Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=O)[C:15](Cl)=[O:16])=[CH:3]1.Cl.C([O:23][C:24](=[NH:38])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=2)[N:28]([CH3:37])[CH:27]=1)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:36][O:35][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([C:25]3[C:24](=[O:23])[NH:38][C:15](=[O:16])[C:14]=3[C:4]3[C:5]4[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:27][N:28]2[CH3:37])=[CH:33][CH:32]=1
Reactant: COc1ccc2c(CC(=N)OC(C)C)cn(C)c2c1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(C3=C(c4cn(C)c5cc([N+](=O)[O-])ccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Yield: 31 %

Procedure:
A suspension of (1-methyl-6-nitro-1H-indol-3-yl)-oxo-acetyl chloride (251 mg, 0.94 mm) and 2-(6-methoxy-1-methyl-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride (280 mg, 0.94 mm) in CH2Cl2(25 mL) was cooled to 0° C., treated with Et3N (0.53 mL, 3.7 mm), and stirred at room temperature while allowing to warm to room temperature overnight. The mixture was then diluted with CH2Cl2 (25 mL), washed with H2O (20 mL), and 0.5 N HCl (20 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was then combined with toluene (4 mL), cooled to 0° C., treated with pTsOH (197 mg, 1 mm), and stirred for 3 hours. The red solids which precipitated were collected and partitioned between CH2Cl2 (50 mL), and H2O (25 mL). The organic fraction was washed with saturated NaHCO3 solution (25 mL), then dried over MgSO4, filtered and evaporated. Rinsing the residue with tetrahydrofuran (THF) afforded 3-(6-methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3yl)-pyrrole-2,5-dione; mp=308-310° C.; in 31% yield.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd].[C]>[OH:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2c(O)cccn12
Temperature: 25 °C

Procedure:
31.45 g (101.3 mmol) of ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate were dissolved in 2 l of ethyl acetate, 3.15 g of 10% Pd/carbon were added and the mixture was stirred at RT and atmospheric pressure with hydrogen for 5 h. The mixture was filtered through kieselguhr, the filter cake was washed thoroughly with ethyl acetate/methanol and the filtrate was evaporated to dryness. This gave 21.94 g of the target compound (98% of theory, purity 99%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:32]([OH:34])[CH3:33])/[CH:3]=[CH:4]/[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14]/[C:15](/[CH3:31])=[CH:16]/[C:17]([O:19]CCCCCCCCC(O)=O)=[O:18])[O:8][CH2:7]1.[OH-:35].[Na+]>>[CH3:1][C@@H:2]([C@@H:32]([OH:34])[CH3:33])[C:3]1[O:35][C:4]=1[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14]/[C:15](/[CH3:31])=[CH:16]/[C:17]([OH:19])=[O:18])[O:8][CH2:7]1
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reactant: [OH-]
Agent: [Na+]
Product: C/C(=C\C(=O)O)C[C@@H]1OC[C@H](CC2=C([C@@H](C)[C@H](C)O)O2)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Pseudomonic acid C (80 mgs) was dissolved in 0.1 M sodium hydroxide (20 ml) and stirred overnight at room temperature. After evaporation to low volume the solution was adjusted to pH 2 (5 M HCl), saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were dried (MgSO4) then evaporated to dryness and chromatographed on silica (2 g) eluting with gradient of 0 to 8% methanol/chloroform. Fractions containing pure product (by hplc and tlc) were combined to give monic acid C (40 mgs, 74%), νmax (KBr) 3400 (broad) 1692 (broad), 1644, 1238, 975 cm-1 ; λmax (EtOH) 218 nm (ε9679); δH (CD3OD) 0.97 (3H, d, J 8 Hz, CH3 -17), 1.08 (3H, d, J 7 Hz, CH3 -14), 2.13 (3H, s, CH3 -15), 5.4 (2H, m, H-10, H-11), 5.67 (1H, s, H-2); δC (CD3OD) 170.2 (C1), 159.0 (C3), 135.8, 129.7 (C10, C11), 118.6 (C2), 76.2 (C5), 72.5 (C7), 71.6 (C13), 70.0 (C6), 65.8 (C16), 45.3 (C12), 44.1 (C4), 43.7 (C8), 33.7 (C9), 20.4 (C14), 19.3 (C15), 16.7 (C17). (Found: 284.1624. C16H28O6M.+ -C2H4O requires 284.1623).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: CCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.123 g, 0.443 mmol) was reacted with N-(2-azidoethyl)-4-butylbenzamide (0.109 g, 0.443 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-butylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), δ 7.67 (d, J=7.5 Hz, 2H), δ 7.29 (s, 1H), δ 7.11 (d, J=7.5 Hz, 2H), δ 6.42 (s, 1H), δ 6.25 (s, 2H), δ 4.48 (s, 2H), δ 3.83 (s, 2H), δ 2.56 (t, J=7.2 Hz, 4H), δ 2.21 (s, 2H), 1.47 (m, 13H), δ 1.21 (m, 4H), δ 0.83 (t, J=7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ168.3, 140.6, 149.5, 148.2, 147.1, 138.4, 131.5, 128.7, 127.4, 122.2, 106.4, 84.9, 49.4, 40.2, 35.7, 33.5, 29.2, 28.9, 28.3, 28.1, 27.9, 25.5, 22.4, 14.1 ppm; HRMS (ESI) calcd for C28H41N7O3 (M+) 523.3271. found 523.3261, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-butylbenzamide hydrochloride (0.191 g, 94% yield). 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), δ 7.69 (s, 2H), δ 7.22 (s, 2H), δ 6.44 (s, 1H), δ 4.73 (s, 2H), δ 3.89 (s, 2H), δ 3.34 (s, 2H), δ 2.59 (s, 4H), δ 2.41 (s, 2H), δ 1.54 (s, 4H), δ 1.29 (s, 4H), δ 0.88 (t, J=6.9 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 169.2, 165.1, 160.3, 158.1, 147.4, 141.4, 131.2, 128.5, 127.7, 127.3, 126.9, 92.9, 39.6, 36.3, 33.4, 30.9, 28.0, 27.7, 24.1, 22.2, 13.2, 12.1, 10.9, 8.9, 6.2, 2.5 ppm; HRMS (ESI) calcd for C23H33N7O (M+) 423.2747. found 423.2738.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cr](O)(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH3:23][C:21]1[N:22]=[C:18]([C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:24])[CH2:13][CH:14]=2)[S:19][CH:20]=1
Reactant: Cc1csc(C2=CCN(CCCC(O)c3ccc(F)cc3)CC2)n1
Agent: O=[Cr](=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1csc(C2=CCN(CCCC(=O)c3ccc(F)cc3)CC2)n1
Reaction time: 3 h

