Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.CC1(C)[O:11][CH:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[C:29](=[O:30])[C:28]4[C:27]5[C:22](=[CH:23][C:24]([C:31]#[N:32])=[CH:25][CH:26]=5)[NH:21][C:20]=4[C:19]([CH3:34])([CH3:33])[C:18]=3[CH:35]=2)[CH2:9][O:8]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O>[OH:11][C@H:10]([CH2:9][OH:8])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[C:29](=[O:30])[C:28]3[C:27]4[C:22](=[CH:23][C:24]([C:31]#[N:32])=[CH:25][CH:26]=4)[NH:21][C:20]=3[C:19]([CH3:34])([CH3:33])[C:18]=2[CH:35]=1
Reactant: CC1(C)OCC(COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)O1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)c2cc(OC[C@H](O)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 38 h
Yield: 106.3 %

Procedure:
To the solution of THF and water (4:1, 1 mL) of 8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A14-1, 30 mg, 0.07 mmol), camphor sulfonic acid (36 mg, 0.14 mmol) was added at room temperature. After stirring at room temperature for 38 hr, the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the title compound (white solid, 28 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[NH:5][C:4](=O)[CH:3]=1.P(Br)(Br)([Br:21])=O>>[Br:21][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)[nH]c(=O)c1
Reactant: O=P(Br)(Br)Br
Product: Cc1cc(Br)nc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from 4-methyl-6-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (example A.23 step 1) (25.32 g, 100 mmol) and phosphoryl bromide (86.0 g, 300 mmol) according to the general procedure Ia to d preparation of bromides. Obtained as a light yellow solid (29.27 g, 93%). MS (ISP) 316.0 [(M+H)+] and 318.0 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].C1(S([C:25]2[CH:30]=[CH:29][C:28]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:33])=[O:32])=[CH:27][N:26]=2)(=O)=O)C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])=[CH:27][N:26]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(S(=O)(=O)c2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To 4.08 g of 3,4-dichlorophenol dissolved in a 25 ml THF/25 DMSO mixture was added 2.9 g of t-BuOK and then 8.99 g of 2.5-bis(phenylsulfonyl)pyridine, and the resulting mixture heated at 58° C. for 11/2 hrs. The reaction mixture was cooled to room temperature, then added to 3 to 4 volumes of water and stirred. The brown precipitate which formed was removed by filtration. Recrystallization from CH2Cl2 /ethanol gave the purified product, 2-(3,4-dichlorophenoxy)-5-(phenylsulfonyl)pyridine (68% yield), as white shiny needles, m.p. 113°-114° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:23]([O-])=O)[C:3]1=[O:26]>C(OCC)(=O)C.C(O)C.[Pt]=O>[NH2:23][C:4]1[C:3](=[O:26])[N:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cn1ccc(Nc2cccc(-c3ccccc3C#N)c2)c([N+](=O)[O-])c1=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1ccc(Nc2cccc(-c3ccccc3C#N)c2)c(N)c1=O
Reaction time: 2 h

Procedure:
3′-(1-Methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-ylamino)biphenyl-2-carbonitrile (0.11 g, 0.32 mmol) was suspended in ethyl acetate (10 ml) and ethanol (10 ml), platinum oxide (7.3 mg, 0.03 mmol) added and the mixture hydrogenated at 45 psi on a Parr hydrogenator for 2 h. The catalyst was filtered off through a glass fibre filter paper and the filtrate evaporated to give 3′-(3-amino-1-methyl-2-oxo-1,2-dihydropyridin-4-ylamino)biphenyl-2-carbonitrile as an orange oil. The oil was dissolved in formic acid (4 ml) and heated at 95° C. for 24 h. The mixture was allowed to cool to ambient temperature and evaporated. The residue was made basic by the addition of concentrated ammonia solution, then diluted with water (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography on silica eluting with dichloromethane (+1% concentrated ammonia) on a gradient of methanol (2-4%). Collecting appropriate fractions, followed by trituration with diethyl ether (5 ml), gave 3′-(5-methyl-4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)biphenyl-2-carbonitrile (64 mg, 61%) as a white solid: δH (400 MHz, CDCl3) 3.69 (3H, s), 6.66 (1H, d, J 7), 7.24 (2H, m), 7.52-7.58 (2H, m), 7.65-7.67 (2H, m), 7.69-7.74 (2H, m), 7.84 (1H, dd, J 8 and 1), 7.99 (1H, s); m/z (ES+) 327 (M++H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([OH:67])=[C:39]2[C:44]=1[CH:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:42]([S:50]([C:53]1[CH:58]=[CH:57][C:56]([O:59][C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)=[CH:55][CH:54]=1)(=[O:52])=[O:51])[CH2:41][CH2:40]2.C(N(CC)CC)C.[N:75]1([CH2:81][CH2:82]O)[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1>ClCCl>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:67][CH2:82][CH2:81][N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[C:39]2[C:44]=1[CH:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:42]([S:50]([C:53]1[CH:58]=[CH:57][C:56]([O:59][C:60]3[CH:61]=[CH:62][C:63]([F:66])=[CH:64][CH:65]=3)=[CH:55][CH:54]=1)(=[O:52])=[O:51])[CH2:41][CH2:40]2
