Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:26]3[O:25][CH:24]([CH3:27])[C:23](=[O:28])[N:22]([CH3:29])[C:21]=3[CH:20]=[C:19]([Cl:30])[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH+:14]([O-:39])[C:15]([C:17]2[C:26]3[O:25][CH:24]([CH3:27])[C:23](=[O:28])[N:22]([CH3:29])[C:21]=3[CH:20]=[C:19]([Cl:30])[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1Oc2c(C(=O)NC3CCN(Cc4ccccc4)CC3)cc(Cl)cc2N(C)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1Oc2c(C(=O)[NH+]([O-])C3CCN(Cc4ccccc4)CC3)cc(Cl)cc2N(C)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2.7 g of N-(1-benzyl-4-piperidyl)-6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide in 150 ml of chloroform is added portionwise 2.7 g of metachloroperbenzoic acid under cooling and stirring. After 0.5 hour, ammonia gas is bubbled through the reaction solution under stirring and the precipitate is filtered off. The mother liquor is distilled off under reduced pressure followed by recrystallizing the residue from ethanolisopropyl ether to give N-(1-benzyl-4-piperidyl)-6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide N-oxide.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[SH:11][CH2:12][CH2:13][S:14]([O-:17])(=[O:16])=[O:15].[Na+:18].CO.[Na]>CO>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([S:11][CH2:12][CH2:13][S:14]([O-:17])(=[O:16])=[O:15])=[N:7]2.[Na+:18]
Reactant: Clc1ccc2nccn2n1
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=S(=O)([O-])CCSc1ccc2nccn2n1
Yield: 80.1 %

Procedure:
To a solution of 1.35 g of 6-chloroimidazo[1,2-b]pyridazine in 30 ml of methanol were added 1.45 g of sodium 2-mercaptoethanesulfonate and 1.80 ml of 28 W/W/% sodium-methanol solution, followed by refluxing for 5 hours. The precipitated crystals were collected by filtration and washed with methanol to obtain 1.98 g of sodium 2-[(imidazo[1,2-b]pyridazin-6-yl)thio]ethanesulfonate.
Reaction SMILES: Br[C:2]1[N:3](C(OC(C)(C)C)=O)[C:4]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:10]=[C:9]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:8]=2)=[CH:5][CH:6]=1.[NH:37]1[CH:41]=[CH:40][C:39](B(O)O)=[N:38]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:28][O:27][CH2:26][C@H:25]([CH3:29])[O:24][C:9]1[CH:8]=[C:7]([C:4]2[NH:3][C:2]([C:41]3[CH:40]=[CH:39][NH:38][N:37]=3)=[CH:6][CH:5]=2)[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[CH:10]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(Br)n2C(=O)OC(C)(C)C)c1
Reactant: OB(O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3cc[nH]n3)[nH]2)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 50.8 %

Procedure:
t-Butyl 2-bromo-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1-carboxylate (375 mg, 0.446 mmol) synthesized in Example (13c) and commercially available 1H-pyrazol-3-ylboronic acid (120 mg, 1.00 mmol) were dissolved in a mixed solvent of 1,2-dimethoxyethane (20 mL) and water (5 mL), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (28 mg, 0.034 mmol) and an aqueous potassium carbonate solution (3M, 0.65 mL, 1.95 mmol) were added, and stirring was carried out at 100° C. for 7 days under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-80%) to afford the desired compound (106 mg, yield 35%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.[N:47]([CH3:50])=[C:48]=[O:49]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]5[NH:24][C:25]([CH:27]6[CH2:32][CH2:31][N:30]([C:48]([NH:47][CH3:50])=[O:49])[CH2:29][CH2:28]6)=[CH:26][C:19]=45)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: CN=C=O
Reactant: Fc1cncc(Cn2cnc3ccc(-c4ccnc5[nH]c(C6CCNCC6)cc45)cc32)c1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC(c2cc3c(-c4ccc5ncn(Cc6cncc(F)c6)c5c4)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 12D trifluoroacetate salt (30.0 mg, 0.070 mmol) in N,N-dimethylformamide (0.3 mL) was added triethylamine (0.05 ml, 0.352 mmol) and isocyanatomethane (6.0 mg, 0.106 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and purified by reverse-phase HPLC (Phenomenex Luna C8 AXIA column, 100 Å) eluting with a gradient of 10-95% acetonitrile/0.1% trifluoroacetic acid in water with 10 mM ammonium acetate to afford the title compound. 1H NMR (400 MHz, dimethylsulfoxide-d6) δ 1.51-1.66 (m, 2 H) 1.87-1.98 (m, 2 H) 2.61 (d, J=4.58 Hz, 3 H) 2.74-2.91 (m, 3 H) 4.04 (m, 2 H) 5.66 (s, 2 H) 6.11 (s, 2 H) 7.10 (d, J=4.88 Hz, 1 H) 7.57 (dd, J=8.54, 1.53 Hz, 1 H) 7.61-7.68 (m, 1 H) 7.76-7.83 (m, 2 H) 8.16 (d, J=5.19 Hz, 1 H) 8.42 (s, 1 H) 8.47-8.52 (m, 2 H) 11.32 (s, 1 H). MS (ESI) m/e 484 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][Si](C=[N+]=[N-])(C)C.C(OCC)C>C1(C)C=CC=CC=1.CO>[CH3:18][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([N:6]2[C:2]([NH2:1])=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1cnn(-c2cccc(C(=O)O)c2)c1N
Solvent: CCOCC
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(-n2ncc(C#N)c2N)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
Title compound 8A, 3-(5-amino-4-cyanopyrazol-1-yl)benzoic acid (3.2 g, 1.0 eq, 14.04 mmol) was suspended in a toluene/methanol [3:1] solution (70 ml). This was then cooled to 0° C. and trimethylsilyldiazomethane was added drop wise as a 2M solution in diethyl ether (7.7 ml, 1.1 eq, 15.44 mmol). The reaction was allowed to warm to room temperature over 2 hours. A further portion of trimethylsilyidiazomethane (1.54 ml, 0.2 eq, 2.8 mmol) was added. The reaction was stirred at room temperature for a further 45 minutes and solvent was then removed in vacuo to give the title compound as an orange solid (3.4 g, 14.04 mmol, 100%). LCMS: [M+H]+=243, Rt=1.05 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:8]([CH2:11][CH2:12][C:13](O)=[O:14])=[CH:9][CH:10]=1)=[O:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[CH:17]=2)[C:8]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 0.03 h
Yield: 73.2 %

