Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:12]2[N:11]3[C:13]([CH3:16])=[N:14][N:15]=[C:10]3[CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:7]2[CH2:8][CH2:9][C:10]3=[N:15][N:14]=[C:13]([CH3:16])[N:11]3[C:12]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]2=3)=[CH:20][CH:19]=1
Reactant: Cc1nnc2n1-c1c(F)cccc1NCC2
Reactant: Clc1ccc(I)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Product: Cc1nnc2n1-c1c(F)cccc1N(c1ccc(Cl)cc1)CC2
Temperature: 90 °C
Yield: 35.6 %

Procedure:
A disposable tube was charged with 10-fluoro-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (22 mg, 0.101 mmol), 1-chloro-4-iodobenzene (31.3 mg, 0.131 mmol), RuPhos precat. (3.67 mg, 5.04 μmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (2.352 mg, 5.04 μmol), sodium 2-methylpropan-2-olate (19.38 mg, 0.202 mmol), and a stirbar before being evacuated and purged with nitrogen three times. Toluene (1 mL, 0.4 M) was added, and the mixture was stirred at 90° C. 6 h. The mixture was cooled, diluted with ethyl acetate, filtered, and concentrated before being purified by silica gel chromatography (eluting with methylene chloride/methanol/1% ammonium hydroxide) and reverse phase HPLC to yield the title compound as a white amorphous solid (0.012 g, 0.036 mmol, 36%).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[N:37]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:42]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:43])[CH2:7]1)#[N:2]
Reactant: O=C(Cl)N1CCCC1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)N2CCCC2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 85 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and 1-pyrrolidinecarbonyl chloride. LCMS (M+H)+: m/z=593.2.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[N:55]=[C:54]([S:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:59]=2[F:65])[N:53]=[C:52]([O:66][C@H:67]([CH3:71])[C@H:68]([OH:70])[CH3:69])[CH:51]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:65][C:59]1[C:60]([F:64])=[CH:61][CH:62]=[CH:63][C:58]=1[CH2:57][S:56][C:54]1[N:55]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:51]=[C:52]([O:66][C@H:67]([CH3:71])[C@H:68]([OH:70])[CH3:69])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: C[C@@H](O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1-sulfonamide (150 mg), tris(dibenzylideneacetone)dipalladium (0) (25 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (25 mg), cesium carbonate (244 mg) and (2R,3R)-3-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)butan-2-ol (200 mg) in anhydrous dioxane (10 ml). Purification was by reverse phase HPLC eluting with acetonitrile/aq. 0.1% ammonium acetate mixtures to give title compound as a white solid. Yield: 79 mg
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](O)([CH3:18])[O:9][N:8]=2)=[CH:4][CH:3]=1.[K+].[Br-]>>[C:12]1([C:11]2[C:7]([C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:8][O:9][C:10]=2[CH3:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(C2=NOC(C)(O)C2c2ccccc2)o1
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(-c2noc(C)c2-c2ccccc2)o1
Yield: 60 %

Procedure:
Prepared with 60% yield by dehydration/aromatisation of 3-(5-methylfuran-2-yl)-4-phenyl-5-hydroxy-5-methyl-2-isoxazoline. 60% yield. Yellow oil. FT-IR (KBr): 3058, 2924, 2852, 1627, 1598, 1566, 1498, 1435, 1239, 1208, 1149, 1074, 1024, 922, 898, 791, 772, 701 cm−1. 1H NMR (400 MHz, CDCl3, δ): 7.44-7.40 (m, 3H, aromatic protons); 7.31-7.24 (m, 2H, aromatic protons); 6.12 (d, 1H, J=3.3 Hz, furyl protons); 5.94-5.92 (m, 1H, furyl protons); 2.36 (s, 3H); 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 166.3, 153.9, 153.0, 142.2, 130.1, 130.0, 128.6, 128.1, 112.8, 107.3, 13.6, 11.2. GC-MS (70 eV) m/z (int. rel.): 239 (M+, 48), 198 (15), 197 (100), 196 (23), 168 (5), 167 (6), 154 (7), 129 (7), 127 (5), 115 (5), 89 (4), 43 (7). 102 (10), 261 (100), 234 (10), 232 (10), 154 (54), 153 (33), 129 (12), 127 (31), 77 (9), 43 (14). Anal. Calc. for C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.08; H, 5.60; N, 5.90.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH:26]([F:28])[F:27]>O.O1CCOCC1>[F:27][CH:26]([F:28])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(OC(F)F)cc2)cc1
Temperature: 70 °C