Reactant: CCOC(=O)C1c2c(Br)ccc(O)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: OCCN1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1c2c(Br)ccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
0.515 g of PPh3 (polymer-bound, 1.2-1.5 mmol/g) are mixed with 0.13 g of diisopropyl azodicarboxylate in 5 ml of dichloromethane and shaken at room temperature for 15 min. Then 0.17 g (0.31 mmol) of ethyl 8-bromo-2-[4-(4-fluorophenoxy)benzene-sulfonyl]-5-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (crude product, 21D), 0.031 g (0.31 mmol) of triethylamine and 0.04 g (0.31 mmol) of 2-piperidin-1-ylethanol are added, and the mixture is shaken at room temperature until no further increase in conversion can be detected by means of an LCMS check. For workup, the mixture is filtered and the filtrate is washed twice with H2O. The aqueous phases are extracted twice with dichloromethane. The combined organic phases dried with MgSO4 and evaporated. The crude product obtained in this way is purified by prep. HPLC, resulting in 0.08 g of the title compound as trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[CH3:15][CH:16]([CH3:39])[CH:17]([NH:22][C:23]([C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[N:29]=1)=[O:24])[C:18]([O:20][CH3:21])=[O:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:36][C:33]1[CH:34]=[CH:35][C:30]([C:28]2[N:29]=[C:25]([C:23]([NH:22][C@@H:17]([CH:16]([CH3:39])[CH3:15])[C:18]([O:20][CH3:21])=[O:19])=[O:24])[S:26][CH:27]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3Cl)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 2-chloro-4-(trifluoromethyl)-1-isocyanatobenzene and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 9.801 (s, 1H), 8.832-8.804 (d, J=8.4 Hz, 1H), 8.680 (s, 1H), 8.515-8.486 (d, J=8.7 Hz, 1H), 8.348 (s, 1H), 8.095-8.067 (d, J=8.4 Hz, 2H), 7.897-7.893 (d, J=1.2 Hz, 2H), 7.721-7.686 (dd, J=1.8, 9 Hz, 1H), 7.621-7.593 (d, J=8.4 Hz, 2H), 4.401-4.344 (t, J=8.1, 9 Hz, 1H), 3.702 (s, 3H), 2.351-2.280 (m, 1H), 1.003-0.955 (t, J=7.2 Hz, 6H); MS (ESI) m/z 553 (M−H), 555 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12)#[N:2]
Reactant: NC(=O)c1ncn2ccsc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ncn2ccsc12
Yield: 97.9 %

Procedure:
To a suspension of 997 mg of 7-carbamoylimidazo[5,1-b]-thiazole in 80 ml of dichloromethane were add under ice-cooling 7.28 ml of N,N-diisopopylethylamine and 2.23 ml of phosphorus oxychloride. After the reaction mixture was stirred at the same temperature, it was poured onto ice-water, adjusted pH to 7.5 with aqueous sodium hydrogen carbonate, and extracted three times with dichloromethane. The organic layer was 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=15:1) to give 871 mg of 7-cyanoimidazo[5,1-b]thiazole.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22][C:21](=O)[CH2:20]1)[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=5)(=[O:37])=[O:38])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22]/[C:21](=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])/[CH2:20]1)[CH3:18]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC[C@@H]1CC(=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C1\C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a slurry of NaH (0.034 g, 0.85 mmol) in THF (5 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (0.177 mL, 0.886 mmol) at rt. After about 30 min, a solution of (3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.300 g, 0.708 mmol, Preparation #25) in THF (1 mL) was added. After about 4 h, EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL) were added. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with EtOAc/heptane/DCM (2:1:1) to provide (E)-ethyl 2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (0.260 g, 74%). LC/MS (Table 1, Method a) Rt=2.54 min; MS m/z: 494 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH:44]=[N:43][C:42](OS(C(F)(F)F)(=O)=O)=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+].O>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:42]4[N:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Oc1cc2cccc(Cl)c2cn1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5cccc(Cl)c5cn4)c3)cn2)CC1
