Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:46])[N:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:35](=[O:38])[NH:36][N:37]=2)=[O:31])=[CH:25][C:24]=1[F:47].[CH2:48](Br)[C:49]#[CH:50].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][CH:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([C:32]2[C:33](=[O:46])[N:34]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[C:35](=[O:38])[N:36]([CH2:50][C:49]#[CH:48])[N:37]=2)=[O:31])=[CH:25][C:24]=1[F:47]
Reactant: C#CCBr
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4n[nH]c(=O)n(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C#CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)c1=O
Yield: 21.8 %

Procedure:
A mixture of example 107 (25 mg, 0.046 mmol), propargyl bromide (10 uL, 0.1 mmol), and potassium carbonate (10 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) was stirred at rt 18 h. The mixture was filtered, solvent was removed and the product was purified by reverse phase HPLC to give an off-white solid (7 mg, 30%). LCMS m/z=586 (M+1); 1H NMR (DMSO) δ: 10.99 (s, 1H), 8.71 (d, 1H, J=6.1 Hz), 8.0 (dd, 1H, J=2.3, 12.7 Hz), 7.68 (s, 1H), 7.65-7.58 (m, 2H), 7.4 (s, 1H), 7.37-7.35 (m, 4H), 6.84 (d, 1H, J=5.8 Hz), 4.88 (d, 2H, J=2.3 Hz), 4.01 (2 s, 6H), 3.53 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[C:9]([NH:10][CH:11]([CH2:14]OS(C)(=O)=O)[CH2:12][CH3:13])=[CH:8][C:7]([CH3:20])=[N:6][C:5]=1[O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=1[CH3:31].[I-].[Na+].[CH3:35][S:36](C)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:32])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][S:36][CH3:35])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:20])=[N:6][C:5]=1[O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=1[CH3:31]
Reactant: CCC(COS(C)(=O)=O)Nc1cc(C)nc(Oc2c(C)cc(OC)cc2C)c1C(=O)OC
Reactant: CS(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(CSC)Nc1cc(C)nc(Oc2c(C)cc(OC)cc2C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-methoxy-2,6-dimethyl-phenoxy)-4-(1-methanesulfonyloxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester and sodium iodide in acetonitrile was stirred at rt for 2 hr, then NaSMe was added. The mixture was heated at 60° C. overnight. DMSO and additional NaSMe were added and heated for additional hours until all starting material was consumed. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was separated, dried, concentrated, and purified to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>>[OH:3][CH2:4][C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc2ccccc2o1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: OCc1cc2ccccc2o1
Yield: 79.2 %

Procedure:
The reaction of 2-ethoxycarbonylbenzofurane (27.40 g) with diisobutylaluminum hydride was carried out in the manner similar to that described in Reference Example 3 to give the titled compound (16.91 g) as a colorless oil. This compound was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:32]([NH:31][CH2:29][CH3:30])=[O:33])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: CCN=C=O
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)N1CC=C(c2coc3c(O[C@H](C)c4c(Cl)ccc(F)c4Cl)c(N)ncc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydro-pyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), ethyl isocyanate (0.00310 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD): δ=1.13 (t, J=7.2 Hz, 3H), 1.87 (d, J=6.8 Hz, 3H), 2.48 (br. s., 2H), 3.22 (q, J=7.1 Hz, 2H), 3.62 (t, J=5.8 Hz, 2H), 4.06 (d, J=2.5 Hz, 2H), 6.25 (br. s., 1H), 6.43-6.56 (m, 1H), 7.21 (t, J=8.7 Hz, 1H), 7.39 (dd, J=9.0, 4.9 Hz, 1H), 7.65 (s, 1H), 8.16 (s, 1H). MS (ES+): m/z 493.02/495.04 (100/68) [MH+]. HPLC: tR=2.95 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[N-:13]=[N+]=[N-].[Na+].CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:13][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a mixture of 6-Methoxy-1-indanone (15 g, 92.6 mmol), sodium azide (26.7 g, 277.8 mmol), in CHCl3 was added methane sulfonic acid (60 g, 926 mmol) via addition funnel at 0° C. Reaction mixture was warm to room temperature. Stirring was continued for 3 hr, then poured into cold water. The organics were extracted with methylene chloride and washed with water, sat. NaCl and dried over Na2SO4. Organic solution was concentrated in vacuo and the residue was purified with silica gel eluting with 20% EtOAc/Hexane to give the title compound as a yellow solid (10.5 g, 63%). MS (ES) m/z 178.1.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3([CH3:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.Cl[C:23]1[C:24]2[C:31]([CH3:32])=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>CS(C)=O>[NH:4]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([C:15]3([CH3:21])[CH2:20][CH2:19][N:18]([C:23]4[C:24]5[C:31]([CH3:32])=[CH:30][NH:29][C:25]=5[N:26]=[CH:27][N:28]=4)[CH2:17][CH2:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: CC1(C(=O)Nc2cccc(-c3nnn[nH]3)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(-c5nnn[nH]5)c4)CC3)c12
Temperature: 105 °C
Yield: 4.3 %

