8.63 (dd, J=4.2, 1.9 Hz, 1H), 8.37 (s, 1H), 8.29 (d, J=8.3 Hz, 1H), 7.24-7.36 (m, 1H), 4.32 (dt, J=13.2, 6.6 Hz, 1H), 3.42-3.51 (m, 1H), 3.35-3.41 (m, 1H), 3.25 (s, 3H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[C@@H:22]1[CH2:24][C@H:23]1[CH:25]=O.[CH3:27][NH:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:22]1[CH2:24][CH:23]1[CH2:25][N:28]([CH3:29])[CH3:27]
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@H]3C=O)c3cc(F)c(F)cc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CC1CC1c1c[nH]c2cc(F)c(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
A solution of trans-2-[5,6-difluoro-1-(p-toluenesulfonyl)indol-3-yl]cyclopropane-carboxaldehyde (0.48 g, 1.28 mmol), dimethylamine (3 ml, 6 mmol, 2M/THF) and tetrahydrofuran (15 ml) was treated with sodium triacetoxyborohydride (1.35 g, 6.39 mmol) and stirred at ambient temperature for 1 h. The resulting solution was evaporated in vacuo and the residue treated with 10 N sodium hydroxide (10 ml) and methyl alcohol (10 ml). The solution was heated at a gentle reflux for 2 h then cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide, and brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo to an amber colored oil. Silica gel column chromatography (chloroform/2M ammonia in methanol, 9:1) afforded [2-(5,6-difluoro-1H-indol-3-yl)-cyclopropylmethyl]-dimethyl-amine (100 mg, 31%) as a light oil which solidified upon standing. 1H-NMR (400 MHz, CDCl3) 8.09 (1H, br s), 7.40 (1H, m), 7.10 (1H, dd, J=10.6, 6.6), 6.89 (1H, d, J=2.2 Hz), 2.38 (2H, m), 2.34 (6H, s), 1.69 (1H, m), 1.18 (1H, m), 0.90 (1H, m), 0.78 (1H, m).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[CH2:29][CH2:30][CH3:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (91 mg, 91%), MS (ISP) m/z=401.5 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and butyric acid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.C([O-])(C)(C)C.[K+:36].CCCCCCC>C(O)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][N-:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[K+:36]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[n-]n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To 40.81 g losartan of Example 1 in 110 ml i-propanol was added 10.86 g of potassium t-butanolate a temperature between 10° C. and 25° C. The reaction mixture clarified. A dense white precipitate was formed when 150 ml of n-heptane was added and stirred at room temperature for 1 hour. It was filtered and washed with 75 ml n-heptane, dried at 50° C. C in vacuo overnight to yield 43.25 g of losartan potassium.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]([NH2:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].[OH-]>C1(C)C(C)=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:18][C:11]([CH3:17])([CH3:10])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)CC(C)(C)N
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(Cl)n1

Procedure:
Example 1(b) was repeated, except that the amounts of cyanuric chloride, mixed xylene, 1,1,3,3-tetramethylbutylamine and 20% aqueous hydroxide solution were changed to 53.0 grams (0.287 mole), 132 grams, 38.0 grams (0.294 mole) and 58.8 grams, respectively, to obtain a xylene solution of 2,4-dichloro-6-(1,1,3,3-tetramethylbutylamino)-1,3,5-triazine.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH:7]=[O:8]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:7][OH:8]
Reactant: O=Cc1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A 20 g portion of sodium borohydride was suspended (partially dissolved) in 80 ml of ethanol, and 380 ml of ethanol solution containing 125 g of 3,5-difluorobenzaldehyde to the suspension which was cooled in an ice bath. After the dropwise addition, this was stirred for 1 hour, the solvent was evaporated and the resulting residue was mixed with 400 ml of water. This was extracted with 700 ml of ethyl acetate, washed with water and saturated brine in that order and then dried with anhydrous sodium sulfate. By evaporating the solvent, 120 g of 3,5-difluorobenzyl alcohol was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12](OCC)=O.NC1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>O>[OH:24][CH:21]1[CH2:22][CH2:23][CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:19][CH2:20]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of ethyl 1,3-dioxoisoindoline-2-carboxylate (1.67 g, 7.19 mmol) in water (16 mL) was added 4-aminocyclohexanol (1.31 g, 8.63 mmol), followed by K2CO3 (1.59 g, 11.5 mmol). The mixture was stirred at room temperature for 2 h. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was filtered and the solid was dried under vacuum to give 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione (1 g, 56.82%) as a brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[CH:9][C:10]([N+:16]([O-])=O)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13])(=[O:6])=[O:5]>[Pd]>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([NH2:16])=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)CCO)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc(S(=O)(=O)CCO)cc1C(=O)O