Procedure:
A mixture of 20 g of 4-hydroxy-4'-octyloxybiphenyl, 13.6 g of NaOH, 100 ml of water and 150 ml of dioxane is heated to 70° C. with stirring. 10 g of chlorodifluoromethane are passed into the cooled two-phase mixture with vigorous stirring. The reaction mixture is poured into water, and the product is extracted with petroleum ether. The organic phase is dried over Na2SO4, evaporated, and the residue is filtered through a short silica gel column using petroleum ether as eluent. The product is recrystallized from acetonitrile. Colorless crystals are obtained. m.p.: 104° C., c.p.: 20° C. (extrapolated), Δn=0.093, viscosity: 17.
Reaction SMILES: CC(C)([O-])C.[K+].C([N:10]1[CH2:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:11]1=[O:23])(=O)C.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C.O>[CH:24]1([CH:30]=[C:14]2[NH:10][C:11](=[O:23])[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:13]2=[O:15])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)N1CC(=O)N(c2ccccc2F)C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=CC2CCCCC2)C(=O)N1c1ccccc1F
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (1.12 g, 10.0 mmol) was added in one portion to a solution of N-acetyl-3-(2-fluorophenyl)imidazolidine-2,4-dione (2.36 g, 10.0 mmol) and cyclohexanecarboxaldehyde (1.23 g, 11.0 mmol) in DMF (10 mL) at 0° C. The solution was allowed to warm to RT overnight with stirring, then diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine (saturated) dried (over MgSO4), filtered and concentrated. The crude product was recrystallized from hexane/ethyl acetate to give 5-cyclohexylmethylene-3-(2-fluorophenyl)-imidazolidine-2,4-dione, as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[N:7]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[N:7]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1nc(C=O)ccc1O
Product: COC(=O)CCc1nc(C=O)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 29.3 %

Procedure:
Under the conditions of example 1 D, 510 mg of 3-(6-formyl-3-hydroxy-2-pyridyl)-propionic acid methyl ester is reacted with 730 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 284 mg of 3-{6-formyl-3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-2-pyridyl}-propionic acid methyl ester of melting point 66°-69° C. is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C([O-])(O)=O.[Na+].CO>[CH:33]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]3[N:8]=[C:7]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])[C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)([CH3:35])[CH3:32]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1CCN(c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3A.13 (29 mg, 0.069 mmol), acetone (18 μL, 0.24 mmol) and sodium triacetoxyborohydride (66 mg, 0.31 mmol) in THF (1.0 mL) was stirred at room temperature over the weekend. The reaction was diluted with saturated NaHCO3 (aq) and methanol. The mixture was concentrated to dryness and the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate (R)-4-((R)-1-((6-(4-(4-isopropylpiperazin-1-yl)phenyl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.35 (19 mg) as its trifluoroacetic acid salt.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[C:15]([C:18]3[N:19]=[CH:20][N:21]4[CH:25]=[CH:24][S:23][C:22]=34)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[C:15]([C:18]3[N:19]=[CH:20][N:21]4[CH:25]=[CH:24][S:23][C:22]=34)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10]
Reactant: C=CCOC(=O)C1=C(c2ncn3ccsc23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(c2ncn3ccsc23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
To a solution of 460 mg of allyl (1S,5R,6S)-6-((1R)-1-t-butyldimethylsilyloxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 14 ml of THF were added 860 μl and 3.76 ml of a 1 M tetra-n-butylammonium fluoride in THF, and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with 120 ml of ethy acetate, washed with 30 ml of semi-saturated aqueous saline, and then with 30 ml of a mixed solution of semi-saturated aqueous saline and a saturated aqueous sodium hydrogen carbonate solution (1:1), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=97:3-95:5) to give 286 mg of allyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-7-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3]C(C1CC2C(=CC=CC=2)N1)=O)C.[CH2:15]([O:17][C:18]([CH:20]1[CH:28](OC)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:31](=[O:34])[CH:32]=[CH2:33])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:3][CH3:1])[CH:26]=2)[N:21]1[C:31](=[O:34])[CH:32]=[CH2:33])=[O:19])[CH3:16]
Reactant: CCOC(=O)C1Cc2ccccc2N1
Reactant: C=CC(=O)N1c2ccccc2C(OC)C1C(=O)OCC
Product: C=CC(=O)N1c2ccc(OC)cc2CC1C(=O)OCC

