Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[S:7][C:8]3[N:9]=[C:10]([N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]4[CH2:30][CH3:31])[N:11]=[C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:13]=3[N:14]=2)[CH2:2]1.[OH:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:13]3[N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:34](=[O:35])[C:33]([OH:32])([CH3:38])[CH3:37])[CH2:4]4)[S:7][C:8]=3[N:9]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)sc2n1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A mixture of 2-azetidin-3-ylmethyl-5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (209 mg, 0.48 mmol), 2-hydroxyisobutyric acid (56 mg, 0.54 mmol), HATU (200 mg, 0.53 mmol) and DIPEA (94 μL, 0.54 mmol) in DCM (5 mL) was allowed to stir at r.t. for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-2%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 5-98%) affording 814 as a white solid (89 mg, 35%). LCMS (method I): RT 3.39 min, [M+H]+ 522.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.28-7.28 (2 H, m), 4.62-4.12 (7 H, m), 4.05-3.92 (1 H, m), 3.88 (4 H, t, J=4.76 Hz), 3.45 (1 H, s), 3.43-3.38 (2 H, m), 3.33 (2 H, q, J=7.47 Hz), 3.27-3.21 (1 H, m), 1.43-1.42 (9 H, m)
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:36]([C:38]1[CH:39]=[C:40]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:41]([F:46])=[C:42]([CH:45]=1)[CH:43]=[O:44])[CH3:37]>C1COCC1>[CH2:36]([C:38]1[CH:39]=[C:40]([N:47]2[CH2:48][CH2:49][O:50][CH2:51][CH2:52]2)[C:41]([F:46])=[C:42]([CH:43]([C:9]2[N:10]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[OH:44])[CH:45]=1)[CH3:37]
Reactant: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CCc1cc(C=O)c(F)c(N2CCOCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
To a solution of Intermediate 8.1 (122 mg, 0.316 mmol) in 2 mL THF at 0° C., was added BuLi (1.6 M in THF, 0.236 mL, 0.379 mmol). The mixture was stirred at 0° C. for 45 min, then a solution of Intermediate 406.1 (75 mg, 0.316 mmol) in 0.9 mL THF was added dropwise. The mixture was stirred at rt for 30 min, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 162 mg of Intermediate 406.2 as a colorless glass. LCMS (2 min gradient) RT=1.93 min, 624.26 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]([CH2:18][F:19])([CH2:16][F:17])[CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:21]>>[F:19][CH2:18][C:5]1([CH2:16][F:17])[CH:4]=[C:3]([C:1]([NH2:2])=[O:21])[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6]1
Reactant: N#CC1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: O=S(=O)(O)O
Product: NC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 36 h

Procedure:
A mixture of 3 g of 4-cyano-2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran and 20 ml of sulfuric acid was stirred for 36 hours. The reaction mixture was poured into ice water and the separated crystal was collected by filtration. The above-obtained crystal was diluted with ethyl acetate and the organic layer was washed with water and dried. The solvent was distilled off to obtain 3 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboamide represented by the following formula.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[CH:49]=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51][Mg]Br.[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[CH:49]([OH:50])[CH3:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To the solution of aldehyde 101 (390 mg, 0.55 mmol) in THF (5.5 mL) was added methyl magnesiumbromide (3.0 M in ether, 0.28 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was poured into a saturated NH4Cl solution and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography provided the desired secondary alcohol 103 (300 mg, 75%) as a solid. MH+723.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11].[S:18]([O-])(=[O:21])(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][S:18]([O:11][CH2:10][C:9]([O:15][CH2:16][CH3:17])([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][CH2:13][CH3:14])(=[O:21])=[O:20]
Reactant: CCCC(CO)(OCC)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)[O-]
Solvent: c1ccncc1
Product: CCCC(COS(C)(=O)=O)(OCC)c1ccc(Cl)cc1Cl

Procedure:
