Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:37]=[CH:36][C:15]3[N:16]=[C:17]([C:19]4[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:27][C@@H:28]5[CH2:32][O:31]C(C)(C)[O:29]5)=[CH:21][C:20]=4[CH3:35])[NH:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[OH-].[Na+].O>CO.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:37]=[CH:36][C:15]3[N:16]=[C:17]([C:19]4[C:20]([CH3:35])=[CH:21][C:22]([O:26][CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])=[CH:23][C:24]=4[CH3:25])[NH:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OC[C@@H]5COC(C)(C)O5)cc4C)[nH]c3c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OC[C@@H](O)CO)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2,6-dimethylphenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide (120 mg, 0.24 mmol) in MeOH (3 mL) was added 1N HCl (3 mL) and the solution was stirred at ambient temperature for 3 h. The solution was basified to pH 10 with 1N NaOH and the mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the organic layer was washed with water, brine, dried with MgSO4, filtered and concentrated. Purification by HPLC gave the title compound as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.22 (s, 1H), 7.90 (dd, 1H), 7.70 (d, 1H), 7.47 (s, 1H), 7.44 (dd, 1H), 7.13 (d, 1H), 6.80 (s, 2H), 4.11 (m, 1H), 4.03 (m, 2H), 3.72 (m, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 2.14 (s, 6H). MS (m/z) 460.1 (M+1); Retention time: 1.23 min (Method 10).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:32]3[CH:31]=[C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:24][CH:25]=4)[CH:35]=[CH:34][CH:33]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cccc(-c4ccccc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 3-bromobiphenyl.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:25]=[C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>>[CH2:29]([O:28][C:26]1[CH:27]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])[CH:23]=[C:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccccc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccccc3)c2)c1CCC(=O)O
Yield: 79.5 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[3-[6-(5-benzyloxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (224 mg, 0.34 mmol) and 1.0 N aqueous sodium hydroxide (5 mL) to afford 4-[3-[6-(5-benzyloxy-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (165 mg, 80%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C38H42O7 (M+Na)+ 633.2823. found 633.2820.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:11])=[O:10])[CH2:2]1.[CH3:15][N:16]=[C:17]=[O:18]>C1C=CC=CC=1>[CH3:15][NH:16][C:17]([N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[CH:7]=2)[CH2:2]1)=[O:18]
Reactant: CN=C=O
Reactant: NC(=O)c1cccc(OC2CNC2)c1
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2cccc(C(N)=O)c2)C1
Reaction time: 1 h

Procedure:
To a stirring solution of 7.0 g. (0.036 mole) of 3-(3-azetidinyloxy)benzamide in 75 ml. of dry benzene was slowly added 2.0 g. (0.036 mole) of methylisocyanate. Stirring was continued at room temperature for one hour. The solid which separated was filtered and recrystallized from 60% ethanol. The product weighed 6.0 g. (67%) and melted at 238°-240° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10]([NH:13][C:14](=[O:16])[OH:15])=[N:9][C:8]=2[C:7]([O:17][CH3:18])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O>[OH:3][CH:1]([C:4]1[C:12]2[S:11][C:10]([NH:13][C:14](=[O:15])[OH:16])=[N:9][C:8]=2[C:7]([O:17][CH3:18])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1ccc(C(C)=O)c2sc(NC(=O)O)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)O)c2sc(NC(=O)O)nc12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
0.05 g of (7-acetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyll ester (0.00018 Mol) were dissolved in ethanol (30 ml) and 0.028 g of NaBH4 (0.00072 Mol) were added. After stirring at 40° C. for 24 hrs. the reaction mixture was diluted with water, extracted with CH2Cl2, the organic phase washed with brine and dried over MgSO4. After chromatography on silicagel with CH2Cl2/MeOH 97:3 the title compound was obtained as a white solid (38%); F.p.: 179° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([NH:21]C(OC(C)(C)C)=O)[CH2:11][C@H:10]([O:12][C:13](=[O:15])[CH3:14])[C@@H:9]2[C@H:7]1[C@H:8]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.ClCCl>[CH2:1]([O:3][C:4]([C@:6]1([NH2:21])[CH2:11][C@H:10]([O:12][C:13](=[O:15])[CH3:14])[C@@H:9]2[C@H:7]1[C@H:8]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2OC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
Dissolve (1S,2S,4S,5R,6R)-4-acetyloxy-2-(tert-butoxycarbonyl)aminobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (1.25 g, 3.13 mmol, Preparation 19) in a solution of 95% TFA in dichloromethane (60 mL) and stir under nitrogen at room temperature for 5 minutes. After this time remove the TFA/dichloromethane in vacuo. Dissolve the crude product in a suspension of NaHCO3 (1.00 g) in dichloromethane (50 mL) and stir for 30 minutes. Filter the suspension, wash with dichloromethane (3×25 mL), and concentrate in vacuo to afford 916 mg (98%) of the product as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-:12].[Na+].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N+:2]=1[O-:12]
Reactant: c1cc2c(cn1)CCCC2
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc2c(c1)CCCC2