Temperature: 105 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (70.1 mg, 0.149 mmol), trifluoromethanesulfonic acid 8-chloroisoquinolin-3-yl ester (47.9 mg, 0.154 mmol), and Pd(PPh3)4 (11.5 mg, 0.00995 mmol) in 1,4-dioxane (2.3 mL, 29 mmol in a sealable microwave tube was added a solution of Cs2CO3 (95.5 mg, 0.293 mmol) in H2O (0.65 mL, 36 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The reaction mixture was diluted with DCM, washed with water, sat. NaHCO3 solution, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, yielding the title compound as a glassy, yellow solid. 1H NMR (400 MHz, CDCl3): δ=9.70 (t, J=0.8 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.04 (d, J=0.4 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.82 (dt, J=5.8, 3.0 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.67 (d, J=0.8 Hz, 1H), 7.66-7.62 (m, 2H), 6.47 (brs, 2H), 4.40-4.19 (m, 3H), 2.92 (brt, J=11.6 Hz, 2H), 2.19 (brdd, J=12.2 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=505.16/507.13 (100/42) [MH+], 449.05/451.07 (3/1) [MH+-isobutene]. HPLC: tR=3.15 min (polar—5 min, ZQ3).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1B(O)O>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:19]=1[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(N)nn12

Procedure:
5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine (0.5 g, 2.3 mmol), and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.76 g, 3.4 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.63 g, 87%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.79-7.73 (m, 2H), 7.49-7.44 (m, 2H), 7.15 (d, J=8.9 Hz, 1H), 6.85 (t, J=4.2 Hz, 1H), 4.45 (brs, 2H), 3.85 (s, 3H). MS=309 (MH)+. 239b) To a stirred solution of 5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine (0.076 g, 0.25 mmol) in acetonitrile (5 mL, 100 mmol), was added acetic anhydride (0.015 g, 0.15 mmol), at 0° C. along with pyridine (0.02 mL, 0.2 mmol). The reaction was stirred at RT for one hour. White solid was formed that was taken up in dichloromethane and washed with 1N Hydrochloric acid and brine. Organic layer was dried over sodium sulfate and was purified via chromatography utilizing an ISCO automated purification apparatus (silica gel 40 g 5%→100% ethyl acetate in hexane). Product was isolated as a solid (0.043 g, 84%). MP=260-262° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83-7.77 (m, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 1.6 (s, 3H). MS=351 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]#[C:18][C:19]1[CH:20]=[CH:21][C:22]3[O:31][CH2:30][CH2:29][N:28]4[C:24](=[N:25][C:26]([C:32](=[O:34])[NH2:33])=[CH:27]4)[C:23]=3[CH:35]=1)([OH:16])[CH2:12]2)=O)(C)(C)C.[ClH:36].CCOC(C)=O>CO>[OH:16][C:11]1([C:17]#[C:18][C:19]2[CH:20]=[CH:21][C:22]3[O:31][CH2:30][CH2:29][N:28]4[CH:27]=[C:26]([C:32]([NH2:33])=[O:34])[N:25]=[C:24]4[C:23]=3[CH:35]=2)[CH2:10][C@H:9]2[NH:8][C@H:13]([CH2:14][CH2:15]2)[CH2:12]1.[ClH:36]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(C#Cc1ccc3c(c1)-c1nc(C(N)=O)cn1CCO3)C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)C[C@H]4CC[C@@H](C3)N4)ccc1OCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a solution of 3-(2-Carbamoyl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-9-ylethynyl)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.5 g, 1.1 mmol) in methanol (20 mL) was added HCl/EtOAc (4 M, 20 mL) at 0° C. The solution was stirred for 3 h at room temperature. The reaction mixture was filtered and washed with EtOAc to afford desired product as HCl salt (400 mg, 96%). 1H NMR: (DMSO-d6, 400 MHz): δ 9.44 (s, 1H), 9.10 (s, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 7.46 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.55 (s, 4H), 3.96 (s, 2H), 2.45-2.17 (m, 6H), 1.91-1.88 (m, 2H). LCMS [M+H]+=379.0.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:20]([N:24]=[C:25]=[S:26])([CH3:23])([CH3:22])[CH3:21]>C(O)C>[C:20]([NH:24][C:25]([NH:8][C@@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[S:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: N[C@@H](CO)Cc1ccc(O)cc1