Procedure:
N-(3-(1H-tetrazol-5-yl)phenyl)-4-methylpiperidine-4-carboxamide from step B (93 mg, 0.29 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (49 mg, 0.29 mmol), N,N-diisopropylethylamine (0.19 g. 1.45 mmol), isopropanol (4.0 mL), and DMSO (0.5 mL) were combined in a pressure rated sealed tube and heated at 105° C. for 18 hours. The mixture was concentrated, and the residue was purified by preprative HPLC to give the title compound in 4.3% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[CH:20]=[CH:21][C:14]=2[CH2:13][CH2:12]1)=O>O.CO.C1COCC1>[CH2:13]1[C:14]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][C:15]=2[CH2:16][CH2:17][NH:11][CH2:12]1
Reactant: CC(=O)Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCNCC2
Temperature: 0 °C
Yield: 125.2 %

Procedure:
29.2 g potassiumcarbonate in 100 mL of water was added to 17.5 g N-[3-(2,2,2-Trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-acetamide in 400 mL MeOH and 50 mL THF at 5° C. The reaction mixture was stirred in the ice bath for 2 h and 2 h at RT. The solvent was removed and the residue was extracted with brine and dichloromethane, the organic fraction was dried and the solvent removed to yield 14.9 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[O:13][N:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:10]=2)[C:6](=[S:17])[NH:5][C:4](=[O:18])[CH:3]=1.[N:19]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:19][C:3]1[C:4](=[O:18])[NH:5][C:6](=[S:17])[N:7]([CH2:8][C:9]2[O:13][N:12]=[C:11]([CH:14]([CH3:15])[CH3:16])[CH:10]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: CC(C)c1cc(Cn2c(N)cc(=O)[nH]c2=S)on1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC(C)c1cc(Cn2c(N)c(N)c(=O)[nH]c2=S)on1
Yield: 33.2 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(c) by using 6-amino-1-[(3-isopropylisoxazol-5-yl)methyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.20 g, 0.75 mmol, obtained from Example 15(b)), sodium nitrite (0.060 g, 0.83 mmol) and sodium dithionite (0.26 g, 1.5 mmol) giving the title compound (0.070 g, 33% yield). MS (ESI) m/z 282 (M+1).
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3Br)[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[N:1]1([C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:24]3[CH:23]=[CH:22][C:21]([C:35]4[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=4)=[C:20]([F:19])[CH:25]=3)[CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Brc1ccccc1Oc1cc(N2CCC2)ncn1
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3cc(N4CCC4)ncn3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(azetidin-1-yl)-6-(2-bromophenoxy)pyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C23H19FN6O, 414.16; m/z found, 415.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=1.5, 2H), 8.11 (d, J=0.9, 1H), 7.60-7.52 (m, 2H), 7.50-7.41 (m, 1H), 7.41-7.31 (m, 3H), 7.17 (dd, J=8.1, 1.2, 1H), 6.89 (s, 2H), 5.73 (d, J=0.9, 1H), 3.98 (t, J=7.5, 4H), 2.41-2.27 (m, 2H).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O=[C:12]([CH3:24])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.N1CCCCC1.O>C1C=CC=CC=1>[CH3:24][C:12]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[NH:10][C:1](=[O:9])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[O:4]1
Reactant: NC(=O)c1ccccc1O
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC1(COc2ccc([N+](=O)[O-])cc2)NC(=O)c2ccccc2O1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a stirred mixture of salicylamide (6.85 g, 50 mmol) and 4-[2-oxo-propoxy]nitrobenzene (9.75 g, 50 mmol) in benzene (500 mL) was added piperidine (0.52 mL, 5 mmol). The reaction mixture was immersed in a pre-heated oil bath (˜100° C.) and refluxed for 10 h with continuous removal of water using Dean-Stark water separator. The reaction mixture was cooled to room temperature End the precipitated brown coloured solid was filtered, washed with benzene and dried to afford the title compound (13.5 g, 86%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]4[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Temperature: 90 °C

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester (200 mg) and 4-(methanesulfonyl)phenylboronic acid (119 mg) in N,N-dimethylformamide (2 mL) a 2 M aqueous Na2CO3 solution (0.68 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (44 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, water (20 mL) is added and the mixture is extracted three times with ethyl acetate. The organic phase is dried (Na2SO4) and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 1:22:1) to give the title compound. Yield: 149 mg (62% of theory); LC (method 1): tR=1.29 min; Mass spectrum (ESI+): m/z=444 [M+H]+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].OO>O1CCCC1>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCC/C=C/c1ccc(-c2ncc(OCCCCCCCCCC)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 169.4 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 5.0 g (13 mmol) of 5-decyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-1-heptenylcatecholborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 4.5 g (yield 86%) of 5-decyloxy-2-{4-(1-trans-heptenyl)-phenyl}-pyrimidine. ##STR17## 1H-NMR revealed no presence of cis form at all.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.O=[CH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[C:17]4[CH2:22][N:21]([CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: O=CCCC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(CCCC(=O)O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
To a solution of (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 3) as a HCl salt (100 mg, 0.23 mmol) and triethyamine (64 μL, 0.46 mmol) in DCE (3 mL, anhydrous), and DMF 0.5 mL, anhydrous) was added 4-oxobutanoic acid (45 μL, 0.46 mmol). Reaction mixture was stirred at room temperature for 30 mins. To this sodium triacetoxyborohydride (97 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature until analysis by LCMS indicated reaction was complete. Solvent was then removed in vacuo. Purified by prep. HPLC (high pH) to afford a white solid (4.2 mg, 0.008 mmol, 4%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CCSc1ccc(C(=O)OC)c(O)c1
Product: CCSc1ccc(C(=O)OC)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 85 %

