Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:30]([CH:40]1[C:49]2[N:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH2:43][CH2:42][CH2:41]1)[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1.[BH4-].[Na+]>CO>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:30]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][CH2:16][C:8]2[NH:7][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[CH:34][CH:33]=1)[CH:40]1[C:49]2[N:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH2:43][CH2:42][CH2:41]1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCc2nc3ccccc3[nH]2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a stirred solution of 1-(2-trimethylsilylethoxymethyl)-2-formyl-benzimidazole (prepared as described by Bridger et al. U.S. patent application Ser. No. 09/535,314) (0.150 g, 0.54 mmol) in dry MeOH (2.5 mL) was added a dry MeOH (2.5 mL) solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.215 g, 0.54 mmol) under an argon atmosphere. The mixture was stirred at room temperature for 1.5 h then concentrated under reduced pressure and analyzed by 1H NMR. The residue was dissolved in dry MeOH (5 mL) and to the resultant solution was added sodium borohydride (41 mg, 1.08 mmol) and the reaction mixture stirred for 16 h (see General Procedures XX). Purification of the crude product by radial chromatography on a 2 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 100:1:1 followed by 50:1:1) afforded the desired product (0.165 g, 47%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=O)[CH:25]=[CH:26][CH:27]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][CH:10]2[CH:15]3[CH2:16][CH:12]([CH:13]=[CH:14]3)[CH:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1cccc(F)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)C1C2C=CC(C2)C1Nc1c(Cl)cnc2[nH]c(-c3cccc(F)c3)nc12
Yield: 56 %

Procedure:
In a similar fashion compound to CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 3-FC6H4CHO (23.2 mg, 0.187 mmol) and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to yield 37.94 mg (56%) of the title compound. (300 MHz, DMSO-d6) 13.40 (s, 1H), 7.99 (m, 2H), 7.91 (s, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.29 (m, 3H), 6.39 (s, 2H), 5.15 (m, 1H), 2.90 (s, 1H), 2.80 (s, 1H), 2.62 (s, 1H), 2.26 (s, 1H), 1.38 (s, 1H). MS=398 (M+H), HPLC: 2.55 min. (G Method)
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].Br[C:25]1[N:30]=[C:29]([CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:32][OH:33])[CH:28]=[CH:27][CH:26]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:33][CH2:32][CH:31]([C:29]1[N:30]=[C:25]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:8]=[N:9][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:11][CH:12]=3)=[N:4][C:3]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:26]=[CH:27][CH:28]=1)[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1N
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1

Procedure:
The title compound was prepared as described in Example 3, Step 1 using ethyl 5-amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxylate (114 mg, 0.34 mmol), 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Example 3, Step 1) (98 mg, 0.34 mmol), Pd2(dba)3 (9.4 mg, 10.2 μmol), X-PHOS (24.4 mg, 0.051 mmol), potassium carbonate (51.8 mg, 0.38 mmol), and tert-amyl alcohol (1.7 ml) as starting materials. LRMS (APCI) calc'd for (C26H33N6O5S) [M+H]+, 541.2; found 541.1.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>C1COCC1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(CCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A solution of dibenzyl malonate (20 g) in anhydrous THF (200 ml) was treated at 0° C. with sodium hydride (60% dispersion in mineral oil, 3.1 g). The mixture was allowed to warm to room temperature and stirred for 30 minutes under nitrogen. The mixture was then treated with a solution of N-(3-bromopropyl)phthalimide (20.5 g) in THF (100 ml) and heated at reflux for 12 hours. The reaction was then cooled, filtered, and the filtrate evaporated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous ammonium chloride (150 ml). The organic layer was washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexane to yield the title compound (17.5 g, 50%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C1(C)C=CC=CC=1>[OH:12][C@H:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@@H:2]([N:1]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]2=[O:18])[CH2:3][CH2:4]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](O)c2ccccc21
Yield: 79.7 %