Procedure:
By substituting 2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid ethyl ester for 2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester in the procedure for Example 6, 2,3-dihydro-3-methoxy-1-(1-oxo-2-propenyl)-1H-indole-2-carboxylic acid ethyl ester was prepared.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][O:37]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][O:37]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CCCO1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydrofuran (0.56 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.94 g, 55%).
Reaction SMILES: CO[C:3](=[O:40])[CH:4]([NH:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1.O.[OH-].[Li+].[N:44]1([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.C(N(CC)CC)C.[PH2](Cl)=O>CO.O>[CH2:13]([O:12][C:9]1[N:8]=[CH:7][C:6]([CH2:5][CH:4]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:27][CH2:28]2)=[O:22])[C:3]([N:53]2[CH2:54][CH2:55][CH:50]([N:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[CH2:51][CH2:52]2)=[O:40])=[CH:11][CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)nc1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: O=[PH2]Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC(Cc1ccc(OCc2ccccc2)nc1)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(6-benzyloxy-pyridin-3-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (59 mg, 0.11 mmol) in methanol (3 mL) was added a solution of lithium hydroxide monohydrate (9.1 mg, 2 equiv) in water (0.5 mL). The reaction was stirred 2 h at room temperature, cooled to 0° C., quenched by addition of 1N hydrochloric acid (0.15 mL), and concentrated. The crude product was used without purification. The crude acid was dissolved in methylene chloride (2 mL, 0° C.), and treated sequentially with 4-piperidino-piperidine (34 mg, 1.8 equiv), triethylamine (35 μL, 2.3 equiv.), and bis-2-oxo-3-oxazolidinyl)phoshinic chloride (34 mg, 1.2 equiv). The ice bath was removed and the reaction allowed to stir overnight. The reaction was concentrated and purified by Prep TLC to give 30.3 mg (41%). LC/MS: tR=1.49 min, 680.29 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=O.[C@@H:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH2:5][NH:24][C@@H:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cc(F)cc(C(F)(F)F)c1
Product: Fc1cc(CN[C@H]2CCCc3ccccc32)cc(C(F)(F)F)c1

Procedure:
3-Fluoro-5-(trifluoromethyl)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[N:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[N:23]([CH3:29])[C:22]=3[CH:30]=2)[C:14](=[O:31])[CH:13]=1.[H-].[Na+].CC(N(C)C)=O>O>[CH:26]1([C:24]2[N:23]([CH3:29])[C:22]3[CH:30]=[C:18]([N:15]4[CH:16]=[CH:17][C:12]([O:9][CH2:8][C:5]5[S:6][CH:7]=[C:3]([CH:2]([F:10])[F:1])[N:4]=5)=[CH:13][C:14]4=[O:31])[CH:19]=[CH:20][C:21]=3[N:25]=2)[CH2:27][CH2:28]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Reactant: OCc1nc(C(F)F)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C(F)F)cs4)cc3=O)cc21
Temperature: 120 °C
Yield: 19.7 %

Procedure:
A mixture of (4-(difluoromethyl)-1,3-thiazol-2-yl)methanol (50 mg), 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)-one (69.5 mg), NaH (60% in oil, 12.1 mg) and DMA (1 ml) was heated at 120° C. under microwave irradiation for 2 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (17 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[S:16])=[CH:13][CH:12]=1>CCO>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]2[S:16][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:17]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccc(Cl)cc2)n1

