Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:22]([OH:24])=[O:23])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CC(C)([O-])C.[K+].Cl>O>[CH2:2]([C:1]1[NH:18][C:19]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:21]([C:22]([OH:24])=[O:23])[CH:20]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A mixture of 3-(n-hexadecanamido)-4-methylbenzoic acid (6.0 g) and potassium tert-butoxide (22.0 g) was placed in a preheated Woods Metal bath (temperature range 240°-260° C.). The temperature of the bath was rapidly raised to between 290° and 305° C. and was maintained within this region for 15 minutes. The mixture was then left to cool to room temperature. Water (100 ml) was added to the mixture and the resultant suspension was treated with dilute hydrochloric acid (100 ml of strength 2N) and the mixture was extracted with diethyl ether (3×100 ml). The organic extract was washed with water (2×100 ml), dried over magnesium sulphate and was evaporated in vacuo to give a solid. The solid was recrystallised from glacial acetic acid and then toluene to give 2-(n-pentadecyl)indole-6-carboxylic acid (3.05 g), in the form of an off-white solid, m.p. 140°-142° C.
Reaction SMILES: BrC1C(=O)OC(O)C=1Br.[Br:10][C:11]1[C:15](OC)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[O:14][C:13](=[O:26])[CH:12]=1.BrC1C(OC2C=CC(C([O-])=O)=CC=2)(C2C=CC(OC)=CC=2)OC(=O)C=1.[B-]1(O)(O)O[C@]2(O)[C@@H](O)CO[C@]2(C)O1.OC1C(=O)C(C)OC=1C.COC1(C2C=CC=CC=2)C(=O)C(C2C=CC=CC=2)=CO1.C(C1C(=O)CCC=1)CCCC>>[Br:10][C:11]1[CH:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[O:14][C:13](=[O:26])[CH:12]=1
Reactant: COc1ccc(C2(OC)OC(=O)C=C2Br)cc1
Agent: CC1=C(O)C(=O)C(C)O1
Agent: CCCCCC1=CCCC1=O
Agent: COC1(c2ccccc2)OC=C(c2ccccc2)C1=O
Product: COc1ccc(C2OC(=O)C=C2Br)cc1

Procedure:
3,4-dibromo-5-hydroxy-2(5H)-furanone (manufactured by SIGMA), Compound 3: 4-bromo-5-methoxy-5-(4-methoxyphenyl)-2(5H)-furanone (manufactured by SIGMA), and Compound 4: 4-{[3-bromo-2-(4-methoxyphenyl)-5-oxo-2,5-dihydro-2-furanyl]oxy}benzoate (manufactured by SIGMA) were used as test drugs. As positive controls, three (3) kinds of known compounds as an AI-2 inhibitory compounds, such as Compound 5: 4-hydroxy-2,5-dimethyl-3(2H)-furanone (manufactured by SIGMA), Compound 6: 2-methoxy-2,4-diphenyl-3(2H)-furanone (manufactured by SIGMA), and Compound 7: 2-pentyl-2-cyclopentene-1-one (manufactured by SIGMA) were used (see Bassseler et al., Bacteriol. 179, p. 4043-4045, 1997; Yoshida A. et al., Appl. Environ. Microbiol., 71(5), p. 2372-2380, 2005; and Wen Z. T. et al., J. Bacteriol., 189(9), p. 2682-2691, 2004).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([NH2:13])=[O:12])[C:8]2[C:4](=[CH:5][N:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[N:7]=2)[CH:3]=1.[BH4-].[Na+].[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34][O:35][C:36](Cl)=[O:37])=[CH:30][CH:29]=1>CO>[NH2:13][C:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[CH2:25][CH2:24][CH2:23][N:22]([C:36]([O:35][CH2:34][C:31]5[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=5)=[O:37])[CH2:21]4)=[CH:18][CH:19]=3)[N:7]=2)[CH:3]=[C:2]([F:1])[CH:10]=1)=[O:12]
Reactant: NC(=O)c1cc(F)cc2cn(-c3ccc(-c4cccnc4)cc3)nc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc(F)cc2cn(-c3ccc(C4CCCN(C(=O)OCc5ccccc5)C4)cc3)nc12