Procedure:
5,6,7,8-Tetrahydroisoquinoline (10 g) was added to methylene chloride (100 ml) and a 10% aqueous solution (100 ml) of sodium carbonate. Under vigorous stirring, a 70% solution of m-chloroperbenzoic acid (20 g) in methylene chloride (100 ml) was dropped thereinto at 0° C. Then the reaction solution was extracted with methylene chloride. The methylene chloride layer was washed with brine, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system) to give the title compound (7.50 g) as a colorless oil. (283-2) 5,6,7,8-Tetrahydroisoquinolin-5-ol
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=C)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].I([O-])(=O)(=O)=[O:43].[Na+]>O1CCCC1.O.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=[O:43])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(COCC=O)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
Osmium tetroxide (90 mg., 0.354 mmoles) was added to a solution of 1,2-di-O-(n-hexadecyl)-3-O-allyl-glycerol (4.5 g., 7.75 mmoles) in tetrahydrofuran:water (3:1, 120 ml.), and the resulting solution stirred for 5 minutes at room temperature. Sodium periodate (9 g., 42 mmoles) was then added and the reaction solution stirred for 16 hours at room temperature under nitrogen. The reaction solution was then diluted with water (150 ml.) and extracted with ether (2×150 ml.). The combined ether extract was washed with water (150 ml.), dried (MgSO4) and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene:ethyl acetate) [2.6 g., 57% yield, waxy solid, ir (CHCl3) 1735 cm-1, n.m.r. (CDCl3) δ 9.38 (t, J=1 Hz, 1, --OCH2CHO) and 4.07 (d, J=1 Hz, 2, --OCH2CHO)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:14])[C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=1.[CH3:15][S:16]([O-:18])=[O:17].[Na+].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CS(C)=O.[Cu]I>[F:14][C:4]1[C:5]2[O:10][CH2:9][C@H:8]([CH2:11][OH:12])[O:7][C:6]=2[CH:13]=[C:2]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:3]=1
Reactant: OC[C@H]1COc2c(F)cc(Br)cc2O1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CO)CO2

Procedure:
Preparation according to Preparation 21 using [(2S)-7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (2.35 g, 8.9 mmol), sodium methanesulfinate (85%) (1.29 g, 107 mmol), CuI (0.34 g, 1.8 mmol), L-proline (0.41 g, 3.6 mmol) and NaOH (0.071 g, 1.8 mmol) in DMSO (6 ml). Yield 0.98 g. MS m/z (rel. intensity, 70 eV) 262 (M+, bp), 231 (35), 183 (22), 152 (23), 57 (30).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=S.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CCOCC.O.C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][NH:7][C:8]1=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCCNC(=S)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(N=C2NCCCO2)cc1
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A solution of sodium hydroxide (23.8 mg) and water (0.6 ml) was added under argon and with stirring to a solution of 1-(3-hydroxypropyl)-3-phenylthiourea (50 mg) and THF (1.5 ml). Subsequently, a solution of p-toluenesulfonyl chloride (49.9 mg) and THF (0.5 ml) was added dropwise over fifteen minutes. After stirring for 30 minutes, the reaction mixture was added to water, and extraction was effected three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Chromatography using silica gel (initially 50:1 methylene chloride/methanol, at the end 100:1 methanol/saturated ammonia solution) afforded 27.4 mg of the desired product.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])[C:7]([OH:24])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccc(F)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(-c3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(4-fluoro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 355 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:18]([CH2:28][O:29]CC=C)[O:17][C@@H:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:6]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C=C.II.O>O1CCCC1.C(Cl)(Cl)Cl.[Ir]>[CH2:34]([O:33][C@@H:6]1[C@@H:5]([OH:4])[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:18]([CH2:28][OH:29])[O:17][C@H:7]1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C=CCOC[C@H]1O[C@@H](OCCCCCCCC)[C@H](OCc2ccccc2)[C@@H](OCC=C)[C@H]1OCc1ccccc1
Agent: [Ir]
Agent: II
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Yield: 84.8 %

