Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:10]2=[N:11][C:12]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:14]=[C:9]2[CH:8]=1)(=O)C.[OH-].[Na+].Cl.CCCC(C)C>CCO.CCOC(C)=O.O>[OH:4][CH2:5][CH2:6][C:7]1[N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:10]2=[N:11][C:12]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[N:14]=[C:9]2[CH:8]=1
Reactant: CCOC(=O)CCCCCCn1c(CCOC(C)=O)cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc3cc(CCO)n(CCCCCCC(=O)O)c3nc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 7-(6-(2-acetoxyethyl)-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (step 4)(17 mg, 0.031 mmol) in EtOH (1 ml) at RT was treated with 2M NaOH (0.047 ml, 0.094 mmol) and stirred at RT for 4 hours. Further 2M NaOH (0.047 ml, 0.094 mmol) was added and the mixture was stirred at RT for 16 hours overnight. Further 2M NaOH (0.047 ml, 0.094 mmol) was added and the orange RM was stirred at RT overnight. The resulting mixture was added to water (30 ml) and the pH was adjusted to pH1 by addition of 2M HCl. The aqueous was extracted with DCM (×4) and the combined extracts were passed through a phase separating column and concentrated under reduced pressure to afford an orange oil. The oil was dissolved in EtOAc and an excess of iso-hexane was added. The resulting suspension was sonicated and removed by filtration. The filtrate was concentrated under reduced pressure and the crude product was dissolved in DCM (minimal) and loaded onto a S±20 mm×20 mm preparative TLC plate. Using a solvent system of 10% MeOH in DCM (200 ml) the TLC plate was eluted and the appropriate strip of Si on the plate was scrapped off the plate. The Si was suspended in 10% MeOH/DCM and sonicated. The suspension was filtered, rinsing the solid with 10% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([NH:21][CH2:22][CH2:23][OH:24])[CH:13]=[C:14](Br)[CH:15]=3)[C:10](=[O:25])[C:9]=2[CH:8]=[C:7](Br)[CH:6]=1.CN(C)C=O.[C:32]1([S-:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Na+]>CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([NH:21][CH2:22][CH2:23][OH:24])[CH:13]=[C:14]([S:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:15]=3)[C:10](=[O:25])[C:9]=2[CH:8]=[C:7]([S:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=1
Reactant: [S-]c1ccccc1
Reactant: O=C1c2cc(Br)cc(NCCO)c2C(=O)c2cc(Br)cc(NCCO)c21
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2cc(Sc3ccccc3)cc(NCCO)c2C(=O)c2cc(Sc3ccccc3)cc(NCCO)c21
Temperature: 120 °C

Procedure:
24 g of 1,5-bis(2-hydroxyethylamino)-3,7-dibromoanthraquinone are introduced at RT into 100 ml of dimethylformamide (DMF). After the addition of 16.3 g of sodium thiophenolate, the mixture is heated to 120° C. and maintained at that temperature for one hour. After cooling the mixture to RT, 100 ml of methanol are added thereto. The precipitate is filtered off, washed with a methanol/water mixture (1:1) and dried in vacuo.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:55][C:56]1[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([NH2:63])[CH:57]=1>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:62][C:59]3[CH:60]=[CH:61][C:56]([CH3:55])=[CH:57][C:58]=3[NH2:63])=[O:24])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)CCCCCNC(=O)C=C2c3ccccc3-c3ccccc32)c(N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.9 %

Procedure:
6-(2-(9H-fluoren-9-ylidene)acetamido)hexanoic acid (335 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-methyl-o-phenylenediamine (146 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (369 mg, 84% yield) as a brown solid. 1H NMR (DMSO-d6) δ1.39 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.11 (s, 3H, CH3), 2.31 (t, J=8.0 Hz, 2H, CH2CO), 3.27 (m, 2H, NCH2), 4.72 (s, 2H, benzene-NH2), 6.31 (d, J=8.0 Hz, 1H, Ar—H), 6.61 (s, 1H, Ar—H), 6.99 (d, J=8.0 Hz, 1H, Ar—H), 7.08 (s, 1H, ═CH—CO), 7.33 (m, 2H, Ar—H), 7.40 (m, 2H, Ar—H), 7.76 (d, J=8.0 Hz, 1H, Ar—H), 7.82 (m, 2H, Ar—H), 8.53 (t, J=4.0 Hz, 1H, CONH), 8.69 (d, J=8.0 Hz, 1H, Ar—H), 9.08 (s, 1H, benzene-NH). LC-MS (m/z) 440 (M+1).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22]>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:15]3/[C:14](=[O:22])[NH:13][C:21]4[C:16]/3=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(I)n[nH]c2c1