Procedure:
To a stirred solution of (D4) in dry MeOH (0.2 M), NaBH4 (1.2 eq) was added and then dropwise Cbz-Cl (1.2 eq) at −65° C. The reaction was allowed to reach RT O/N, and then quenched with H2O. MeOH was concentrated under reduced pressure and EtOAc was added. The organic phase was washed with sat. aq. NaHCO3 solution, dried (Na2SO4). Evaporation of the solvent gave (D5) which was used in the next step without further purification. MS (ES) C27H25FN4O3 requires: 472. Found: 473 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[OH-].[Na+].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCC(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Reaction time: 12 h

Procedure:
3.0 g of 6-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-6-(3-pyridyl)hex-5-enoic acid are dissolved in 50 ml of 0.3N sodium hydroxide solution and hydrogenated with 1 g of palladium/charcoal at 40° C. and 3.5 bar for 12 hours. The catalyst is then removed by suction filtering and the filtrate is adjusted to pH 4 to 5. The product precipitated is separated off and taken up in chloroform. The organic extract is washed with water, dried and evaporated down. Then the mixture is chromatographed over a silica gel column using the eluant ethylene chloride/ethyl acetate/glacial acetic acid (70:30:2). The third fraction contains the desired product.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([NH:6][C:7]1[CH:15]=[N:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O>C(OC(=O)C)(=O)C>[CH2:3]([C:4]1[O:10][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][N:14]=[CH:15][C:7]=2[N:6]=1)[CH:2]([CH3:16])[CH3:1]
Reactant: CC(C)CC(=O)Nc1cnccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1nc2cnccc2c(=O)o1
Temperature: 125 °C

Procedure:
To 3-[(3-methylbutanoyl)amino]isonicotinic acid (3.30 g, 14.84 mmol) was added acetic anhydride (20 mL, 0.78M) and the reaction was heated to 125° C. with a short path distillation head. The reaction was heated for 2 h and then cooled to room temperature. Excess acetic anhydride was then removed by vacuum distillation (20 Torr, 70° C.). The residue was cooled to room temperature and azeotroped twice with toluene to provide the title compound as a tan oil. 1H NMR (500 MHz, CDCl3) δ 1.06 (d, J=6.5 Hz, 6H), 2.31-2.35 (m, 1H), 2.61 (d, J=7 Hz, 2H), 7.96 (d, J=5 Hz, 1H), 8.78 (d, J=4.5 Hz, 1H), 9.03 (s, 1H). MS [M+H] C11H12N2O2=205.3
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[C:3]=1[NH:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[H][H]>[C].[Pd].CO>[NH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([OH:1])[C:3]=1[NH:4][C:5](=[O:20])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: CN1CCCN(c2ccc(C(=O)Nc3c(O)cccc3[N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCCN(c2ccc(C(=O)Nc3c(N)cccc3O)cc2)CC1
Yield: 81.9 %