Procedure:
Iridium complex (1,5-cyclooctadiene bis(methyldiphenylphosphine)iridium hexafluorophosphate, 172 mg, 0.15 mmol) was suspended in tetrahydrofuran (5 mL), and activated by stirring under H2 flow. Compound 15 (811 mg, 1.47 mmol) dissolved in tetrahydrofuran (5 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour under argon gas flow. Iodine (745 mg), water (38 mL), and tetrahydrofuran (15 mL) were added thereto, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was diluted with chloroform, and then washed successively with saturated sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate, and saturated brine. The chloroform layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:EtOAc=5:2) to obtain Compound 16 (589 mg, 82.1%). Rf: 0.35 (toluene:AcOEt=2:1)
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:41][C:42]1[CH:43]=[N:44][C:45]2[C:50]([C:51]=1I)=[CH:49][CH:48]=[CH:47][CH:46]=2>>[F:41][C:42]1[CH:43]=[N:44][C:45]2[C:50]([C:51]=1[C:5]1[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=1)=[CH:49][CH:48]=[CH:47][CH:46]=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: Fc1cnc2ccccc2c1I
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3c(F)cnc4ccccc34)nc21

Procedure:
Following the procedure for 165, 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol and 3-fluoro-4-iodoquinoline were reacted to give 225. LCMS m/z: 520.2 (MH+)
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:32])[CH:14]([CH3:31])[C:15](=[O:30])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)(C)(C)C>ClCCl>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][CH:15]([OH:30])[CH:14]([CH3:31])[C:13]([OH:32])=[O:12])=[CH:23][CH:22]=1
Reactant: CC(C(=O)CCc1ccc(-c2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)O)C(O)CCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.2 %