Procedure:
The compound of step 2 (150 mg, 0.428 mmol) was dissolved in THF. N-methylmorpholine (56 mg, 0.556 mmol) and isobutylchloroformate (70 mg, 0.514 mmol) were added at room temperature. After stirring for 2 minutes, the mixture was filtered and rinsed with THF. Sodium borohydride (65 mg, 1.71 mmol) was added to the filtrate and thereafter slowly methanol until intensive foaming indicated the start of the reaction. After 5 minutes the reaction was complete as indicated by LC-MS analytics. Volatiles were evaporated in vacuo, the remainder was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the combined organic extracts were dried over sodium chloride and evaporated to dryness. This raw material was purified by silica gel chromatography with a heptane/ethyl acetate gradient to yield the title compound (106 mg)
Reaction SMILES: C(O)=O.[F:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].Br[CH2:19][C:20](=[O:36])[CH2:21][C@H:22]1[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]1[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31]>>[F:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:19][C:20](=[O:36])[CH2:21][C@H:22]3[C@H:27]([O:28][CH3:29])[CH2:26][CH2:25][CH2:24][N:23]3[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: CSc1cc2c(=O)[nH]cnc2cc1F
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Solvent: O=CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(F)c(SC)cc2c1=O

Procedure:
In the manner of Example 4, 0.462 g (0.0018 mol) of 7-fluoro-6-methylthioquinazolin-4(3H)-one formic acid salt and 0.750 g (0.00224 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.50 g (60%). 1H-NMR(CDCl3) 1.4-2.1 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.3 (doublet, 1H, aromatic H), 7.9 (singlet, 1H, N=CH--N), 8.0 (doublet, 1H, aromaic H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[C]=O.[C:12]1([N:18]=C=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C2C3NC(=CC=3)C(C3C=CC=CC=3)=C3N=C(C=C3)C(C3C=CC=CC=3)=C3NC(C=C3)=C(C3C=CC=CC=3)C3=NC=2C=C3)C=CC=CC=1.[Pd].ClC1C=CC=CC=1Cl>[N:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Pd]
Agent: C1=Cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Agent: [C]=O
Solvent: Clc1ccccc1Cl
Product: c1ccc(N=Nc2ccccc2)cc1
Temperature: 235 °C
Reaction time: 4 h