Procedure:
A mixture of 2.14 g of 2′-hydroxy-4-(4-methyl-1,4-diazepan-1-yl)-6′-nitrobenzanilide, 43 ml of methanol and 467 mg of 10% palladium-carbon (wetting rate: 54.2%) was stirred in a hydrogen atmosphere of atmospheric pressure at 30° C. until the absorption of hydrogen had stopped. The catalyst was filtered out and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using chloroform-methanol (20:1 to 10:1) to give 1.61 g of 2′-amino-6′-hydroxy-4-(4-methyl-1,4-diazepan-1-yl)benzanilide.
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([B:22]4[O:26]C(C)(C)C(C)(C)[O:23]4)=[C:18]([CH:31]=O)[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO>[CH:1]1([O:6][C:7]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]4[B:22]([OH:26])[O:23][CH2:31][C:18]=4[CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(OC4CCCC4)n3)cc2C=O)OC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OC1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2-cyclopentyloxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (2.0 g, 4.60 mmol) in methanol (15 mL) at 0° C. was added sodium borohydride (0.26 g, 6.90 mmol). After 1 h at rt, 2 M HCl was added to it at 0° C. until pH reached to 3˜4. The resulting mixture was stirred at 0° C. for 30 min and then sonicated to give white solid which was filtered and lyophilized to yield D100 (0.85 g, 56%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 7.18 (dd, J=8.2, 1.9 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 4.97 (br. s., 3H), 1.75-1.54 (m, 6H), 1.52-1.33 (m, 2H); MS (ES) m/z: 337 (M+1)+; HPLC purity 99.36% (Maxplot), 99.35% (220 nm); Elemental analysis for C18H17BN2O4.0.25 H2O: Calculated C=63.46%, H=5.18%, N=8.22%. Found C=63.34%, H=5.17%, N=8.34%.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:25])[CH2:10][N+:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH3:26][C:27]([CH3:39])([CH3:38])[C:28](=[O:37])[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[N:11]3[C:12]([CH:13]=[C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH:15]=[CH:16]3)=[C:29]([C:28](=[O:37])[C:27]([CH3:39])([CH3:38])[CH3:26])[C:30]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:25])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)C#Cc1ccccc1
Reactant: O=C(C[n+]1ccc(OCc2ccccn2)cc1)c1ccc(Cl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1c(-c2ccccc2)c(C(=O)c2ccc(Cl)cc2)n2ccc(OCc3ccccn3)cc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
To a suspension of 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(pyridin-2-ylmethoxy)pyridinium bromide (750 mg, 1.79 mmol) and 4,4-dimethyl-1-phenylpent-1-yn-3-one (333 mg, 1.79 mmol) in DMF (10.0 mL) is added TEA (0.37 mL, 2.68 mmol). The mixture is stirred at 70° C. for 18 h then treated with DDQ (406 mg, 1.79 mmol) and stirred for an additional 1 h. The mixture is then cooled to 23° C. and partitioned between water and EtOAc. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 50% EtOAc in hexanes) gives the title compound (121 mg, 13%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([CH3:30])=[CH:24][N:23]=1.[OH-].[Na+]>O>[CH3:29][O:28][C:26]1[C:25]([CH3:30])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[CH:27]=1
Reactant: COc1cc(CCl)ncc1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)ncc1C

Procedure:
7.8 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 200 ml of alcohol and the suspension was treated while cooling with ice with 6.3 g of 2-chloromethyl-4-methoxy-5-methylpyridine hydrochloride. Thereafter, 2.4 g of sodium hydroxide in 100 ml of water were added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×250 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 5,7-dihydro-2-[[(4-methoxy-5-methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 204°-205°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:34])([O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])[CH:21]([F:23])[F:22]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:25]([O:24][C:20]([F:19])([F:34])[CH:21]([F:22])[F:23])[CH:26]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(OC(F)(F)C(F)F)c1
Yield: 36 %

