Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=3[N:19]=2)=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>[Fe].CCO.C1COCC1.O>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=3[N:19]=2)=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(C)ccc2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(N)cc(Cl)c1Sc1nc2cc(C)ccc2s1
Yield: 68 %

Procedure:
To a solution of 1-[3-chloro-5-nitro-2-(5-methyl-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone (264) (3.87 g, 10.2 mmol) in 2:2:1 of EtOH/THF/H2O, was added ammonium chloride (Aldrich 2.74 g, 51.2 mmol) and iron powder (Aldrich, 2.87 g, 51.2 mmol). The mixture was refluxed for 3 hours. The mixture was filtered through Celite pad while it was hot, washed the Celite pad with EtOAc. The filtrate was diluted with saturated aqueous NaHCO3 solution and was extracted 3× with EtOAc (150 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (0-15% EtOAc in CH2Cl2) to yield 2.42 g (68%) of compound 276 as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH:12][O:13][CH3:14].Cl.N1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:12]([O:13][CH3:14])[CH3:11])=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CNOC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cccc(F)c1
Reaction time: 3 h

Procedure:
To a mixture of 3-fluorobenzoyl chloride (11.0 g, 6.70 mmol) and N,O-dimethylhydroxylamine.HCl in CHCl3 (70 mL) at 0° C. was added pyridine (14 mL) over 30 min. After a period of 3 h at room temperature, the reaction mixture was treated in the usual manner to give 12.5 g of the title compound.
Reaction SMILES: Cl.FC1C=CC=C(F)C=1C([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:23][C:16]=23)=[C:10]([F:30])[CH:9]=1)=O.[O:36]=[C:37]1[C:42]([C:43]([OH:45])=O)=[CH:41][CH:40]=[CH:39][N:38]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[F:30][C:10]1[CH:9]=[C:8]([NH:7][C:43]([C:42]2[C:37](=[O:36])[N:38]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:39]=[CH:40][CH:41]=2)=[O:45])[CH:13]=[CH:12][C:11]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:21][C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:23][C:16]=12
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1c(F)cccc1F
Reactant: O=C(O)c1cccn(-c2ccccc2)c1=O
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1)c1cccn(-c2ccccc2)c1=O

Procedure:
Prepared in a similar manner as Example 239 using 3-fluoro-4-(2-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (Compound E of Example 237) and 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid. 1H NMR (DMSO-d6) δ 12.87 (s, 1H), 12.18 (s, 1H), 9.39 (s, 1H), 8.70-8.85 (m, 2H), 8.60 (d, 1H, J=7.1 Hz), 8.00-8.25 (m, 3H), 7.94 (s, 1H), 7.30-7.75 (m, 8H), 6.77 (t, 1H, J=6.6 Hz), 6.45 (d, 1H, J=4.6 Hz), 4.21 (s, 2H), 3.68 (s, 2H), 2.43 (s, 6H); LC/MS(ESI+) m/z 518 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].CN(C)[CH:19]=[O:20].P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>ClC(Cl)C>[CH:19]([C:14]1[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][C:12]=2[Cl:15])[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[O:20]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Combine 2-carboethoxy-4,6-dichloroindole (10.0 g, 0.039 mol), and dimethylformamide (4.5 mL, 0.057 mol) in dichloroethane (20 mL). Add phosphoryl chloride (8.9 g, 0.058 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture to ambient temperature and combine with aqueous 1M sodium acetate solution and stir. After 18 hours, filter, rinse with water, and dry to give 3-formyl-2-carboethoxy-4,6-dichloroindole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17][NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]
Reactant: COC(C=O)OC
Reactant: NCCNC(=O)c1ccccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(CNCCNC(=O)c1ccccc1O)OC
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of N-(2-aminoethyl)-2-hydroxybenzamide (332 mg, 1.85 mmol), dimethoxyacetaldehyde (0.475 mL, 1.85 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyboro hydrid (588 mg, 2.80 mmol). The resulting mixture was stirred overnight, then diluted with EtOAc (50 mL), washed with 10 mL of water and then brine, dried over MgSO4, and conc in vacuo to yield 441 mg (97%) of the product as a colorless oil. MS (ESI) 269 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:20])[CH2:10][C:11]1[NH:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[N:12]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(c1ccccc1F)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.54 mmol) of 1-(2-Fluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example XXXXVII, 58.6 mg (1.08 mmol) of sodium methylate and 45.6 mg (0.54 mmol) methyl propiolate.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.[Cl-].[NH4+]>CO.ClCCl.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.2 %