Procedure:
Into the autoclave previously described, 2 grams of palladium tetraphenylporphyrin and 30 grams of nitrobenzene are introduced and the total volume adjusted to 100 ml by means of orthodichlorobenzene. The reactor is closed and after scavenging with nitrogen, carbon monoxide is introduced until the pressure reaches 200 bars at 20° C. The autoclave is isolated and while maintaining an agitation is heated at 235° C. for 3 hours, then at 240° C. for 4 hours, 30 minutes. After cooling, the mixture is analyzed. The O.C.R. of the nitrobenzene is 94.7% and the selectivity for phenylisocyanate is 60.2%. No azobenzene is formed.
Reaction SMILES: C([O:8][C@H:9]1[C@H:16]([O:17]CC2C=CC=CC=2)[C@@H:15]([O:25]CC2C=CC=CC=2)[C@H:14]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[CH:43][CH:42]=3)[CH:34]=2)[C:11]2([CH2:13][CH2:12]2)[C@@H:10]1[CH2:49][O:50]CC1C=CC=CC=1)C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>C1COCC1.CO.[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:14]2[C@H:15]([OH:25])[C@@H:16]([OH:17])[C@H:9]([OH:8])[C@@H:10]([CH2:49][OH:50])[C:11]32[CH2:12][CH2:13]3)=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][CH3:48])=[CH:45][CH:46]=1
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc([C@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@@H](COCc4ccccc4)C34CC4)ccc2Cl)cc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)C34CC4)ccc2Cl)cc1
Yield: 37.3 %

Procedure:
To a solution of (4R,5R,6R,7S,8S)-5,6,7-tris(benzyloxy)-4-(benzyloxymethyl)-8-(4-chloro-3-(4-ethylbenzyl)phenyl)spiro[2.5]octane (36, 20 mg, 25.7 μmol) in a mixture of THF (0.2 mL) and methanol (0.8 mL) was added 1,2-dichlorobenzene (58 μL, 515 μmol) followed by 14 mg of palladium on charcoal (10%). The mixture was stirred under 1 atmosphere of hydrogen for 40 minutes. The mixture was filtered through a small pad of Celite in a 6 mL syringe and the Celite pad was washed with methanol (1 mL). Solvent was evaporated under reduced pressure and the residue was purified on preparative TLC plate (8:1 DCM:EtOH) to get 4 mg (37%) of compound 37 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.27-6.85 (m, 7H), 4.01 (s, 2H), 3.80 (m, 2H), 3.63 (m, H), 3.35 (d, J=5.1 Hz, 2H), 3.02 (d, J=11.1 hz, 1H), 2.62 (q, J=7.5 Hz, 2H), 2.06 (m, 1H), 1.21 (t, J=7.5 Hz, 3H), 0.40 (m, 1H), 0.29 (m, 1H), 0.076 (m, 1H), −0.326 (m, 1H). LC-ESI-MS m/z 418 (M+H), 440 (M+Na).
Reaction SMILES: CS(Cl)(=O)=O.C(Cl)Cl.O[CH2:10][CH2:11][CH2:12]/[C:13](=[CH:23]\[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[C:14](=[S:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[Na+]>O.C(N(CC)CC)C>[C:25]1([S:24]/[CH:23]=[C:13]2/[C:14](=[N:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)/[S:22][CH2:10][CH2:11][CH2:12]/2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCC/C(=C\Sc1ccccc1)C(=S)Nc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C(\Sc1ccccc1)=C1\CCCS\C1=N/c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
0.48 g of methanesulfonyl chloride was added to 20 ml of methylene chloride solution including 0.4 g of (E)-5-hydroxy-N-phenyl-2-(phenylthiomethylene) pentanethioamide, 0.46 g of triethylamine and 0.69 of sodium iodide. The resulting solution was stirred at room temperature for 3 hours, and added with water, extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.23 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:13]([N:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:23]([F:24])[CH:22]=[CH:21][CH:20]=3)[NH:1][C:26]2=[O:28])[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: O=c1[nH]c2c(F)cccc2c(=O)n1C1CCN(Cc2ccccc2)CC1
Yield: 258.9 %

Procedure:
To a solution of 2-amino-N-(1-benzylpiperidin-4-yl)-3-fluorobenzamide (750 mg, 2.29 mmol) in dichloromethane (30.0 mL) at 0° C. was added triphosgene (227 mg, 0.33 equiv.) as a solution in dichloromethane (5 mL). The ice bath was removed and the reaction heated at reflux for 6 h. The reaction was concentrated, dissolved in ethyl acetate, washed with saturated sodium bicarbonate, then water, then brine, dried over magnesium sulfate, and concentrated to give 700 mg of a white solid. The crude product was purified by flash chromatography to give 205 mg (25%) as a white solid. Mass spec.: 354.13 (MH)+.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[OH:29]>>[OH:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[NH:23][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N[C@@H]2CCC[C@H]2O)s1
Yield: 75 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using trans-(−)-2-aminocyclopentanol hydrochloride instead of rac-2-amino-1-butanol, to the title compound (146 mg, 75%) which was obtained as an off white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=390.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5](O)=[O:6].O=P(Cl)(Cl)Cl.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([N:22]=[N+:23]=[N-:24])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(N2CCOCC2)c(F)c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(=O)c1ccc(N2CCOCC2)c(F)c1