Procedure:
A solution of Intermediate A (150 mg, 0.92 mmol) and phthalic anhydride (143 mg, 0.97 mmol) in toluene (9 mL) was stirred and heated at reflux for 19.5 h. After cooling, the mixture was concentrated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound as white powder (215 mg, 79%). LCMS (Method 3): Rt 3.36 min, m/z 316 [MNa+].
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Br:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](O)=[O:28])[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(Br)c1
Product: O=C(Cc1cccc(Br)c1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(3-bromophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.49 (dt, J=7.8, 1.5 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 3.83 (d, J=4.2 Hz, 4H), 3.69 (s, 2H), 3.09-3.11 (m, 4H); MS (ESI−) M/Z 441 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N:7]2[C:15]3[CH:14]=[C:13]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:27]([O:29][CH3:30])=[O:28].C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:48])([F:47])[F:46]>CN(C)C=O>[N:20]1([CH2:19][CH2:18][NH:17][C:16]([C:13]2[N:12]=[CH:11][C:10]3[N:9]=[CH:8][N:7]([C:5]4[S:4][C:3]([C:27]([O:29][CH3:30])=[O:28])=[C:2]([O:1][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]([F:46])([F:47])[F:48])[CH:6]=4)[C:15]=3[CH:14]=2)=[O:26])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: COC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnc(C(=O)NCCN4CCOCC4)cc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B8, 1.03 g of methyl 3-hydroxy-5-{6-[(2-morpholin-4-ylethyl)carbamoyl]-1H-imidazo[4,5-c]pyridin-1-yl}thiophene-2-carboxylate (compound C4), 326 mg K2CO3 and 683 mg 1-(bromomethyl)-2-(trifluoromethyl)benzene in 11 ml of N,N-dimethylformamide yield the title compound as crude material. The compound was used for the next step (examples 5 and 11) without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:35]=[CH:36][CH:37]=2)[C:18]([C:20]2[CH:34]=[CH:33][C:23]([CH2:24][O:25][Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=2)=[O:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[C:17]([CH:35]=[CH:36][CH:37]=2)[C:18]([C:20]2[CH:21]=[CH:22][C:23]([CH2:24][OH:25])=[CH:33][CH:34]=2)=[O:19])[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1cccc(C(=O)c2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
{4-[3-(2-Ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-ylmethyl)benzoyl]benzyloxy)-tert-butyldimethylsilane (0.898 g, 1.75 mmol) obtained in Step 4 was dissolved in THF (15 mL), and a 1.0 mol/L TBAF-THF solution (5.24 mL, 5.24 mmol) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), followed by crystallization from ethanol to obtain Compound 14 (0.579 g, yield 83%).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])([O:3][CH3:4])=[O:2].[C:17](OC(C)=C)(=[O:19])[CH3:18].S(=O)(=O)(O)O>>[C:17]([O:16][C:12]1[CH2:13][CH2:14][CH2:15][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])(=[O:19])[CH3:18]
Reactant: C=C(C)OC(C)=O
Reactant: COC(=O)CCCCCCC1CCCC1=O
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Temperature: 25 °C

Procedure:
This preparation illustrates methods for preparing 1-acyloxy-2-(carboalkoxy-alkyl)-cyclopent-1-ene. In this example, 26.5 g. of 2-(6-carbomethoxy-hexyl)-1-oxo-cyclopentane is added to 250 ml. of isopropenyl acetate containing 0.4 ml. of concentrated sulfuric acid. The mixture is then slowly distilled for 21/2 hours and then cooled to room temperature and poured into an ice saturated solution of aqueous sodium bicarbonate. The mixture is then extracted with methylene chloride. The methylene chloride extract is washed with water and then washed with saturated brine, then dried over anhydrous sodium sulfate and evaporated to dryness affording a crude residue of 1-acetoxy-2-(6-carbomethoxyhexyl)-cyclopent-1-ene, which is further purified by high vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Fc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(Cl)c(Cl)c4)ncnc3cn2)cc1
Temperature: 52 °C
Reaction time: 240 h
Yield: 63.6 %