Procedure:
A 1.4 g. portion of 3,6-dihydro-α-(p-fluorophenyl)-4-(4-methyl-2-thiazolyl)-1(2H)-pyridinebutanol, prepared as described in Example 12, in 30 ml. of acetic acid is stirred at room temperature. A 24 ml. portion of chromic acid in acetic acid is added dropwise. The mixture is stirred for 3 hours and then allowed to stand overnight. The mixture is poured onto ice water and neutralized with sodium carbonate. The mixture is extracted 3 times with ether. The extracts are dried over magnesium sulfate, filtered and evaporated, giving an oil which solidifies. This solid is recrystallized twice from aqueous methanol yielding a tan solid, m.p. 81°-82°C.
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH2:3][CH2:4][CH:5]([OH:7])[CH3:6].[O-]CCCC.[K+].[Cl:15][C:16]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>O1CCCC1>[Cl:15][C:16]1[CH:23]=[C:22]([O:7][CH:5]([CH3:6])[CH2:4][CH2:3][CH:2]([OH:8])[CH3:1])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: CC(O)CCC(C)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: CCCC[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(O)CCC(C)Oc1ccc(C#N)c(Cl)c1
Yield: 46.6 %

Procedure:
To a solution of 2,5-hexanediol (28 mg, 0.240 mmol) in tetrahydrofuran was added an excess of potassium butoxide. The admixture was stirred, briefly, and 2-chloro-4-fluoro-benzonitrile (37 mg, 0.240 mmol) was added. The admixture was stirred at room temperature for 72 hours. Purification by reverse phase high pressure chromatography eluting with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) provided 28.4 mg of 2-chloro-4-(4-hydroxy-1-methyl-pentyloxy)-benzonitrile. 1H NMR (CDCl3) δ 7.50 (d, 1H), 6.95 (m, 1H), 6.79 (br d, 1H), 4.43 (m, 1H), 3.79 (m, 1H), 1.89-1.40 (m, 4H), 1.30 (d, 3H), 1.17 (d, 3H); MS m/z 253.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N+:14]([O-])=O>[Pd].CCO.C1COCC1>[NH2:14][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[CH:8][N:7]=2
Reactant: Cn1c(=O)c([N+](=O)[O-])c(N)c2cccnc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(=O)c(N)c(N)c2cccnc21
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 4-amino-1-methyl-3-nitro-1H-[1,8]naphthyridin-2-one (1.35 g, 6.13 mmol) in 1:1 EtOH/THF (25 mL) was hydrogenated over 10% Pd/C (1.30 g, 1.23 mmol) at room temperature. After 2 h, the catalyst was removed by filtration, rinsing with MeOH. The filtrate was concentrated to provide 3,4-diamino-1-methyl-1H-[1,8]naphthyridin-2-one (1.10 g, 94% yield). 1H-NMR (DMSO): δ 8.39 (dd, 1H, J=4.8, 1.6 Hz), 8.19 (dd, 1H, J=6.4, 1.6 Hz), 7.24 (dd, 1H, J=8.0, 4.8 Hz), 5.58 (s, 2H), 4.52 (s, 2H), 3.69 (s, 3H). MS: calculated for C9H10N4O+H 191.1; found: 191.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>C(Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:23]([CH2:22][O:21][C:18](=[O:20])[CH3:19])=[O:24])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of 5-Amino-indan-1-one (commercially available, 100 mg, 0.679 mmol, 1 eq.) in DCM (5 mL) is added pyridine (0.066 mL, 0.815 mmol, 1.2 eq.). The resulting solution is cooled to 0° C. followed by the addition of acetoxy acetyl chloride (0.073 mL, 0.679 mmol, 1 eq.). After stirring at 0° C. for 15 min., the reaction is warmed to 25° C. and stirred for 12 h. The reaction is diluted with DCM and sequentially washed with 1 N HCl (aq) and saturated aqueous NaHCO3. The resulting organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (1:6 hexanes/EtOAc) to give Acetic acid (1-oxo-indan-5-ylcarbamoyl)-methyl ester as an off-white solid (136 mg, 81% yield). [MS: (ES+) 248.1 (M+1)+].