6.93 g (25 mmoles) of 2-(2,4-dichlorophenyl)-2-ethoxy-pentan-1-ol are dissolved in 20 ml of pyridine and converted into the corresponding mesylate by adding 3.15 g (27.5 mmoles) of methanesulfochloride. The reaction takes place exothermically with the precipitation of pyridine hydrochloride. After a reaction time of 1 hour, water is added and the mixture is extracted with diethyl ether. The combined extracts are washed with half-saturated sodium chloride solution, dried over sodium sulfate, filtered and freed from solvent in vacuo. Yield 8.6 g. 100 MHz-1H-NMR (CDCl3): δ=4.7 ppm ##STR37## 3.2-3.6 ppm (q, 2H, --OCH2CH3); 2.8 ppm (s, 3H, --OSO2CH3); 1.8-2.5 ppm (m, 2H, --CH2CH2CH3); 1.3 ppm (t, 3H, --OCH2CH3); 0.7-1.3 ppm (m, 5H, --CH2CH2CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:15])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C1(O)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: Cc1cc(Cl)ccc1C1(O)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of the 4-(4-chloro-2-methyl-phenyl)-piperidin-4-ol (0.160 g, 0.71 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.59 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.130 g, 36%). 1H-NMR (CDCl3): δ 1.57 (s, 6H), 1.92 (d, 2H), 2.30 (t, 2H), 2.49 (s, 3H), 2.48–2.63 (m, 2H), 2.74–3.11 (m, 6H), 3.40 (s, 1H), 5.21 (bs, 2H), 6.09 (t, 1H), 6.75 (d, 1H), 7.06 (d, 1H), 7.08 (s, 1H), 7.20(d, 2H), 7.22–7.36 (m, 1H), 7.57 (d, 1H), 8.36 (dd, 1H). ESI-MS m/z: 519 (M+1), retention time 1.61.
Reaction SMILES: [C:1]([S:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31]OS(C)(=O)=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:37][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][S:20][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: CS(=O)(=O)OCCOCCOCCOCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: FCCOCCOCCOCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 71 %

Procedure:
A stirring solution of methanesulfonic acid 2-{2-[2-(2-tritylsulfanyl-ethoxy)-ethoxy]-ethoxy}-ethyl ester (71.67 mg, 0.14 mmol) and tetrabutylammonium fluoride (1.1 M in THF, 127 μl, 0.14 mmol) was heated at 90° C. for 30 minutes. The mixture was cooled to ambient temperature and evaporated to dryness. Purification of product was by flash chromatography using ethyl acetate/hexane, (1:1) to give the product (71%) as a colourless oil.
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:9]2[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=2)[CH:13]=[O:14])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.CC(C)=O.Cl>O>[OH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)=[CH:10][C:11]=1[OH:17]
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: OCc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A solution of sodium borohydride (NaBH4) (0.66 g, 17 mmol) in water (25 mL) was treated with 4-morpholinylsalicylaldehyde (1.8 g, 9 mmol) in small portions over 30 min and stirred at room temperature for 3 h. The reaction was quenched with acetone (5.1 mL, 100 mmol), acidified to pH 7 with 7.8 mL of 5% hydrochloric acid (aqueous) and extracted with chloroform (CHCl3) (2×100 mL). The combined CHCl3 extracts were dried over sodium sulfate (Na2SO4) and concentrated in vacuo to yield 0.7 g of pale yellow solid which was purified by trituration with 60/40 CHCl3/ethyl acetate (EtOAc) to yield the product as a white solid (0.25 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]([F:15])([F:14])[F:13])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.CN(C=O)C>[F:15][C:12]([F:13])([F:14])[C:6]1[C:5]2[C:9](=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc2c(C(F)(F)F)c[nH]c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0.5 mL) at 0° C. was added BH3.THF complex (1 M in THF, 1 mL, 0.95 mmol) dropwise. The reaction mixture was stirred for 5 min at 0° C. then for 3 h at room temperature. The reaction mixture was quenched by adding very carefully 6M HCl (3.5 mL) until no more gas release was observed. The reaction mixture was then stirred at 80° C. for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to provide 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[CH:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[NH2:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:26]=[CH:27][C:28]=1[NH:29][C:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:15]