Procedure:
The title compound was synthesized from 3-iodo-1H-indazole-6-carbaldehyde (15 mg, 0.0551 mmol) and oxindole (8 mg, 0.0616 mmol) according to the method described for Example A11B and purified by column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 96:4) to obtain 6.9 mg, 33% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.89-7.82 (m, 2H), 7.63-7.49 (m, 3H), 7.23 (t, J=8.21 Hz, 1H), 6.91 (d, J=7.07 Hz, 1H), 6.89-6.83 (m, 1H); MS ESI 388.0 [M+H]+, calcd for [C16H10IN3O+H]+ 387.99.
Reaction SMILES: Br[C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)(Cl)Cl.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C.CCOC(C)=O.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]>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Br)nc2N1C1CCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3N3CCCC3)nc2N1C1CCCC1
Temperature: 130 °C
Yield: 38.3 %

Procedure:
(R)-2-(2-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 65, 150 mg, 0.37 mmol), pyrrolidine (52 mg, 0.74 mmol), Pd2dba3.CHCl3 (76 mg, 0.074 mmol), BINAP (69 mg, 0.11 mmol) and K2CO3 (153 mg, 1.11 mmol) were dissolved in 1 mL of degassed t-BuOH and the resulting solution was heated at 130° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic extracts were dried with Na2SO4, filtered and evaporated, and the residue was purified by preparative HPLC to give the title compound (56 mg). LCMS: 396.2 m/z (M+H)+; ret. Time: 2.76 min (Analytical Method A).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([F:41])=[C:36]([N:38]=[C:39]=[O:40])[CH:37]=1>ClCCl>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([F:41])=[C:36]([NH:38][C:39]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:40])[CH:37]=1
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Reactant: O=C=Nc1cc(Cl)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
0.022 g (purity: 76% corresponds to 0.04 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 58E) was suspended in 1 ml dichloromethane. The reaction mixture was treated at room temperature with 0.031 ml (0.22 mmol, 5 eq.) of triethylamine and at 0° C. with 8 mg (0.05 mmol, 1.1 eq.) 5-chloro-2-fluorophenyl isocyanate. The solution was stirred overnight and warmed up to room temperature. The solution was evaporated. The crude product was purified by flash chromatography (20 g amine-silica, ethyl acetate/n-heptane 1:1, 4:1, 9:1, 100%, ethyl acetate/ethanol 95:5, 9:1) to give 0.010 g (48%) of the title compound as white solid. MS: 467.4 (MH+, Cl).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:37]([N:39]1[CH2:52][CH2:51][CH2:50][C@H:40]1[C:41]([NH:43][C@H:44]([C:47]([NH2:49])=[O:48])[CH2:45][SH:46])=[O:42])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH2:19][C:20](=[O:22])[OH:21])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[NH:10])[NH2:9].[OH2:53].[OH-].[NH4+].O=O>C(#N)C>[CH:34]1[CH:33]=[CH:32][C:31]2[NH:30][CH:29]=[C:28]([CH2:27][C@@H:26]3[NH:25][C:23](=[O:24])[C@H:18]([CH2:19][C:20]([OH:21])=[O:22])[NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH2:9])=[NH:10])[NH:1][C:47](=[O:53])[CH2:44][CH2:45][S:46][S:46][CH2:45][C@@H:44]([C:47]([NH2:49])=[O:48])[NH:43][C:41](=[O:42])[C@H:40]4[N:39]([CH2:52][CH2:51][CH2:50]4)[C:37]3=[O:38])[C:36]=2[CH:35]=1
Reactant: O
Reactant: N=C(N)NCCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(N)=O
Agent: O=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: N=C(N)NCCCC[C@@H]1NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](CC(=O)O)NC(=O)CNC1=O