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[K+].[K+]>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:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:38]3[CH:37]=[CH:36][N:35]=[C:34]([Cl:33])[CH:39]=3)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(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: [K+]
Product: Cc1cc2nc(-c3ccnc(Cl)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 90 °C

Procedure:
(S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (400.0 mg, 0.742 mmol), 2-chloro-4-pyridinylboronic acid (140.2 mg, 0.891 mmol), potassium carbonate (307.7 mg, 2.227 mmol), and Pd(PPh3)4 (128.7 mg, 0.111 mmol) were placed in a microwave vial and the vial was vacuum pumped and flushed with argon three times. To this mixture was added degassed 1,4-dioxane (3.5 mL) and water (0.7 mL). The reaction mixture was heated at 90° C. for 4.5 h then cooled to rt. The aqueous layer was separated and extracted three times with ethyl acetate. All organic layers were combined, dried over Na2SO4, and concentrated. Purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) provided the final compound. LCMS-ESI+: calc'd for C30H33Cl2N2O3S: 571.2 (M+H+); Found: 571.1 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=4.9 Hz, 1H), 7.93 (s, 2H), 7.77 (d, J=5.0 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 7.50 (d, J=7.4 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 4.82 (dd, J=8.9, 2.7 Hz, 1H), 4.42 (dd, J=11.2, 9.3 Hz, 1H), 4.29 (dd, J=11.5, 3.2 Hz, 1H), 2.80 (s, 3H), 1.14 (s, 9H), 0.97 (s, 9H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: Cc1ccccc1CN
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Cc1ccccc1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-methylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): m/e 316.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.43 (br s, 1H); 8.05 (br s, 1H); 7.85 (d, J=8.7 Hz, 1H); 6.84 (d, J=5.4 Hz, 1H); 4.73 (d, J=5.7 Hz, 1H); 2.43 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:18])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 18 h
Yield: 57.4 %

Procedure:
A solution of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated while stirring with 3 ml (0.04 mole) of 57% ammonium hydroxide. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 6.6 g. Recrystallization from ethanol-water yielded 3.0 g of white granular crystals, m.p. 179°-184° C. A second recrystallization from isopropanol yielded 2.7 g (51.7%) of fine white crystals, m.p. 185°-187° C.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)[N:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH:1]([OH:3])=[O:2].[CH2:44]([N:11]([C:10]1[C:5]([NH2:4])=[N:6][C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)=[N:8][C:9]=1[NH2:16])[C:12](=[O:15])[O:13][CH3:14])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)Nc1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccccc1)c1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 100 mg (0.22 mmol) of methyl {4,6-diamino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-5-yl}carbamate formate were initially charged in THF (0.94 ml), and 44.4 mg (0.24 mmol) of a 2 N solution of sodium bis(trimethylsilyl)amide in THF were added. After 30 min at 0° C., 52 μl (0.44 mmol) of benzyl bromide were added and the mixture was stirred at 20° C. for 20 hours. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (acetonitrile/water (+0.1% formic acid) gradient). This gave 105 mg of the target compound (87% of theory).
Reaction SMILES: [O:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CO.C(#N)C.[Pd]>[O:1]1[CH2:2][CH2:3][CH2:4][C@H:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6]1
Reactant: O=C(O)C1=COCCC1
Reactant: BrCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@H]1CCCOC1
Temperature: 40 °C
Reaction time: 10 h
Yield: 58.6 %