Procedure:
A mixture of compound 204 (2.95 g, 9.55 mmol) and 4-methoxybenzylamine (12.6 mL, 95.5 mmol) in dry DMSO (20 mL) was stirred under a nitrogen atmosphere at 52° C. (bath temperature) for 10 days. The solution was then cooled and petroleum ether (200 mL) was added. It was stirred at room temperature for 10 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (2×200 ml). Water (200 mL) was added and the mixture was stirred at room temperature for 15 min. It was filtered and washed solid with water (5×30 mL), then with petroleum ether (3×30 mL). The sticky yellow/orange solid was stirred with acetone (100 mL) at 35-45° C. (internal temperature) for 10 min. Water (100 mL) was added and stirred at room temperature for 20 min. The solid was collected by suction-filtration, washed with water/acetone (1:1) (5×20 mL), and dried in vacuum over silica-gel/KOH to give pure N4-(3,4-dichlorophenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (213) (2.59 g, 64%) as a yellow/orange solid, mp 209-211° C.; 1H NMR δ [(CD3)2SO] 9.76 (s, 1H), 8.77 (s, 1H), 8.42 (s, 1H), 8.30 (poorly resolved d, J=2.1 Hz, 1H), 7.89 (dd, J=8.8, 2.1 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.38-7.25 (m, 3H), 7.17 (s, 1H), 6.92-6.83 (m, 2H), 4.49 (d, J=6.3 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C21H17Cl2N5O: C, 59.17; H, 4.02; N, 16.43%. Found C, 58.93; H, 4.17; N, 16.12%.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2Br)=[O:8])C.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>COCCOC.C1(P([Pd-4](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)C=CC=CC=1>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:27]=[C:28]([C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]3[C:12]=2[S:11][C:10](=[O:22])[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:3])=[O:23])=[O:8])=[C:18]3[OH:19])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Br)c2sc1=O
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2sc1=O
Yield: 74.5 %

Procedure:
[(8-Bromo-6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (22(d)) (500 mg, 1.2 mmol) was dissolved in DME-aqueous sodium carbonate (2M) (7 mL: 1.5 mL). To the solution was added 3,5-bis-trifluoromethyl-phenyl boronic acid (372 mg, 1.44 mmol) and tetrakis(triphenylphosphino) palladium(0) (275 mg, 0.24 mmol). The mixture was heated to reflux for six hours, cooled and concentrated. The residue was triturated with hot methanol (20 mL) and filtered to provide the title compound (470 mg.) MS ESI(−) m/e: 524.114, 526.018 (M−1).
Reaction SMILES: [C:1]1([C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20]O.[OH-].[Na+].O>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]1([C:7]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH2:9][CH2:10][C:11]([NH2:12])=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCC=C(Cc1ccccc1)c1ccccc1
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NC(=O)CCC=C(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5,6-Diphenyl-4-hexenenitrile (36 g) was dissolved in methylene chloride (180 mL) at 0° C. and stirred vigorously while 50% H2O2 (100 mL), tetrabutyl ammonium hydrogen sulfate (13 g) and 20% NaOH (100 mL) were added successively. The resulting mixture was stirred at 0° C. for 30 minutes, then for 2 hours without cooling. The reaction mixture was poured into CH2Cl2 and water and the organic layer was separated, washed with water and brine and dried (MgSO4). Concentration of the solvent afforded the crude amide which was purified by silica gel chromatography and elution with 50% ethyl acetate: hexane, then ethyl acetate to give the amide as a solid (30 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([O:21][N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2Cl)[CH2:11][CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:32]>C(O)C>[Si:1]([O:8][CH2:9][CH:10]([O:21][N:22]1[CH:30]=[N:29][C:28]2[C:23]1=[N:24][CH:25]=[N:26][C:27]=2[NH2:32])[CH2:11][CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)ncnc21)OCC
Reactant: N
Solvent: CCO
Product: CCOP(=O)(CCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N)ncnc21)OCC
Temperature: 25 °C
Yield: 43 %