Procedure:
A solution of trifluoroacetic acid in dichloromethane (20%; 10 mL) was added to 5-biphenyl-4-yl-2-methyl-3-oxo-pentanoic acid tert-butyl ester (Intermediate 7, 130 mg, 0.382 mmol) and the resulting solution stirred at room temperature for 1.5 hour. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (1:2 ethyl acetate: 40–60 petroleum ether) to give the title compound (60 mg, 56%) as a white solid, mixture of diastereoisomers. LC/MS: 3.22 min; z/e 302, calcd (M+NH4) 302. 1H NMR (400 MHz: CDCl3): 7.59 (2 H), 7.51 (2 H), 7.40 (2 H), 7.28 (3 H), 4.21, 4.01 3.75, 2.91, 2.76, 2.62, 1.88, 1.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][O:20][CH3:21])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26].C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([NH:16][C:17](=[O:23])[CH:18]([NH:22][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])[CH2:19][O:20][CH3:21])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COCC(N)C(=O)NC(Cc1ccc2ccccc2c1)C(=O)OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COCC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)NC(Cc1ccc2ccccc2c1)C(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(2-Amino-3-methoxy-propionylamino)-3-naphthalen-2-yl-propionic acid methyl ester, 58, (4.43 g, 12.1 mmol) and 2-nitrobenzene sulfonyl chloride (2.8 g, 12.7 mmol) are dissolved in any THF (20 mL). The mixture is cooled to 0° C. and triethyl amine (5 mL) is added to the reaction mixture which is then allowed to stir overnight at room temperature. Water (100 mL) is added and the reaction mixture pH adjusted to 3 with 1M KHSO4. The solution is extracted with EtOAc (3×100 mL) and the organic layers are combined and dried over Na2SO4. The solvent is removed in vacuo to afford 6.4 g (quantitative yield) of the desired product. 1H NMR (300 MHz, CDCl3, δ): 8.02 (m, 1H), 7.8 (m, 4H), 7.60 (m, 3H), 7.48 (m, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.58 (d, J=6.25 Hz, 1H), 4.57 (quartet, J=6.25 Hz, 1H), 4.02 (quartet, J=6.25 Hz, 1H), 3.70 (s, 3H), 3.47 (m, 2H), 3.44 (m, 2H), 3.49 (s, 3H); 13C NMR, δ 171.5, 168.7, 147.9, 134.2, 133.6, 133.5, 133.2, 132.7, 131.0, 128.4, 128.3, 127.9, 127.5, 126.5, 126.1, 125.9, 72.3, 59.1, 56.6, 53.8, 52.7, 38.0.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH2:14][C:15]1([NH2:19])[CH2:18][O:17][CH2:16]1.C(N(CC)CC)C>CO>[NH2:19][C:15]1([CH2:14][NH:13][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:18][O:17][CH2:16]1
Reactant: NCC1(N)COC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: CO
Product: NC1(CNc2nc(Cl)nc3ccccc23)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 2,4-dichloroquinazoline (1.0 g, 5.024 mmol) in methanol (15 mL) was added 3-(aminomethyl)oxetan-3-amine (855 mg, 60%, 5.024 mmol) and triethylamine (101 mg, 1.005 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 1.2 g of the desired product as a white solid (yield was 92%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](B(O)O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:22])=[CH:17][CH:16]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:22])=[CH:17][CH:16]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Product: O=C(c1ccc(-c2ccc3c(c2)OCCO3)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from 2,3-Dihydro-1,4-benzodioxin-6-yl boronic acid and (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone. MS (ES+) 393.2
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:28])=[CH:13][N:14]3[C:21](=[O:22])[C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:18]=[C:15]32)=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+]>CO>[C:1]([NH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:28])=[CH:13][N:14]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=[C:15]32)=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cnc2c3cc(NC(=O)C(C)(C)C)ccc3c(C)cn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn2c(=O)c(C(=O)O)cnc2c2cc(NC(=O)C(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.7 %

Procedure:
A mixture of ethyl 10-pivaloylamino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (400 mg) and 1N sodium hydroxide (3.1 ml) in aqueous methanol (19 ml) was stirred at ambient temperature for 2 days. Aqueous methanol was added to the reaction mixture and then heated on a water bath until almost all the precipitate was dissolved. The solution was filtered, and the filtrate was acidified with 1N hydrochloric acid. The resultant precipitate was collected, washed successively with water and methanol, and dried. Recrystallization from a mixture of N,N-dimethylformamide and water gave pure 10-pivaloylamino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (0.31 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].CCN(C(C)C)C(C)C.[CH2:19](Br)[O:20][CH3:21]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:19][O:20][CH3:21]
Reactant: Oc1ccc(F)cc1F
Reactant: COCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(F)cc1F
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 2,4-difluorophenol (11.0 g, 85 mmol) and DIPEA (15.5 mL, 89 mmol) in DCM (150 ml) at 0° C. under nitrogen was added MOM-Br (7.33 mL, 89 mmol) over 1 hr and the reaction mixture then maintained at RT for 16 hr. The resulting mixture was washed successively with water, aq 2M NaOH solution, water and brine, and was then dried (MgSO4) and evaporated in vacuo to afford 2,4-difluoro-1-(methoxymethoxy)benzene as a colourless oil (13.7 g, 88% yield). Rt 3.17 min (Method 1, basic, no ionization observed), which was used directly in the next step (below).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=O.O>CO>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: O
Solvent: CO
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a solution of the amine (4) (363 mg, 1.39 mmol) and 3,5-dimethoxybenzaldehyde (301 mg, 1.81 mmol) in methanol (10 mL) was added borane-pyridine complex (445 μL, 4.18 mmol) at 40° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (5) as a pale yellow solid (329 mg, Yield: 57%).