Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=1.[CH2:37]([O:39][C:40](=[O:56])[CH:41]([O:43][P:44]([CH2:53][CH:54]=O)([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])[CH3:42])[CH3:38].[BH3-]C#N.[Na+]>C(O)(=O)C.CN(C=O)C>[CH2:37]([O:39][C:40](=[O:56])[CH:41]([O:43][P:44]([CH2:53][CH2:54][N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:9](=[O:23])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:24][C:25]4[N:30]=[C:29]([C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:28]=[CH:27][N:26]=4)[CH:4]=3)=[CH:15][CH:14]=2)[CH2:22][CH2:21]1)([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])[CH3:42])[CH3:38]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CCOC(=O)C(C)OP(=O)(CC=O)Oc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)OP(=O)(CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1)Oc1ccccc1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
A solution of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1-ylmethyl-benzamide (20 mg, 0.04 mmol) and 2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester (60 mg, 0.2 mmol) in 1% Acetic Acid/DMF (1.5 mL) solution was stirred at room temperature for 7 hours followed by an addition of NaCNBH3 (30 mg, 0.24 mmol). The resulting mixture was stirred for additional 30 min when completion of the reaction was observed by LCMS. After evaporation of solvent, the residue was taken up in CH2Cl2 and then extracted with saturated aqueous NaHCO3 The organic extracts were dried in vacuo and the residue was purified by silica gel chromatography using MeOH—CH2Cl2 (7%) to afford 8 mg (26%) of the product. 31P NMR (121.4 MHz, CDCl3) δ 27.2, 28.6; MS (m/z) 764 [M+H]+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.O1CCCC1.[C:16]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C>[OH:23][C:16]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: CCOC(=O)N1CCC(C(=O)c2ccccc2)CC1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(OC)cc2)CC1
Reaction time: 2 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 15 parts of magnesium, 112.2 parts of 1-bromo-4-methoxybenzene and 540 parts of tetrahydrofuran, was added dropwise a solution of 80 parts of ethyl 4-benzoyl-1-piperidinecarboxylate in 360 parts of tetrahydrofuran at reflux temperature. Upon completion, stirring was continued for 2 hours at reflux. After cooling overnight, the reaction mixture was poured onto a mixture of 300 parts of crushed ice and 40 parts of acetic acid at 10° C. After stirring for 15 minutes, the layers were separated. The organic layer was dried, filtered and evaporated. The residue was taken up in methylbenzene and the latter was evaporated. The residue was suspended three times in 70 parts of 2,2'-oxybispropane and the latter was decanted each time. The residue was evaporated to dry, yielding 106 parts of ethyl 4-[hydroxy(4-methoxyphenyl)phenylmethyl]-1-piperidinecarboxylate as a residue (intermediate 31).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:57][CH2:58][CH2:59][N:60]1[CH2:64][CH2:63][CH:62]([NH:65][C:66](=[O:68])[CH3:67])[CH2:61]1>CN(C=O)C>[C:66]([NH:65][CH:62]1[CH2:63][CH2:64][N:60]([CH2:59][CH2:58][NH:57][C:31](=[O:33])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:61]1)(=[O:68])[CH3:67]
Reactant: CC(=O)NC1CCN(CCN)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(CCNC(=O)Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (260 mg, 0.5 mmol) in DMF (3 mL) was added HOBt (101 mg, 1.5 eq.), EDAC.HCl (144 mg, 3 eq.) and TEA (152 mg, 1.5 eq.). After stirring at rt for 30 mins, to the mixture was added N-[1-(2-amino-ethyl)-pyrrolidin-3-yl]-acetamide (128 mg, 1.5 eq.). After stirring at 40° C. for overnight, the cooled reaction was concentrated and the residue was purified on a silica gel column to give the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][C:14](=[O:18])[CH2:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[OH-].[Na+].O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[CH2:16][CH2:15][CH:14]([OH:18])[CH2:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)n1)CCC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)n1)CCC(O)C2
Reaction time: 16 h
Yield: 772.3 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-2-isopropyl-5,8-dihydro-6H-quinazolin-7-one (0.126 g) in EtOH (3 mL) was added NaBH4 (0.053 g). After 16 h, the mixture was treated with 1 M NaOH (5 mL) and water (10 mL). The mixture was stirred for 30 min then extracted with CH2Cl2. The organic layer was dried and concentrated. Chromatography on SiO2 (10 to 35% EtOAc/hexanes) afforded 0.98 g of the title compound. TLC (SiO2, 50% EtOAc/hexanes): Rf=0.18. MS (ESI): exact mass calcd. for C17H19FN2O, 286.15; m/z found, 287.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(CO)nc2cc(Br)cnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.35 g of 6-bromo-2-hydroxymethyl-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 59), 2.60 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.39 ml of tributylphosphine, 1.41 g of 1,1'-(azodicarbonyl)dipiperidine and 35 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.43 g of the title compound, melting at 97-100° C. (softening).