Procedure:
To a solution of 3-bromo-2-cyclopropylmethoxy-5-nitro-pyridine (600 mg, 2.19 mmol) in methanol (30 ml) were added water (15 ml), zinc dust (1 g, 15.37 mmol) and ammonium chloride (1.28 g, 24.09 mmol) at 25° C., and the reaction mixture was stirred for 45 min at 25° C. After total consumption of starting material (monitored by TLC), the reaction mixture was filtered through a bed of celite, and the filtrate was evaporated under reduced pressure to get the crude residue. The residue was dissolved in dichloromethane and washed with water and brine. The organic part was dried over Na2SO4 and evaporated to get the compound (507 mg, 95%). This compound was used in next step without further purification. MS (LC/MS): 244.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Br:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:35])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Br:18])=[C:12]([CH2:17][Br:35])[CH:13]=2)[N:8]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2cc(Br)c(C)cc2c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2cc(Br)c(CBr)cc2c1=O

Procedure:
A mixture of 7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-6-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester (3.5 g, 8 mmol), prepared according to the procedure outlined in PCT application WO97/14682, Reference Example 3, NBS (1.5 g, 8.4 mmol) and 2,2′-azobisisobutyronitrile (AIBN, 100 mg) in DCM (200 mL) was stirred at reflux for 4 h. Additional NBS (750 mg) was added and the mixture was refluxed for 4 h. Column chromatography (hexanes:ethyl acetate=3:7) yielded the product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([O:13]C)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Li])(C)(C)C.[CH2:22]1[O:24][CH2:23]1.[Cl-].[NH4+]>CCOCC>[OH:13][CH2:12][CH2:15][C:16]1[C:23]([O:24][CH3:22])=[CH:17][CH:11]=[CH:10][C:9]=1[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: C1CO1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cccc(NC(=O)OC(C)(C)C)c1CCO
Temperature: -20 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
A stirred solution of N-tert-butoxycarbonyl-anisidine (431 g, 1.93 mol) in ether (2 L) under an argon atmosphere was cooled to −20° C. A solution of tert-butyllithium (1.7 M, hexanes, 2.5 L, 4.25 mol) was added dropwise and the reaction was stirred for 3 h at −20° C. The reaction was cooled to −50° C. and ethylene oxide (136 g, 3.09 mol) was added dropwise. The reaction was warmed to 0° C. over 1 h and then stirred at room temperature for 1 h. The reaction was poured onto saturated aqueous ammonium chloride solution (2.5 L) and the mixture was extracted with ether (3×2.5 L). The organic extracts were combined and concentrated in vacuo to afford a pale yellow oil which was purified by column chromatography [SiO2; heptane-ethyl acetate (5:1)] to afford the title compound (176 g, 37%) as a yellow crystalline solid; NMR (400 MHz, CDCl3) δH 1.51 (9H, br s), 2.91 (2H, t, J 6.0 Hz), 3.79 (3H, s), 3.87 (2H, q, J 5.0 Hz, 10.5 Hz), 6.64 (1H, d, J 8.0 Hz), 7.18 (1H, t, J 9.0 Hz), 7.38 (1H, m), 7.55 (1H, br s); IR νmax (Nujol)/cm−1 3407, 3212, 2955, 2854, 1721, 1592, 1508, 1476, 1438, 1370, 1267, 1234, 1162, 1047 and 773.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][CH2:24][OH:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Cl)Cl>[Pd].CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](/[CH:21]=[CH:22]\[CH2:23][CH2:24][OH:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCO)cc2c1O
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(/C=C\CCO)cc2c1O
Reaction time: 3 h
Yield: 55.2 %

Procedure:
A solution of the title compound of Example 94 (0.393 g), pyridine (3 mL), and Pd/C (10%, 80.0 mg) in 3:1 CH2Cl2 :MeOH is maintained under an atmosphere of H2 (balloon) for 3 hrs. More Pd/C (10%, 40 mg) is added and the reaction mixture is placed under the Parr hydrogenator at 25 psi H2 for an additional 3 hrs. The reaction mixture is filtered over celite. The filtrate is condensed and then placed under high vac to remove residual pyridine. The crude product is recrystallized with EtOAc/hexanes to afford 0.218g of the desired product as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4]([N:5]([CH3:20])[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21
Reaction time: 8 h
Yield: 101.8 %