Procedure:
This compound may be prepared from (14) in a one pot reaction utilizing POCl3 in DMF (Vilsmeier complex) and NaN3 following the literature procedure of Sridhar et al. (Syn. Comm. 2003, 33, 607-611).
Reaction SMILES: [CH2:1]([O:8][NH:9][C@@H:10]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])C>C(O)=O>[CH2:1]([O:8][N:9]([C@H:10]([CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:18])([CH3:19])[NH:14][C:13]1=[O:20])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=1)[CH:30]=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)NC(=O)N(C[C@H](COc2ccc(Br)cc2)NOCc2ccccc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC1(C)NC(=O)N(C[C@H](COc2ccc(Br)cc2)N(C=O)OCc2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of Example 3H (57.7 g) in formic acid (200 mL) was treated with a mixture of acetic anhydride (35 mL) in formic acid (35 mL) over 10 minutes, stirred for 10 minutes, and concentrated. The concentrate was dissolved in ethyl acetate (500 mL), washed sequentially with 1:1/water:brine, saturated NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was dissolved in warm (60° C.) toluene, cooled, and filtered. The solid was washed with 1:1/toluene:heptane then dried under vacuum (100 mm Hg) at 50° C. with a nitrogen bleed to provide 51.7 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ8.42 (br s, 0.5H), 8.38 (br s, 0.5H), 8.32 (br s, 0.5H), 8.10 (br s, 0.5H), 7.4 (m, 7H), 6.95 (m, 2H), 5.00 (m, 1H), 4.91 (m, 1H) 4.80 (m, 0.5H), 4.55 (m, 0.5H), 4.28(m, 1H), 4.17 (m, 1H), 3.88 (dd, 1H, J=9, 14 Hz), 3.60 (m, 1H), 1.25 (s, 3H), 1.22 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:35]=[CH:34][C:26]3[N:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[S:29][C:25]=3[CH:24]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCO.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=[C:2]([C:23]3[CH:35]=[CH:34][C:26]4[N:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[S:29][C:25]=4[CH:24]=3)[C:10]=12
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1nc2ccc(-c3nn(C(C)C)c4ncnc(N)c34)cc2s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
A mixture of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (104) (1.88 g, 6.2 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (I-5) (2.0 g, 6.3 mmol), Pd(OAc)2 (0.28 g, 1.24 mmol), triphenyl phosphine (0.98 g, 3.7 mmol) and Na2CO3 (3.3 g, 31 mmol) was dissolved in a mixture of DMF (5 mL), EtOH (2 mL) and H2O (2 mL). The resulting mixture was degassed and back-filled with argon three times and then stirred at 80° C. for 4 h. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo. The crude product was purified by chromatography eluting with DCM/MeOH (20/1) on a silica gel column (200-300 mesh) to afford the desired product N-(6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]thiazol-2-yl)acetamide (501) (1.1 g, 48.2%) as a white solid. ESI-MS (M+H)+ m/z: 368.4.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[C@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH3:29].C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:29][CH:23]1[CH2:24][CH2:25][CH2:26][CH:27]([CH3:28])[N:22]1[CH2:21][CH2:20][CH2:19][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[CH:12][CH:13]=1
Reactant: C[C@@H]1CCC[C@H](C)N1CCCCl
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC1CCCC(C)N1CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 33.8 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-2,6-cis-dimethyl-piperidine (410 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (280 mg, 33.9%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.85 (d, 2H), 3.93 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.95 (t, 2H), 2.51-2.36 (m, 2H), 2.40 (s, 2H), 2.14-2.04 (m, 2H), 1.96 (s, 6H), 1.93-1.82 (m, 4H), 1.74-1.51 (m, 3H), 1.41-1.21 (m, 3H), 1.13 (d, 6H).
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=2)=[O:21])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: Cc1cccc(C(=O)N2N(C3CCCCCCC3)C(=O)C2(C)C)c1

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 3-methylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C(OCC)C>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]([NH:17][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:16]=1
Reactant: Nc1ccc(NC2Cc3ccccc3C2)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)C(=CNc1ccc(NC2Cc3ccccc3C2)nc1)C(=O)OCC
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A crude mixture of N2-(2,3-dihydro-1H-inden-2-yl)pyridine-2,5-diamine (5 g) and diethyl ethoxymethylenemalonate (5.5 g) was heated under reflux in dry diethyl ether (50 ml) for 1 h. The reaction mixture was then cooled to room temperature, and solvent removed under reduced pressure and the remaining residue finally recrystallised from acetonitrile to give the diethyl 2-((6-(2,3-dihydro-1H-inden-2-ylamino)pyridin-3-ylamino)methylene)malonate (6 g).