Reaction SMILES: [CH:1]([C:4]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:25](=[O:27])[NH2:26])[N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:6]1=[O:24])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:37][C:38]([O:40]C(C)(C)C)=[O:39].O>CN(C)C=O>[CH:1]([C:4]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:25](=[O:27])[NH2:26])[N:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13]([C:15]2[N:16]([CH2:37][C:38]([OH:40])=[O:39])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[C:6]1=[O:24])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1CCCC[C@@H](NC(=O)c2cc3ccccc3[nH]2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C(N)=O)(c1ccccc1)N1CCCC[C@@H](NC(=O)c2cc3ccccc3n2CC(=O)O)C1=O

Procedure:
To a solution of example 46 (1.200 g) under nitrogen in anhydrous dimethylformamide (10 mL) at 0°-5° C. was added sodium hydride (60% dispersion in mineral oil, 0.113 g). After stirring until the reaction mixture was homogeneous, tert-butyl bromoacetate (0.434 mL) was added. The reaction mixture was maintained at 0°-5° C. for 1.5 h and then added to water (100 mL). The resulting slurry was cooled to 0°-5° C., filtered and the filter cake was dried under high vacuum to provide the title compound as an off-white solid (1.482 g). MS(ESI): [M+H]+ =561.2. 1H NMR (300 MHz, CDCl3) d=1.07 (d, J=6.8 Hz, 6H), 1.47-2.20 (m, 6H), 1.56 (s, 9H), 3.17 (m, 1H), 3.64-3.77 (m, 2H), 3.85 (d, J=16.6 Hz, 1H), 4.75 (m, 1H), 4.98 (m, 1H), 5.27 (m, 2H), 7.01 (b, 1H), 7.13 (m, 1H): 7.19-7.31 (m, 3H), 7.41-7.50 (m, 4H), 7.63 (m, 1H), 7.71 (m, 1H).
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:16]=1.[N:29]([C@@H:32]1[C@@H:36]([CH2:37][OH:38])[O:35][C@@H:34](N2C=C(C)C(=O)NC2=O)[CH2:33]1)=[N+:30]=[N-:31]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:34]2[O:35][C@H:36]([CH2:37][OH:38])[C@@H:32]([N:29]=[N+:30]=[N-:31])[CH2:33]2)=[C:17]([O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:16]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: Nc1nc(OC2CCC2)c2nc[nH]c2n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(OC4CCC4)nc(N)nc32)O[C@@H]1CO
Temperature: 50 °C
Yield: 32 %

Procedure:
To 800 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-(cyclobutoxy)-9H-purine (0.164 g, 0.8 mmol) and 3'-azido-3'-deoxythymidine (1.069 g, 4.0 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 40 mL solution of trans-N-deoxyribosylase with an activity of 1500 units/mL was added. The reaction was heated at 50° C. Five days later 0.164 g, 0.8 mmol, of 2-amino-6-cyclobutoxypurine was added to the reaction. Ten days after the reaction was started, another 0.164 g, 0.8 mmol, of 2-amino-6-cyclobutoxypurine and 0.428 g, 1.6 mmol, of 3'-azido-3'-deoxythymidine were added to the reaction. Twenty-one days after the reaction was started, 0.164 g, 0.8 mmol, of 2-amino-6-cyclobutoxypurine was added to the reaction. The reaction was stopped after twenty-six days by heating to 80° C. to precipitate the enzyme. After chilling to 0° C. the mixture was filtered. The aqueous filtrate was extracted with ethyl acetate (3 times) to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered and the solvent removed in vacuo to give a foam. The foam was chromatographed on basic alumina grade 1 eluted with chloroform/methanol (95.5, v/v). The product containing fractions were combined and the solvent removed in vacuo to give the product as a foam, 0.334 g, in 32% yield.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:23]([C:20]1[N:21]=[CH:22][C:17]([N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 140 °C

Procedure:
tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.4 g; 1.9 mmol), prepared as described in (J. Med. Chem., (1998) 41, 674), 5-bromo-2-nitropyridine (0.43 g; 2.27 mmol), prepared as described in (J. Am. Chem. Soc., (1945) 67, 668), and triethylamine (0.23 g; 2.27 mmol) in toluene (10 mL) were heated at reflux for 14 hours. After evaporation of the solvent, additional triethylamine (0.23 g) was added and the mixture further heated at 140° C. for 2 hours. The residue was purified on SiO2 (CH2Cl2:EtOAc 9:1) to provide the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C@@:14]4([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:11]([CH2:12][CH2:13]4)[C:10]=3[C:9](=[O:20])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH2:21]([N:8]1[C:9](=[O:20])[C:10]2[C@@H:11]3[C:16]([CH3:17])([CH3:18])[C@@:14]([CH3:19])([CH2:13][CH2:12]3)[C:15]=2[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)[nH]n1-c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(Cc2ccccc2)n1-c1ccccc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture of (4S,7R)-1-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 8; 1.00 g, 3.7 mmol) and benzyl bromide (0.9 mL, 7.6 mmol) in N,N-dimethylformamide (30 mL) was heated at 100° C. overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Isco 80 g column, eluting with 5-75% ethyl acetate/hexanes to give (4S,7R)-2-benzyl-7,8,8-trimethyl-1-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.01 g, 76%) as a brown oil. ES(+)-MS (M+H) 359.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:16])/[CH:11]=[CH:12]/OCC.C1C(=O)N(Br)C(=O)C1.[NH2:25][C:26]([NH2:28])=[S:27].[OH-].[NH4+]>O1CCOCC1.O>[NH2:28][C:26]1[S:27][C:11]([C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:16])=[CH:12][N:25]=1
Reactant: NC(N)=S
Reactant: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Temperature: 21 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at −10 to 0° C. The slurry was warmed and stirred at 20-22° C. for 3 h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80° C. After 2 h, the resulting solution was cooled to 20-22° and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5° C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9% yield) of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 18.18, 120.63, 126.84, 127.90, 128.86, 132.41, 133.63, 138.76, 142.88, 159.45, 172.02.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:19][C:14]3=[N:13][CH:12]=2)=[CH:7][CH:6]=1.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([N:43]=[C:44]=[O:45])[CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C>CS(C)=O>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:17]=[CH:16][N:15]4[C:11]([C:8]5[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:44]([NH:43][C:39]6[CH:40]=[CH:41][CH:42]=[C:37]([C:36]([F:35])([F:46])[F:47])[CH:38]=6)=[O:45])=[CH:10][CH:9]=5)=[CH:12][N:13]=[C:14]4[CH:19]=3)=[CH:25][CH:24]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CN)cc5)cnc4c3)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CNC(=O)Nc6cccc(C(F)(F)F)c6)cc5)cnc4c3)cc2)CC1
Yield: 52.5 %

Procedure:
Combine {4-[3-(4-aminomethyl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone, bis hydrochloride (0.30 g, 0.56 mmol), 3-trifluoromethylphenyl isocyanate (0.1 mL, 0.73 mmol) and triethylamine (0.4 mL, 2.9 mmol) in DMSO (10 mL). Filter the solution through 10 g SCX column eluting with methanol→2 N ammonia in methanol. Concentrate fractions containing product to give a residue. Purify by chromatography (5% methanol in dichloromethane→10% methanol in dichloromethane→10% 2 N ammonia methanol in dichloromethane) to afford product (0.18 g, 52%). MS(ES), m/z 613 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])=[CH:11][CH:10]=2)#[N:13]
Reactant: C1CCOC1