Procedure:
A mixture of 2.0 g (0.0087 mole) 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one, 1.1 ml (0.0174 mole) methyl iodide, anhydrous potassium carbonate (1 gram) and acetone (100 ml) was heated under reflux, with stirring, overnight. After refluxing had continued 21 hours an additional 1 ml of methyl iodide was added and solids removed from the mixture by suction filtration. The filtrate was evaporated under reduced pressure and the resulting residue dissolved in ethyl acetate, washed with water, then with brine and dried over MgSO4, filtered and solvent stripped off to give B 1.8 g of crude product. Purification by high pressure liquid chromatography gave a solid, mp 79°-82° C.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(n2cnc([N+](=O)[O-])c2)CC1

Procedure:
4-nitroimidazole was alkylated with 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester to provide the title compound: C13 NMR (100 MHz, CDCl3) 28.5, 33.2, 42.7, 56.8, 80.7, 117.5, 134.4, 154.5; MS 297.1 m/z (M+1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:45][CH:46]2[CH2:48][CH2:47]2)[C:6]2[N:11]=[C:10]3[N:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:13]=[C:14]([CH3:15])[C:9]3=[CH:8][C:7]=2[CH2:20][N:21]([CH2:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[C:22]2[N:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=2)[CH2:3][CH2:2]1.[OH-:49].[K+].OO>C(O)C>[CH:1]1([CH2:4][N:5]([CH2:45][CH:46]2[CH2:48][CH2:47]2)[C:6]2[N:11]=[C:10]3[N:12]([C:16]([CH3:17])([CH3:18])[CH3:19])[N:13]=[C:14]([CH3:15])[C:9]3=[CH:8][C:7]=2[CH2:20][N:21]([CH2:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:43])([F:44])[F:42])[CH:32]=2)[C:22]2[N:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:49])=[CH:24][N:23]=2)[CH2:2][CH2:3]1
Reactant: [OH-]
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(C#N)cn3)cc12
Agent: OO
Agent: [K+]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(C(N)=O)cn3)cc12
Temperature: 40 °C

Procedure:
2-(((6-(Bis(cyclopropylmethyl)amino)-1-(tert-butyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)(3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-carbonitrile obtained in Example 10, (0.000074 mmol, 0.050 g) in ethanol was treated with 1% solution of KOH (5 ml) and catalytic amount of hydrogen peroxide. The reaction mixture was heated at 40° C. for 30 min. The reaction mixture was then concentrated under reduced pressure, treated with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography using silica gel and 40% EtOAc in petroleum ether as eluent to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.[C:21](=[O:24])([O-])[O-].[K+].[K+].[CH2:27](Br)CCCCC>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:27][CH2:21][OH:24])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCCCBr
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(OCCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 48.7 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (31 mg, 0.12 mmol), potassium carbonate (32 mg, 0.24 mmol) and hexyl bromide (25 μL, 0.18 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 35 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using 2% methanol in dichloromethane afforded 18 mg (39%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-hydroxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.91 (dd, 1H), 7.49 (dd, 1H), 7.38 (s, 1H), 4.09 (t, 2H), 1.84 (m, 2H), 1.49 (m, 2H), 1.37 (m, 4H), 0.93 (t, 3H).
Reaction SMILES: [N:1]1([C:10]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[N:1]1([C:10]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(O)C1(n2ccc3cccnc32)CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1(n2ccc3cccnc32)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarboxylic acid (394) (1.2 g, 5.21 mmol) in dichloromethane (80 mL) was dropwise added oxalyl chloride (1 mL, 11.47 mmol) at 0° C., followed by dimethyl formamide (0.1 mL). The reaction mixture was stirred for 1 h at room temperature. After completion, the reaction mixture is concentrated under argon atmosphere tog et 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarbonyl chloride (395) (1.3 g, 100%, crude) as a yellow solid which was directly used for the next step without analysis.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[C:8]([I:19])=[C:9]([C:13]([I:18])=[C:14]([NH2:17])[C:15]=1[I:16])[C:10]([Cl:12])=[O:11])=[O:6])[CH:2]=[CH2:3].[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[C:15]([I:16])=[C:14]([NH:17][C:25]([CH2:24][O:23][C:20](=[O:22])[CH3:21])=[O:26])[C:13]([I:18])=[C:9]([C:10]([Cl:12])=[O:11])[C:8]=1[I:19])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=CCNC(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Allylcarbamoyl-5-amino-2,4,6-triiodo-benzoyl chloride (6) (5 g, 8.11 mmol) was dissolved in dry DMA (5 mL) and acetoxyacetylchloride (1.73 mL, 16.2 mmol) was added. The reaction was stirred overnight at room temperature with nitrogen bubbling through. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with ice-water (5×20 mL). The organics were collected, dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The residue was washed with acetonitrile, filtered and dried under vacuum to give acetic acid (3-allylcarbamoyl-5-chlorocarbonyl-2,4,6-triiodo-phenylcarbamoyl)-methyl ester as a white solid. (4.47 g, 77%). The structure was confirmed by 1H and 13C NMR, and purity by LCMS.
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1[OH:16])(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[Br:41][C:42]1[CH:43]=[C:44]([N:48]=[C:49]=[O:50])[CH:45]=[CH:46][CH:47]=1.[C:51]([O:55][CH2:56][CH2:57]C(O)C)(=[O:54])[CH:52]=[CH2:53].[N-]=C=O>>[C:51]([O:55][CH2:56][CH2:57][O:50][C:49](=[O:16])[NH:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([Br:41])[CH:43]=1)(=[O:54])[CH:52]=[CH2:53]
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCCC(C)O
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: [N-]=C=O
Product: C=CC(=O)OCCOC(=O)Nc1cccc(Br)c1
Temperature: 60 °C