Procedure:
Pd/C (10%, 3 g) was added to a solution of 3,4-dihydro-2H-pyran-5-carboxylic acid (7.0 g, 55 mmol) in MeOH (100 mL). The suspension was stirred under hydrogen atmosphere (100 psi) at 40° C. for 10 h. The catalyst was filtered off and washed with MeOH (50 mL). The filtrate and washings were combined and concentrated to dryness to afford crude product. The crude product was dissolved in acetonitrile (200 mL) and benzyl bromide (9.9 g, 58 mmol) and K2CO3 (19.0 g, 138 mmol) were added. The resulting suspension was heated at 50-60° C. for 4 h and then cooled to ambient temperature. The mixture was filtered and the filtration cake was washed with acetonitrile (50 mL). The filtrate and washings were combined and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (Hexane/EtOAc=20:1) to afford a mixture (7.1 g) of (S)-benzyl tetrahydro-2H-pyran-3-carboxylate and (R)-benzyl tetrahydro-2H-pyran-3-carboxylate, which was separated by chiral prep-HPLC to afford (S)-benzyl tetrahydro-2H-pyran-3-carboxylate (2.1 g, 17% yield) and (R)-benzyl tetrahydro-2H-pyran-3-carboxylate (2.0 g, 16% yield), respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19](=[O:21])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3cccnc3n2CC(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Then, under nitrogen atmosphere, piperidine (1.92 g, 0.022 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness, then placed under high vacuum for 3-4 hrs. The residue was treated with water and the solid was collected by filtration, washed with water, and dried under high vacuum at 50°-60° C. overnight. The solid was recrystallized from isopropyl alcohol with refrigeration overnight. The solid was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50°-60° C. overnight to give 3.21 g (62%) of title compound, mp 153°-55° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1)=[O:12].[CH:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[CH:19]1([CH2:25][S:26]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]2[C:11]([O:10][CH3:9])=[O:12])(=[O:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)[C@@H]1CCCCN1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reaction time: 18 h
Yield: 70.5 %

Procedure:
Triethylamine (22.15 ml) was added to a solution of (2S)-2-(methoxycarbonyl)piperidine hydrochloride (10 g) [see Preparation 24] and cyclohexylmethanesulfonyl chloride (16.42 g) [King. J. F. et al,. J. Am. Chem. Soc., 1992, 114(5), 1743-9] in dichloromethane (100 ml). The reaction mixture was stirred for 18 hours after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 95:5 changing to 80:20, by volume, hexane:ethyl acetate to afford methyl (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxylate (11.9 g) as a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH:14]1([CH2:17][NH:18][C:19](=[O:30])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:15]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
tert-Butyl piperazine-1-carboxylate (45.8 mmol, 8.53 g) and 4-(3-(cyclopropylmethyl)ureido)benzoic acid (45.8 mmol, 10.73 g) were mixed in dichloromethane (200 mL) and triethylamine (103 mmol, 14.36 ml, 10.43 g) added followed by 1-propanephosphonic acid cyclic anhydride (68.7 mmol, 40.7 mL, 43.7 g, 50% solution in ethyl acetate). The reaction was stirred for 1 hour and then was poured into saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried (magnesium sulfate), filtered and concentrated under reduced pressure to give the title compound (17.13 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11]O.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:24][C:25]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:29][CH2:28][CH2:27][O:26]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:33]1[CH2:32][CH2:31][CH:30]([C:25]2([CH3:24])[O:26][CH2:27][CH2:28][O:29]2)[CH2:35][CH2:34]1
Reactant: CC1(C2CCNCC2)OCCO1
Reactant: OCC1COc2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1(C2CCN(CC3COc4ccccc4O3)CC2)OCCO1
Temperature: 75 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 22.5 parts of 2,3-dihydro-1,4-benzodioxin-2-methanol 4-methylbenzenesulfonate (ester), 11.1 parts 4-(2-methyl-1,3-dioxolan-2-yl)piperidine, 15 parts of sodium carbonate and 135 parts of N,N-dimethylacetamide was stirred overnight at 75° C. Water was added. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, yielding 20.6 parts (100%) of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-(2-methyl-1,3-dioxolan-2-yl)piperidine as an oily residue (intermediate 86).