Reactant: N#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C#N)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 729 mg (2.56 mmol) 6-amino-4-[(3-cyanophenyl)amino]-3-quinolinecarbonitrile in 2 ml hot DMF, added 12 ml THF and cooled to 0° C. under N2. Added 392 μl (2.81 mmol) triethylamine and 234 μl (2.81 mmol) acryloyl chloride. Removed ice bath after 15 minutes and stripped solvent at 2 hours. Washed residue with water and collected solids. Recrystallized from ethyl acetate and dried in vacuo, giving 318 mg of yellow solid: mass spectrum (electrospray m/e): M+H=340.1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([F:9])=[CH:4][N:3]=1.C(O)(=[O:12])C.O>>[F:9][C:5]1[C:6]([I:8])=[CH:7][C:2](=[O:12])[NH:3][CH:4]=1
Reactant: CC(=O)O
Reactant: Fc1cc(I)c(F)cn1
Solvent: O
Product: O=c1cc(I)c(F)c[nH]1
Reaction time: 8 h
Yield: 99 %

Procedure:
2,5-Difluoro-4-iodopyridine (500 mg, 2.08 mmol) was suspended in acetic acid:water (2:1, 30 mL). The mixture was heated to reflux and stirred at this temperature overnight. The reaction was concentrated to dryness to afford the title compound as a yellow solid (491 mg, 99.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, J=5.07 Hz, 1 H) 7.69 (d, J=2.34 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[N:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:56]([CH:58]([CH2:61][CH3:62])[CH2:59][NH2:60])[CH3:57]>CN(C=O)C>[CH2:56]([CH:58]([CH2:61][CH3:62])[CH2:59][NH:60][C:11](=[O:13])[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:14])[CH3:57]
Reactant: CCC(CC)CN
Reactant: O=C(O)Cn1cccc([N+](=O)[O-])c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(CC)CNC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product 2-(3-nitro-2-oxopyridin-1(2H)-yl)acetic acid (˜14.7 mmol), 4.71 g (14.7 mmol) of TBTU, 1.98 g (14.7 mmol) of HOBT and 4.99 mL (29.3 mmol, 2 eq) of DIPEA are dissolved in 60 mL of DMF (argon atmosphere). 1.97 mL (14.7 mmol) of 2-ethyl-butylamine ((→pH=6) and another eq DIPEA (→pH=8) are added. After 1 h a half eq DIPEA is further titrated and stirred overnight at RT. If the TLC control shows incomplete conversion, it is stirred for further 3 h at 45° C. The solvent is removed in vacuo and the residue is taken up in 500 mL of DCM/MeOH (8/2). It is subsequently washed with 10% citric acid (3×100 mL), saturated NaHCO3 solution (3×100 mL) and brine (75 mL). The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The crude product (3.5 g) is treated with 10 mL of ethyl acetate, 30 mL of PE (40-60) is added and stirred for 15 min at RT. The solid is filtered off, washed with some amount of PE and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:32]1[CH:31]=[C:30]([C:29]([F:44])([F:43])[F:28])[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (142 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3,5-bis-trifluoromethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17]4=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:16]4[N:15]=[CH:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17]4=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=[C:16]4[N:15]=[CH:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1)=[O:34]
Reactant: CSc1nc2ccc(Cn3cnc4cc(C(F)(F)F)cnc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(C(F)(F)F)cnc43)cc2s1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A mixture of 2-(methylthio)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole (200 mg, 0.53 mmol) and m-CPBA (114 mg, 0.66 mmol) in DCM (5 mL) was stirred in an ice-water bath for 2 h. The mixture was diluted with DCM and washed with aq Na2S2O3, aq NaHCO3 and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(methylsulfinyl)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole as a yellow solid (180 mg, 87.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.23 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.66-7.62 (m, 1H), 5.77 (s, 2H), 3.06 (s, 3H). LCMS (ESI) m/z 397 (M+H)+.