Procedure:
A solution of 9-[1-(t-butyldimethylsilyloxymethyl)-3-(diethoxyphosphoryl)propoxy]-6-chloropurine (0.30 g) in ethanol (10 ml) saturated with ammonia gas was heated in a sealed vessel at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature overnight, the ethanol evaporated under reduced pressure and the residue chromatographed on silica gel using dichloro-methane-methanol (98:2) as eluant. Starting material (0.06 g) was recovered and the eluant was changed to dichloromethane-methanol (95:5) to afford the title compound (0.10 g, 43%) as an oil. 1H NMR: δH ((CD3)2)2SO) 0.00, 0.61 (6H, 2 x s, SiMe2). 0.81 (9H, s, SiBut), 1.20 (6H, t, J=7Hz, (OCH2CH3)2), 1.7-2.2 (4H, m, --CH2CH2P), 3.82 (2H, d, J=4.1 H, CH2OSi), 4.0 (4H, m, (OCH2CH3)2), 4.44 (1H, m, OCHCH2), 7.35 (2H, s, D2O exchangeable, N2), 8.3 (1H, s), 8.27 (1H, s). Found: C, 47.82; H, 7.61; N, 14.41%. C19H36N5O5SiP requires: C, 48.16; H, 7.66; N, 14.79%. m/z: C19H36N5O5SiP requires: 473.2221. Observed: 473.2219.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[N:10](OCCOC)[N:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[O:32])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COCCOn1nc(-c2ccc(F)cc2)c2cc(N)ccc21
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-(2-methoxyethoxy)-1H-indazole-5-ylamine (115 mg, 0.36 mmol) in dioxane (5 mL) was added 4-fluorophenyl isocyanate (50 μL, 0.44 mmol). The reaction was stirred overnight at room temperature. It was then 35 filtered and the solid dried in a vacuum oven. The solid was then taken up in 6N HCl (10 mL) and methanol (10 mL) and heated to 80° C. for 2 hours. The reaction was then cooled to room temperature and quenched with NaHCO3 (100 mL) and extracted with ethyl acetate (3×40 mL). The organic layers were combined and dried with magnesium sulfate (MgSO4) and concentrated to a solid to afford the title compound (25 mg, 19% yield). 1H NMR (CDCl3) δ 13.1 (br s, 1H), 9.32 (s, 2H), 8.28 (s, 1H), 7.94 (dd, 2H), 7.52 (d, 1H), 7.48 (dd, 2H), 7.38 (t, 2H), 7.33 (dd, 1H), 7.11 (t, 2H); ES-MS (m/z) 364 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH3:17])[CH:5]=[CH:4][CH:3]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:20])[CH3:19]>>[CH2:14]([C:12]1[C:11](=[O:16])[NH:10][C:9]([CH3:17])=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][S:28]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:27][CH:26]=3)(=[O:30])=[O:29])[N:7]=2)[CH:13]=1)[CH3:15]
Reactant: CCc1cc(-c2cccc(N)n2)c(C)[nH]c1=O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1cc(-c2cccc(NS(=O)(=O)c3ccc(NC(C)=O)cc3)n2)c(C)[nH]c1=O

Procedure:
Example 277 is substantially repeated except for utilizing 6-amino-5′-ethyl-2′-methyl-1′H-[2,3′]bipyridinyl-6′-one and 4-acetylamino-benzenesulfonyl chloride to afford the title compound. MS: m/e=427 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]Cl.[Na+].[CH3:21][OH:22]>C(O)(=O)C>[CH3:21][O:22][C:16]([CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)=[O:17]
Reactant: O=CC1CCC(COCc2ccccc2)CC1
Reactant: CO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: COC(=O)C1CCC(COCc2ccccc2)CC1
Yield: 65 %

Procedure:
4-Benzyloxymethyl-cyclohexanecarbaldehyde (1.70 g, 2.0 mmol) is dissolved in acetic acid (0.24 mL) and 2 mL of methanol. The reaction mixture is cooled to 0° C. to 5° C. and stirred while 10% NaOCl solution (2.5 mL, 4 mmol) is added dropwise over 20 minutes. The cooling bath is removed, and the mixture is allowed to come to room temperature. After addition of saturated aqueous NaHCO3, the mixture is extracted with EtOAc. The combined organic layer after dried over MgSO4 is concentrated to obtain 4-benzyloxymethyl-cyclohexanecarboxylic acid methyl ester as clear oil (343 mg, 65%) after purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.O.NN>C(Cl)Cl>[NH2:3][O:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)N1CCC(ON)CC1
Reaction time: 3 h
Yield: 62.8 %

Procedure:
Compound 2a (3.31 g, 10 mmol) was dissolved in DCM (21 mL) and treated with hydrazine hydrate (1.52 mL, 31 mmol). After stirring for 3 h, the mixture was chilled in an ice-bath and filtered. The precipitate was washed with a minimal volume of DCM and the resulting filtrate was concentrated under vacuum to afford 1.27 g (63%) of 2b as a colorless oil; LC-MS 203.1 (MH+).