Procedure:
Method H2 was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid to afford the title compound as a light pink solid (69 mg, 36%). 1H-NMR (δ, ppm, DMSO-d6): 6.49 (d, 1H, HPy,5, J=5.8 Hz), 6.86 (t, 1H, CF2H, J=51.7 Hz), 6.94 (d, 1H, Harom, J=7.2 Hz), 7.44 (t, 1H, Harom, J=8.2 Hz), 7.54 (d, 1H, Harom, J=7.6 Hz), 7.62-7.67 (m, 3H, Harom), 7.80-7.82 (m, 2H, Harom), 7.95 (d, 1H, Harom, J=7.8 Hz) 10.49 (s, 1H, NHamide), 11.25 (s, 1H, NHurea), 11.44 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 105.81 (CF2), 106.61, 107.79 (CF2) 110.90, 113.78, 114.68, 116.38, 120.76, 124.77, 126.26, 130.2, 130.40, 136.62, 140.51, 141.35, 144.60, 147.17, 148.04, 154.22, 154.75, 164.17. HRMS (EI): m/z [M+H] calcd for C21H14F4N4O4: 463.1024, found: 463.1022.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[C:36]1[N:41]=[C:40]([NH:42][C@@H:43]([CH:45]2[CH2:48][CH2:47][CH2:46]2)[CH3:44])[C:39]2[N:49]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][CH:54]=3)[CH:50]=[N:51][C:38]=2[CH:37]=1.C[C:64]([N:66](C)C)=O>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].[C-]#N.[Zn+2].[C-]#N>[CH:45]1([C@H:43]([NH:42][C:40]2[C:39]3[N:49]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([C:59]([F:61])([F:60])[F:62])=[CH:57][CH:58]=4)[CH:50]=[N:51][C:38]=3[CH:37]=[C:36]([C:64]#[N:66])[N:41]=2)[CH3:44])[CH2:48][CH2:47][CH2:46]1
Reactant: CC(=O)N(C)C
Reactant: C[C@@H](Nc1nc(Cl)cc2ncn(Cc3ccc(C(F)(F)F)cc3)c12)C1CCC1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: C[C@@H](Nc1nc(C#N)cc2ncn(Cc3ccc(C(F)(F)F)cc3)c12)C1CCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A vial containing 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (67.6 mg, 0.142 mmol) and allylpalladium(II) chloride dimer (26 mg, 0.071 mmol) in DMA (400 ul) was evacuated and refilled with Ar (3×). The resulting solution was warmed to 70° C. for 20 minutes. In a separate vial was added zinc cyanide (92 mg, 0.78 mmol), (R)-6-chloro-N-(1-cyclobutylethyl)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridin-4-amine (290 mg, 0.71 mmol) and DMA (500 uL). The mixture was degassed with Ar for 15 minutes, and the catalyst solution was added to the mixture. The resulting mixture was stirred at 120° C. overnight. The mixture was cooled to room temperature and concentrated. The residue was dissolved in DCM purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to give (R)-4-((1-cyclobutylethyl)amino)-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C21H20F3N5 [M+H]+ 400. found 400.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.N#N.II.[CH:23](N1CCCCC1)=[O:24].Cl>C1COCC1.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH:23]=[O:24])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C#Cc2ccc(Br)cc2)cc1
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: II
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a dry 100 mL three-necked flask containing magnesium turnings (0.447 g; 18.38 mmol) in dry THF (8 mL), a small portion of 4-[(4-bromophenyl) ethynyl] phenyl methyl ether (VIIa) (0.300 g; 1.044 mmol) was added in one portion, at reflux under a flow of N2. N2 flow and stirring were stopped. The reaction mixture was heated at reflux for 5 minutes then iodine crystals were added, while reflux is maintained to start the reaction. A solution of remaining amount of 4-[(4-bromophenyl) ethynyl] phenyl methyl ether (VIIa) (4.5 g; 15.67 mmol) in dry THF (30 mL) was added drop wise into the reaction mixture while keeping gentle reflux. Reflux was maintained for 15 minutes then temperature was allowed to cool to RT under stirring for 1 h. The reaction mixture was cooled to 3° C. and a solution of dry 1-formyl-piperidine (2.8 mL; 25.07 mmol) in dry THF (10 mL) was added drop wise maintaining temperature at 5° C. The reaction mixture was then allowed to warm to RT and it was stirred overnight. The reaction mixture was cooled to 18° C. and 3N HCl (30 mL) was added. Water was added (50 mL) and extraction was performed with MTBE (50 mL×3). Organic phase was washed successively with water (50 mL×2), saturated solution of NaHCO3 (50 mL×1) and brine (50 mL×1). It was then dried over MgSO4, filtered and concentrated to give a yellow solid. It was taken up in Pet ether (40 mL) and left at 4° C. After 16 h the suspension was filtered and washed with Pet ether (2×30 mL) to give after drying under vacuum a clear yellow solid. The title compound was obtained (m=3.06 g) in a 77% yield. Melting point: 106° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[C:15]4=[N:16][CH:17]=[CH:18][CH:19]=[C:14]4[C:13]([C:20]([OH:22])=O)=[CH:12]3)[C:5]=2[CH:4]=[CH:3]1.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][C:20]([C:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]([C:10]2[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:6]=3[N:7]=[CH:8][N:9]=2)[CH:12]=1)=[O:22]
Reactant: Cn1ccc2c(-n3cc(C(=O)O)c4cccnc43)ncnc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1ccc2c(-n3cc(C(=O)Cl)c4cccnc43)ncnc21
Temperature: 20 °C
Yield: 125.3 %