Reactant: CC(C)n1cc(C(=O)O)c2ccccc21
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(NC(=O)c2cn(C(C)C)c3ccccc23)c(Cl)c1
Temperature: -15 °C
Yield: 91.1 %

Procedure:
To a solution of 1-isopropylindole-3-carboxylic acid (159.6 mg, 0.785 mmol) in methylene chloride (3.5 ml) was added oxalyl chloride (101.0 μl, 1.178 mmol) under stirring at −15° C. The reaction mixture was stirred for 2.5 hours at room temperature and then distilled under reduced pressure to remove the solvent. The residue was dissolved in methylene chloride (3.5 ml), followed by the addition of a solution of methyl 3-chloro-4-aminophenylacetate (164.6 mg, 0.824 mmol) in methylene chloride (3.5 ml) and triethylamine (0.35 ml, 2.474 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then distilled under reduced pressure to remove the solvent. The residue was dissolved in chloroform. The resulting solution was washed successively with 1N HCl and saturated saline, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 3-chloro-4-((1-isopropyl-3-indolylcarbonyl)amino)phenylacetate (275.3 mg, 91%) was obtained as a brown solid. The resulting compound was provided for the subsequent reaction without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:15]([Cl:28])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:28][C:15]1[CH:14]=[N:13][C:12]2[NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:6]=3)[CH2:4][CH2:3][CH2:2][O:27][C:23]3[CH:22]=[C:21]([CH2:20][CH2:19][NH:18][C:16]=1[N:17]=2)[CH:26]=[CH:25][CH:24]=3
Reactant: Oc1cccc(CCNc2nc(Nc3cccc(CCCBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cnc2nc1NCCc1cccc(c1)OCCCc1cccc(c1)N2
Yield: 9.7 %

Procedure:
To a solution of 3-{2-[(2-{[3-(3-bromopropyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]ethyl}phenol (50.0 mg, 0.108 mmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium hydroxide in water (1.0 mL, 1.0 M). The resultant solution was stirred at rt for 60 hours until the reaction was complete. The reaction mixture was neutralized with HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by silica gel column chromatography to give the desired product as a white powder (4.0 mg, 10%). LCMS for C21H22ClN4O (M+H)+: m/z=381.0. 1H NMR (400 MHz, CD3OD): δ 7.95 (s, 1H), 7.90 (s, 1H), 7.30 (m, 3H), 7.12 (t, J=7.4 Hz, 1H), 6.94 (m, 1H), 6.65 (m, 2H), 3.70 (t, J=7.6 Hz, 2H), 3.48 (t, J=6.8 Hz, 2H), 2.80 (m, 2H), 2.72 (m, 2H), 2.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc3[nH]ccc3c2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Product: O=C(O)c1c(-c2ccc3[nH]ccc3c2)c2cc(NS(=O)(=O)c3ccccc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-1H,1′H-3,5′-biindole-2-carboxylate and phenylsulfonyl chloride followed the procedure of Example 1 Step 3 as a gray solid: 1H NMR (DMSO-d6) δ 5.75 (s, 2H, 6.46 (t, J=2.0 Hz, 1H, 6.99 (dd, J=8.3, 2.0 Hz, 1H, 7.00-7.10 (m, 4H, 7.18-7.32 (m, 3H, 7.36-7.46 (m, 3H, 7.45-7.55 (m, 3H), 7.60-7.68 (m, 3H, 9.88 (s, 1H, 11.14 (s, 1H, 12.80 (br s, 1H; MS (ESI) m/z 522 (MH+); MS (ESI) m/z 520 [M-H]−; HRMS calcd for C30H24N3O4S: 522.1485; found (ESI+): 522.1473; Anal. calcd for C30H23N3O4S.0.5H2O.0.5 ACN: C, 67.56; H, 4.66; N, 8.90. Found: C, 67.54; H, 4.57; N, 8.76.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH3:16])[C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1 g of 6-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (5.06 mmol) in DMF (20 ml) were carefully added 265 mg of sodium hydride (55% dispersion in oil, 6.07 mmol) at 0° C. and the mixture was stirred at RT for 30 min. Then 0.47 ml of methyl iodide (7.60 mmol) were added and stirring at RT was continued over night. Water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated and the remaining residue was purified by crystallization from heptane. This yielded 513 mg of 6-chloro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (48%) as an off-white solid. 1HNMR (DMSO-d6, 300 MHz): δ 3.45 (s, 3H), 7.47 (d, J=8.9 Hz, 1H), 7.89 (dd, J=8.9 and 2.7 Hz, 1H), 7.95 (d, J=2.7 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:27])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[C:15](Cl)=[N:14][CH:13]=1)[CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:27])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:14][CH:13]=1)[CH3:8]