Reactant: CC(C)(C)N=C=S
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccc(O)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
0.15 cm3 of triethylamine is added to a solution of 0.2 g of 4-[(2R)-2-amino-3-hydroxypropyl]phenol in 10 cm3 of absolute ethanol, followed by addition of 0.18 cm3 of tert-butyl isothiocyanate. The mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then heated at a temperature in the region of 60° C. for 4 hours. After cooling, the reaction medium is evaporated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and then chromatographed under an argon pressure of 60 kPa on a column of silica gel (particle size 40-63μ; diameter 2.5 cm; height 29 cm), eluting with a mixture of dichloromethane/methanol (98/2 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 0.2 g of N-(tert-butyl)-N′-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]thiourea is obtained in the form of a colourless viscous oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.42 (s: 9H); 2.63 (dd, J=13.5 and 8 Hz: 1H); 2.72 (dd, J=13.5 and 5.5 Hz: 1H); from 3.25 to 3.40 (mt: 2H); 4.29 (unresolved complex: 1H); 4.83 (t, J=4.5 Hz: 1H); 6.67 (d, J=8 Hz: 2H); 7.05 (d, J=8 Hz: 2H); 7.15 (d, J=8 Hz: 1H); 7.26 (broad s: 1H); 9.16 (s: 1H)].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC(N(C)C)=O>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccc3c(c2)CCCC3=O)cc1
Reaction time: 4 h
Yield: 82 %

Procedure:
Combine 6-Hydroxytetralone (4.42 g, 27.24 mmol), 4-Fluorobenzonitrile (3.0 g, 24.76 mmol), K2CO3 (5.1 g, 37.14 mmol) and toluene/DMA (30 ml/90 ml), then reflux under nitrogen using a Dean Stark Trap. After 4 hours, cool the reaction to room temperature and add to a separatory funnel. Add Ethyl acetate and wash the organic layer several times with water, then a brine solution, and dry the organic layer over Na2SO4. Flash chromatograph using 4/1 hexanes/ethyl acetate eluant to afford 5.34 g, 20.3 mmol (82% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.1-2.2 (2H, m), 2.6-2.7 (2H, m), 2.9-3.0 (2H, m), 6.85 (1H, s), 6.9-7.0 (1H, m), 7.05-7.15 (2H, m), 7.6-7.7 (2H, m), 8.05-8.10 (1H, m); MS m/z 264 (M+1).
Reaction SMILES: CC([O-])=O.CC([O-])=O.[Pd+2:9].[CH:10]1([P:16]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][C:26]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:24]=2[CH:35]([CH3:37])[CH3:36])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH:10]1([P:16]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[C:28]([CH:29]([CH3:30])[CH3:31])=[CH:27][C:26]([CH:32]([CH3:33])[CH3:34])=[CH:25][C:24]=2[CH:35]([CH3:36])[CH3:37])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Pd:9]
Reactant: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: [Pd]
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of the catalyst was prepared as follows: An oven-dried Wheaton vial equipped with a magnetic stir bar was charged with Pd(OAc)2 (5.60 mg, 0.025 mmol, 1.0 eq.) and 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (4c) (24.5 mg, 0.050 mmol, 2.0 eq.). Toluene (3.0 mL) was added and the vial was sealed with a PTFE-lined plastic cap. The resulting mixture was stirred at 23° C. for 1 h to yield a reddish Pd/4c catalyst solution (0.00833 N Pd in toluene).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=O)[O:25]C2C=CC([N+]([O-])=O)=CC=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:40][NH:41][CH3:42]>ClCCl>[Br:1][C:2]1[C:3](=[O:39])[N:4]([C:19]2[CH:20]=[C:21]([CH:36]=[CH:37][CH:38]=2)[CH2:22][NH:23][C:24](=[O:25])[N:41]([CH3:42])[CH3:40])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CNC
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(CNC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzylcarbamate (from step 1) (0.150 g, 0.250 mmol) and dichloromethane (2.5 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of N,N-dimethylamine in tetrahydrorfuran (0.15 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.065 g, 51%). 1H NMR (400 MHz, DMF-d6) δ 7.58 (app q, J=7.79 Hz, 1H), 7.42 (app t, J=7.65 Hz, 1H), 7.37 (app d, J=7.79 Hz, 1H), 7.08 (s, 1H), 7.03 (app dt, J=1.58, 5.37 Hz, 1H), 6.96 (app dt, J=2.55, 8.39 Hz, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H), 4.95 (app t, J=5.57 Hz, 1H), 4.42 (app dddd, J=5.10, 5.71, 10.20, 15.17 Hz, 2H), 2.90 (s, 6H), 1.96 (s, 3H). ES-HRMS m/z 506.0848 (M+H C23H22BrF2N3O3 requires 506.0885).