Procedure:
To 0.93 g (3.2 mmol) of 1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid in 20 cm3 of chloroform at about 20° C. and under argon atmosphere, was added dropwise 10 cm3 (0.14 mol) of thionyl chloride. The reaction mixture was then heated and stirred at reflux temperature for 1 hour, and then it was cooled to about 20° C. and concentrated to dryness in vacuo (2.7 kPa). The residue was taken up in 20 cm3 of chloform and concentrated to dryness in vacuo (2.7 kPa) to yield 1.25 g of 3-chlorocarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine as a yellow powder which was used directly in the next step.
Reaction SMILES: [Si](Cl)(C)(C)C.[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[C:14](Cl)(=[O:22])[O:15][CH2:16][O:17][C:18](=[O:21])[CH2:19][CH3:20]>CCOCC>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:14](=[O:22])[O:15][CH2:16][O:17][C:18](=[O:21])[CH2:19][CH3:20])=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCC(=O)OCOC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCOCC
Product: CCC(=O)OCOC(=O)Nc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
Me3SiCl (2.3 mL, 18 mmol) is added to 4-chloroaniline (4.6 g, 36 mmol) in Et2O (50 mL) at room temperature with stirring during 20 min. Following an additional 30 min Stirring 7c (4.05 g, purity 90%, 22 mmol) in Et2O (30 mL) is slowly (1 h) added. The stirring is continued overnight. The precipitate is filtered off and the filtrate extracted with ice-cold 0.1N HCl (50 mL), H2O (3×50 mL), dried (MgSO4) and evaporated. The residue (4.9 g) is extracted with hexane (50 mL) to leave 3.3 g (71%) of the title compound, mp 90°-91° C.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:9]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:35])=[N:10][O:11][C:12]=1[C:13]1[CH:14]=[N:15][N:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>O1CCOCC1.ClCCl>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[C:9]1[C:8]([C:6]2[S:45][C:1]([CH3:2])=[N:4][N:5]=2)=[C:12]([C:13]2[CH:14]=[N:15][N:16]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:17]=2[C:18]([F:21])([F:20])[F:19])[O:11][N:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccncc2)c1C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nnc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3ccncc3)c2C(F)(F)F)s1

Procedure:
To a solution of N′-acetyl-3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (0.029 mg, 0.01 mmol) in dioxane (1.5 mL) was added Lawesson's Reagent (23.1 mg, 0.01 mmol). The mixture was stirred at reflux for 30 min. The mixture was then diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:16][CH2:15][C:14](=[O:17])[CH:13]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCC1CC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (WO 02/081435) (2.0 g, 5.2 mmol) in dry tetrahydrofuran (10 mL) was added dropwise to a cooled solution of 0.5 M lithium hexamethyldisilazide in tetrahydrofuran (11.4 mL) at −78° C. The mixture was stirred at this temperature for 2 hours before adding 2-(trimethylsilyl)ethoxymethyl chloride (1.4 mL, 7.8 mmol) and the solution allowed to warm to rt. over 16 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL), and the organic phase separated, dried (MgSO4) and evaporated to dryness. The product was purified on silica eluting with [9:1] hexane-ethyl acetate to yield 1.2 g of the title compound. 1H NMR CDCl3 7.38 (4H, s), 7.24-7.16 (1H, m), 7.12-7.06 (1H, m), 6.97-6.87 (1H, m), 3.66 (1H, dd, J=9.7 and 3.0 Hz), 3.51-3.45 (3H, m), 3.17-3.15 (1H, m), 3.05-2.98 (1H, m), 2.56-2.49 (2H, m), 241-2.35 (2H, m), 2.23-2.17 (1H, m), 0.91-0.87 (2H, m) and 0.03 (9H, s).