Procedure:
Using a procedure analogous to Example 1-D, methyl 2-hydroxy-4-(ethylthio)benzoate and 3-t-butoxycarbonylamino-propanol gave the title compound as a solid (10.41 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:13][Mg]Br.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.CCOC(C)=O.CCCCCC>C1COCC1>[CH3:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: C[Mg]Br
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c([N+](=O)[O-])ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 5-nitroindole (from Aldrich, 0.82 g, 5.1 mmol) in 20 mL of dry THF was added 5.0 mL (15 mmol) of methylmagnesium bromide for 0.5 h period and the resulting reaction mixture was stirred for 1 h at 25° C. Reaction was the quenched by adding a THF solution of tetrachloro-1,4-benzoquinone (1.2 g, 4.9 mmol). Reaction mixture was concentrated in vacuo, yielding a dark solid which was subjected to column chromatography (30% EtOAc/n-Hexane) to yield 0.72 g (4.1 mmol, 80%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3-methylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (85 mg, 0.31 mmol) and lithium hydroxide (129 mg, 3.10 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc to afford the title compound. 45 mg, 57% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.07-2.20 (m, J=12.57, 8.44, 6.21, 6.21 Hz, 1H), 2.35 (s, 3H), 2.50-2.84 (m, 5H), 3.26-3.35 (m, 1H), 6.53 (d, J=1.42 Hz, 1H), 6.98-7.07 (m, 2H), 7.17-7.22 (m, 1H), 7.23-7.34 (m, 1H), 8.84 (br. s., 1H). LCMS m/e 256 (M+H). Purity ˜100% (HPLC).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]2=1)#[N:4].Cl.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1>CN(C=O)C>[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=1)[C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:9][C:8]2=1)#[N:4]
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Reactant: Fc1ccc(CCl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccc(F)cn2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
Suspend sodium hydride (60% in oil, 80 mg, 1.99 mmol) in DMF (2 mL) and chill to 0° C. Add a solution of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (253 mg, 0.90 mmol) in DMF (2 mL) slowly via syringe, and allow to stir 30 min before warming to ambient temperature for 60 min. Add 2-chloromethyl-5-fluoro-pyridine hydrochloride salt (180 mg, 0.99 mmol) and stir the reaction for about 12 h. Quench the reaction with saturated aqueous ammonium chloride (5 mL). Add ethyl acetate (50 mL) and wash the solution with water (50 mL), then brine (2×50 mL). Separate the organic phase and dry over magnesium sulfate, filter, and evaporate under reduced pressure. Titurate the resulting residue with diethyl ether (10 mL) for 5 min and then filter to afford 187 mg (53%) of the title compound as a light yellow solid. mp 235-238° C. (dec); MS (ESI): m/z [391 C23H23FN4O+H]+; 1H NMR (300 MHz, CDCl3): δ 8.43s, 1H), 7.78 (s, 1H), 7.38-7.25 (m, 3H), 6.67 (dd, J=8.6, 4.2 Hz, 1H), 5.58 (d, J=7.8 Hz, 1H), 5.35 (s, 2H), 4.40 (br s, 1H), 3.14 (dd, J=15.4, 5.0 Hz, 1H), 2.79 (br s, 2H), 2.60 (dd, J=15.4, 7.6 Hz, 1H), 2.34 (pentet, J=6.8 Hz, 1H), 2.15 (br s, 1H), 2.02-1.95 (m, 1H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([C@H:4]1[C@H:8]([CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH2:7][N:6]([C@@H](C2C=CC=CC=2)C)[CH2:5]1)[CH:2]=[CH2:3].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].Cl.C(O)C>ClCCl>[CH2:1]([C@H:4]1[C@H:8]([CH2:9][OH:10])[CH2:7][N:6]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC[C@@H]1CN([C@H](C)c2ccccc2)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: C=CC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1CO
Temperature: 55 °C
Reaction time: 10 h
Yield: 85.9 %

Procedure:
(3S,4S)-3-Allyl-4-(tert-butyldimethylsilyloxy)methyl-1-[(1R)-1-phenylethyl]pyrrolidine (213 g, 592 mmol) was dissolved in dichloromethane (420 mL). Benzyl chloroformate (169.2 mL, 1.19 mol) was added dropwise, and the mixture was stirred at 55° C. for 10 hours and then at room temperature for 14 hours. A 1 M solution of hydrochloric acid in ethanol (250 mL, 250 mmol) was further added to the reaction solution, and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with a saturated sodium bicarbonate solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→1:1) to give 140 g of the title compound as a pale yellow oil.