Procedure:
A solution of ethyl bromopyruvate (354 mg, 1.8 mmol) and 4-chlorothiobenzamide (283 g, 1.65 mmol) in EtOH (40 mL) was refluxed for 3 h. The mixture was evaporated to dryness and the resulting oil was purified by flash chromatography to give ethyl 2-(4-chlorophenyl)thiazole-4-carboxylate as a colourless oil: 1H NMR (80 MHz, CDCl3) δ (TMS) 8.15 (s, 1H, thiazole), 7.95 (dt, Jt =2, Jd =8.5, 2H, arom), 7.42 (dt, Jt =2, Jd =8.5, 2H, arom), 4.45 (q, J=7, 2H, OCH2), 1.43 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H10ClNO2S: C 53.84; H 3.76; N 5.23; S 11.97. Found: C 53.65; H 3.77; N 5.23; S 11.51.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:48]=[N:49][N:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=23)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:47]3[CH:48]=[N:49][N:50]4[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=34)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: CC1(C)OB(c2cnn3ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (100 mg, 0.182 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (53.4 mg, 0.219 mmol), sodium carbonate (48.3 mg, 0.455 mmol) and tetrakis(triphenylphosphine)palladium (21.05 mg, 0.018 mmol) in DME (1 mL) and H2O (0.333 mL) was stirred at 85° C. for 3 h. Following reaction, the mixture was filtered and the filtrate was diluted with EtOAc and H2O. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound (53 mg, 46.1%). 1H NMR (500 MHz, CDCl3) δ ppm 1.17-2.03 (m, 17H), 3.74-3.81 (m, 3H), 3.84-3.89 (m, 3H), 4.04 (br s, 1H), 4.26 (br s, 2H), 4.46 (br s, 1H), 4.71 (br s, 2H), 6.36-6.55 (m, 2H), 6.83 (d, J=5.86 Hz, 1H), 7.18-7.31 (m, 2H), 8.42 (br s, 1H), 8.47-8.57 (m, 1H), 9.42 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10]Br.[C:12]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][CH2:23]1
Reactant: Clc1cccc(Cl)c1CCBr
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCc2c(Cl)cccc2Cl)CC1)c1ccccc1
Yield: 41.1 %

Procedure:
2-(2,6-Dichlorophenyl)ethyl bromide (674 mg.) was reacted with 4-benzamidopiperidine (547 mg.) in the presence of anhydrous potassium carbonate (736 mg.) following the procedure of Example 37 to give the title compound as the hydrochloride (412 mg) m.p. 285.7° C after crystallisation from ethanolic hydrogen chloride and ether. (Found: C, 58.0; H, 5.6; N, 6.7. C20H22Cl2N2O. HCl requires C, 58.05; H, 5.6; N, 6.8%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([O:11]C(C)(C)C)=[O:10])=[CH:7][C:6]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:5]1)[CH3:3].Cl>O1CCOCC1.O>[CH3:3][CH:2]([N:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([CH2:16][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[N:5]1)[CH3:1]
Reactant: CC(C)n1nc(CN2CCOCC2)cc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(CN2CCOCC2)cc1C(=O)O
Temperature: 25 °C
Yield: 99.8 %

Procedure:
1,1-Dimethylethyl 1-(1-methylethyl)-3-(4-morpholinylmethyl)-1H-pyrazole-5-carboxylate (628 mg) was dissolved in 1,4-dioxane (2 ml). 4M Hydrogen chloride in 1,4 dioxane (5 ml) was added and the mixture was stirred at RT under nitrogen. After 24 h further 4M hydrogen chloride in 1,4 dioxane (3 ml) was added and the mixture was stirred at RT for 72 h. One drop of water was added and the mixture was stirred at RT for 24 h. The solvent was removed in vacuo, toluene (20 ml) was added and removed in vacuo to give a white solid. The solid was dried in a vacuum oven over-night to give the title compound (513 mg) as a white solid.