Procedure:
The procedures of Examples 17 and 18 are repeated, except that in each case 137.5 parts of 5-hydroxyethylsulfonyl-2-nitrobenzoic acid and also the aqueous mother liquor and the Pd catalyst of the previous batch are used, to give in each case about 122 parts of 5-hydroxyethylsulfonylanthranilic acid of melting point 164° to 166° C. and a purity (diazotization) of >99%, that is, mother liquor and catalyst can each be used at least 10 times without deterioration of the product or decrease in yield.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[CH3:14][S:15]([C:18]1[N:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH:20][N:19]=1)(=[O:17])=[O:16]>O1CCOCC1.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>[CH3:12][C:6]1([CH3:13])[NH:5][C:4]2[CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][N:23]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[N:19]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(S(C)(=O)=O)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2sc(-c3ccnc(S(C)(=O)=O)n3)cc2N1
Yield: 56.3 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.110 g, 0.420 mmol), 2-(methylsulfonyl)-4-(tributylstannyl)pyrimidine (0.225 g, 0.504 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.097 g, 0.084 mmol) in 1,4-dioxane (10 mL) was purged with nitrogen and microwave-irradiated at 150° C. for 1 h. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate) to give the title compound (0.080 g, 56%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].Cl[O-].[Na+].[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([OH:38])[CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH2:35][C:36]#[CH:37])[CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.C(N(CC)CC)C>ClCCl.CO>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[CH:37]=[C:36]([CH2:35][N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C@H:27]([OH:38])[CH2:26][O:25][C:22]3[CH:23]=[CH:24][C:18]4[S:17][C:16]([CH3:15])=[N:20][C:19]=4[CH:21]=3)[CH2:30][CH2:31]2)[O:6][N:5]=1
Reactant: ON=Cc1cccc(Cl)c1Cl
Reactant: C#CCN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2cc(OC[C@@H](O)CN3CCN(Cc4cc(-c5cccc(Cl)c5Cl)no4)CC3)ccc2s1
Reaction time: 0.07 h
Yield: 4.1 %

Procedure:
To a solution of 2,3 dichlorobenzaldehyde oxime (136 mg, 0.725 mmol) in 1 ml of dichloromethane was added aqueous sodium hypochlorite solution (>4%, 1.35 ml, 0.725 mmol). The reaction was sealed in a reaction vessel with a stirbar. The vessel was subjected to microwave under the following conditions: temperature=60° C., time=240(s), high absorbance, fixed hold time=on, pre-stir=10(s). After 4 minutes (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ynylpiperazinyl)propan-2-ol (50 mg, 0.145 mmol) in 1 ml of dichloromethane was added, followed by triethylamine (0.022 ml, 0.145 mmol). The reaction vessel was again subjected to microwave under the following conditions: temperature=110° C., time=240(s), high absorbance, fixed hold time=on, pre-stir=10(s). After 4 minutes, thin layer chromatography (10:1 dichloromethane:methanol) showed consumption of starting material and product formation. The solution was evaporated under reduced pressure and purified by preparative thin layer chromatography (10:1 dichloromethane:methanol) followed by HPLC to yield (2S)-3-(4-{[3-(2,3-dichlorophenyl)isoxazol-5-yl]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol (20) (3.2 mg, M+1=533.21)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[CH2:11][N:12]=2)=[CH:4][C:3]=1[CH3:25].[C:26]([O-])([O-])=[O:27].[Na+].[Na+].C([SiH](CC)CC)C>CN(C)C=O.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:24][C:19]1[CH:18]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:26]=[O:27])=[C:3]([CH3:25])[CH:4]=3)=[N:12][CH2:11]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[SiH](CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 5-(4-bromo-3-methyl-phenyl)-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrole (i.e. the product of Step 4, 2.0 g) in dimethylformamide (DMF) (50 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (“Pd(dppf)Cl2”, 0.16 g), Na2CO3 (0.59 g) and triethylsilane (1.4 mL). The mixture was purged twice with N2, then purged three times with CO and stirred under an atmosphere of CO overnight at 65° C. Then, the reaction was concentrated in vacuum and purified by flash chromatography on silica gel to afford the title compound (1.32 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][Mg]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:17]([CH3:42])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:21]=[C:20]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH2:40][CH3:41])[N:19]=3)([OH:15])[CH3:43])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbonyl]piperidine-1-carboxylic acid tert-butyl ester (177 mg, 0.31 mmol) in THF (3 mL) at 0° C. was added methylmagnesium bromide (130 μL, 0.37 mmol, 3M solution in Et2O) and the resulting mixture stirred for 1 h before further methylmagnesium bromide (130 μL, 0.37 mmol) was added. The resulting mixture was warmed to r.t. and stirred for 16 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a clear oil (104 mg, 57%). LCMS (method A): RT 3.09 min [M+H]+ 591.2
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.N1CCCCC1.[F:23][C:24]([F:29])([F:28])[C:25]([CH3:27])=[O:26]>C1COCC1>[F:23][C:24]([F:29])([F:28])[C:25](=[O:26])[CH:27]=[CH:11][CH:10]=[CH:9][CH:8]=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)C(F)(F)F
Reactant: O=CC=CC=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(C=CC=CC=Cc1ccccc1)C(F)(F)F