Procedure:
0.015 g of 2,6-di-tert.-butyl4-methylphenol, 0.007 g of Desmorapid Z, 9.4 g of 3-bromophenyl isocyanate were initially introduced in a 20 ml sample bottle and heated to 60° C. Thereafter, 5.5 g of 3-hydroxybutyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Cooling was then effected. The product was obtained as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][C:8]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:7][CH:6]=2.NC1C=NC2C(C=1NCCCCNC(=O)OC(C)(C)C)=CC=[C:39]([O:57][CH2:58][C:59]1C=CC=CC=1)[CH:38]=2.C(OCC(Cl)=O)C.COCCC(Cl)=O>>[CH2:26]([O:25][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[N:1]=[C:38]([CH2:39][O:57][CH2:58][CH3:59])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[C:10]=2[CH:9]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: CCOCC(=O)Cl
Agent: COCCC(=O)Cl
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CCCCNC(=O)OC(C)(C)C

Procedure:
For Example 73, a modification of the general method described for Part C of Example 50 was followed using tert-butyl {4-[3-amino-6-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (9.25 g, 21.2 mmol) in lieu of tert-butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate and ethoxyacetyl chloride (2.86 g, 23.3 mmol) in lieu of methoxypropionyl chloride. After the cyclization reaction, the solvent was removed under reduced pressure, and the residue was dissolved in chloroform (400 mL). The resulting solution was washed with water (2×200 mL) and brine (1×200 mL), concentrated under reduced pressure, and dried under high vacuum to provide a brown oil. The crude product was purified by column chromatography on silica gel (400 g, eluting with 95:5 dichloromethane:methanol). The resulting solid was triturated with diethyl ether and isolated by filtration to provide 5.37 g of tert-butyl {4-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31].[C:34]([NH:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH2:48])[CH2:44][CH2:43]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C=O)C.O>[C:37]([O:36][C:34](=[O:35])[NH:41][CH:42]1[CH2:43][CH2:44][CH:45]([NH:48][C:13]2[N:12]=[C:11]3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[C:16]3=[CH:15][N:14]=2)[CH2:46][CH2:47]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncc2c(-c3cccc(Br)c3)n[nH]c2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(3-bromo-phenyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine (from Example 38 supra) (3.0 g, 9.7 mmol), Et3N (5.4 mL, 38.8 mmol) in DMF (50 mL), (2-(chloromethoxy)-ethyl)trimethylsilane (SEM-Cl, 2.0 mL, 11.6 mmol) was added in one portion. The resultant mixture was stirred for 30 minutes at room temperature. To this solution, N-Boc-trans-1,4-cyclohexanediamine (2.48 g, 11.6 mmol) was added. The resulting mixture was stirred for one hour at room temperature. The reaction was then poured into water (200 mL) and extracted with EtOAc (3×200 mL). The EtOAc extract was dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography (silica gel, 200-300 mesh, EtOAc) to give {4-[3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as yellow oil. (Yield 2.2 g, 37.3%).