Reactant: C1COCCN1
Reactant: CCOC(=O)Cc1cnc(Cl)c2cc(OC)c(OC)cc12
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cnc(N2CCOCC2)c2cc(OC)c(OC)cc12

Procedure:
Excess morpholine is added to a suspension of (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid ethyl ester (0.200 g, 0.65 mmol) in toluene (1 ml) and the mixture heated to reflux until the starting material is consumed. After evaporation, the residue is partitioned between water and dichloromethane, the organic phase is dried over magnesium sulfate and evaporated. to afford (6,7-dimethoxy-1-morpholin4-yl-isoquinolin4-yl)-acetic acid ethyl ester [MH]+ 361. The crude ester (0.240 g, 0.66 mmol) is dissolved in ethanol (20 ml), treated with 2M sodium hydroxide (3 ml) and stirred at room temperature overnight. After adjustment to pH 1 with concentrated hydrochloric acid, the solvent is evaporated and the crude acid used directly for formation of the xanthine derivative.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.FC(F)(F)S(O[CH2:32][CH2:33][O:34][C:35]([F:38])([F:37])[F:36])(=O)=O>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:32][CH2:33][O:34][C:35]([F:38])([F:37])[F:36])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C)(C)OC(=O)C(CCOC(F)(F)F)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
300 mg (0.79 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate in the presence of 0.95 ml (0.95 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 207 mg (0.79 mmol, 1.0 eq.) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 244 mg (purity 92%, 58% of theory)
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][O:12][C@H:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C@@H:10]1[CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])(C(C)(C)C)(C)C.Cl>CO>[OH:8][C@@H:9]1[CH2:13][O:12][C@H:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C@H:10]1[CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CC/C=C\CC[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)CC/C=C\CC[C@H]1[C@H](O)CO[C@@H]1c1cccnc1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of 25.7 g (0.0612 mol) of methyl (Z)-(2S,3S,4S)-7-[4-(t-butyldimethylsilyloxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]-4-heptenoate in 257 ml of methanol is bubbled with HCl gas for about 2 min to give a strongly acidic solution. The mixture is allowed to stand at 0° C. overnight and evaporated. The residue is dissolved in 100 ml of water and extracted with ethyl acetate (2×). The ethyl acetate extracts are discarded. The aqueous layer is diluted with 150 ml of methylene chloride and neutralized by portionwise addition of potassium carbonate. The layers are separated and the aqueous layer is extracted with methylene chloride (3×). The combined extracts are washed with brine, dried (MgSO4) and evaporated to give 16.6 g of methyl (Z)-(2S,3S,4S)-7-[4-hydroxy-2-(3-pyridyl)-tetrahydrofuran-3-yl]-4-heptenoate as an oil with elemental analysis: C,65.87; H,7.78; N,4.58 (theory: C,66.86; H, 7.59; N,4.58) and optical rotation [α]D 25=+9.44 (methanol) and mass spectrum m/z 306 (M+1) (cald. MW=305.38).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8].[CH3:22][NH:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[NH:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=1)=[O:25]>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:34]3[N:33]=[C:32]([NH:31][C:30]4[CH:29]=[CH:28][S:27][C:26]=4[C:24](=[O:25])[NH:23][CH3:22])[C:37]([Cl:38])=[CH:36][N:35]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: CN(C)CCCOC(=O)N1CCCOc2cc(N)ccc21
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1sccc1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCCN(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-methylcarbamoyl-thiophen-3-ylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester and 3-(2,5-dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide in an analogous manner to Example 1410. Product isolated as an orange foam (85 mg, 52%). LCMS (m/e) 560 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 11.65 (s, 1H), 9.58 (s, 1H), 8.57-8.45 (m, 1H), 8.32-8.21 (m, 2H), 7.82-7.73 (m, 1H), 7.61-7.50 (m, 1H), 7.33-7.21 (m, 1H), 7.20-7.10 (m, 1H), 4.20-3.90 (m, 5H), 7.75-3.50 (m, 2H), 2.78 (d, 3H, J=4.0 Hz), 2.22-1.85 (m, 11H).