Procedure:
1,1,1-Trifluoro-8-phenyl-3,5,7-octatrien-2-one is prepared as outlined in Scheme IIIA. 1,1,1-Trifluoro-8-phenyl-3,5,7-octatrien-2-one is prepared by reacting 5-phenyl-2,4-pentadienal in THF with an equal amount of acetic acid and piperidine followed by addition of 1,1,1-trifluoroacetone at room temperature under nitrogen.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=2)[C:29]#[N:30])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: N#Cc1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cccc(C#N)c1
Yield: 75.4 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.414 g, 1.55 mmol), α-bromo-m-tolunitrile (0.466 g, 2.38 mmol), KI (53 mg, 0.32 mmol), and DIPEA (0.55 mL, 3.16 mmol) in DMF (8 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.447 g (75%) of 3-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a beige solid. 1H NMR (CDCl3) δ 1.56-1.72 (m, 3H), 2.05-2.10 (m, 1H), 2.18-2.34 (m, 2H), 2.41 (s, 6H), 3.53 (s, 2H), 4.10 (d, 2H, J=11.1 Hz), 6.71 (s, 1H), 6.83 (d, 1H, J=7.8 Hz), 6.93-7.00 (m, 3H), 7.13 (d, 1H, J=7.5 Hz), 7.25-7.27 (m, 2H), 8.39 (dd, 2H, J=4.8, 1.2 Hz); ES-MS m/z 383 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[Na+].[N+:17](CC)([O-])=O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:17]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)c(O)c1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2-hydroxy-4-methoxybenzaldehyde (25.0 g, 164 mmol), sodium acetate (26.4 g, 322 mmol), nitroethane (23 g, 307 mmol) in acetic acid (45 mL) was heated at reflux for 6 h. The mixture was then cooled to room temperature and poured onto ice water. The solids were filtered off, washed with water and dried. Recrystallization of the crude solid in ethyl acetate gave 2-hydroxy-4-methoxy-benzonitrile as a brown solid (15.9 g, 65%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[N:20]1[C:21]([C:29](O)=[O:30])=[CH:22][N:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=12.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:21]3[N:20]=[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][N:23]4[CH:22]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cn2ccncc2n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1cn2ccncc2n1

Procedure:
Following the method described in Example 34(d), the title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.34 g, 1.22 mmol), imidazo[1,2-a]pyrazine-2-carboxylic acid (0.2 g, 1.22 mmol), HOBt (0.25 g, 1.84 mmol), DIPEA (0.64 mL, 3.68 mmol) and EDCI (0.35 g, 1.84 mmol) using 10 mL of DMF as solvent. Yield 0.26 g. 1H NMR (400 MHz; MeOD): δ 1.30 (d, 3H), 4.44 (m, 2H), 4.58 (m, 1H), 6.77 (dd, 1H), 7.59 (dd, 1H), 7.78 (d, 1H), 7.90 (d, 1H), 8.14 (dd, 1H), 8.36 (d, 1H), 8.49 (dd, 1H), 9.06 (bs, 1H).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[CH3:29])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:10]1[CH:11]=[C:12]([S:15][CH2:16][C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:30])=[O:5]
Reactant: Cc1cc(SCC#Cc2ccc(C(F)(F)F)cc2)ccc1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(SCC#Cc2ccc(C(F)(F)F)cc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 75 mg (1.7 mmol) of the above prepared {2-methyl-4-[3-(4-trifluoromethyl-phenyl)-prop-2-ynylsulfanyl]-phenoxy}-acetic acid tert-butyl ester in 2 ml dichloromethane was treated at 0° C. with 0.4 ml TFA and stirred at RT for 3 h. The reaction was evaporated, dissolved in toluene and evaporated again (two times). Purification by flash chromatography on SiO2 with a gradient of CH2Cl2/MeOH (98:2 to 9:1) yielded 30 mg of the title compound as white crystals, mp. 130-131° C.