Procedure:
Mpa-Har-Gly-Asp-Trp-Pro-Cys-NH2 (60 gm; obtained from Ex-19) was charged in to a stirred solution of water (6 L) and acetonitrile (6 L) at 25° C.-35° C. Adjusted the pH of the solution to 8-8.5 with 2% ammonium hydroxide solution (500 ml). Passed oxygen gas in to the reaction mass for about 10 to 12 hrs under pH of about 8.5-about 8.8. Adjusted pH of the reaction mass to about 5 to about 6 with 1% acetic acid 100 ml) and concentrated the reaction solution at 30° C. to 35° C. under high vacuum till 30% of the solution remains in the reaction vessel and then lyophilized the reaction solution to obtain the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH:19]=[O:20])=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2].[BH4-].[Na+]>CCO.C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19][OH:20])=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:28][CH2:29][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:32]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(C=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(CO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-formyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (560 mg, 1.02 mmol) was dissolved in 1:1 EtOH/CH2Cl2 (40 mL) and cooled to 0° C. NaBH4 (77 mg, 2.03 mmol) was added and the mixture allowed to warm to rt with stirring for 2 h. The mixture was diluted with EtOAc (200 mL), washed with water, brine and separated. The organic fraction was dried (Na2SO4) and concentrated under reduced pressure to afford the desired compound (484 mg, 86%) as a white solid. MS: 554.12 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=4[F:30])[C:15]3=[O:31])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:82][S-:83].[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[NH:19][C@H:16]1[CH2:17][CH2:18][N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[CH:3][C:2]([S:83][CH3:82])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[C:15]1=[O:31]
Reactant: C[S-]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(Br)cn4)CC3)C2=O)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CSc1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
(S)-1-(1-(5-Bromopyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (Example 7; 0.10 g, 0.20 mmol), Xantphos (0.056 g, 0.098 mmol), K3PO4 (0.11 g, 0.51 mmol), and Pd2 dba3 (0.045 g, 0.049 mmol) were diluted in degassed toluene (3 mL). Sodium methanethiolate (0.032 g, 0.45 mmol) was added and the reaction was stirred at 100° C. overnight. The material was cooled to ambient temperature and flash chromatographed to give (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(1-(5-(methylthio)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.011 g, 0.023 mmol, 12% yield) as a white solid. Mass spectrum (apci) m/z=480.1 (M+H).
Reaction SMILES: C[C:2]1([C:8](O)=O)[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=C>CC(C)=O>[CH2:8]([CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7])[CH:17]=[CH2:18]
Reactant: CC1(C(=O)O)CCCC1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCC1CCCC1=O
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A stirred solution of methyl 2-carboxycyclopentanone (35.5 g, 250 mmol) in acetone (500 mL) was treated with anhydrous potassium carbonate (138 g, 1.0 mol) and allyl bromide (100 mL, 1.15 mol) and refluxed for 5 h. The mixture was cooled and filtered through Celite® (rinse filter cake with acetone), and the filtrate was concentrated in vacuo. The residual oil was dissolved in methanol (450 mL), treated with 6 N HCl (250 mL), and refluxed for 40 h. The solution was cooled to room temperature, concentrated in vacuo to remove most methanol, and diluted with water (200 mL). The aqueous solution was extracted with dichloromethane (3×250 mL), and the combined organic solution was washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride (200 mL each), dried (Na2SO4), and gently (volatile product) concentrated in vacuo to 75 mL volume. This solution was loaded onto a silica gel column (˜500 cc) and eluted with dichloromethane to afford (after gentile concentration of fractions) 2-allylcyclopentanone (27.3 g, 88%) as a colorless oil. NMR (CDCl3): δ 5.65-5.75 (m, 1 H), 4.90-5.05 (m, 2 H), 2.40-2.50 (m, 1 H), 2.20-2.30 (m, 1 H), 1.85-2.15 (m, 5 H), 1.65-1.75 (m, 1 H), 1.45-1.55 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.P(Br)(Br)[Br:13].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[Br:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1O
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1Br
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A sample of 3-methyl-5-nitropyridin-2-ol (1.44 g, 9.34 mmol) was placed in 35 mL pressure vessel and dissolved in a mixture of toluene/DMF (10:1 ratio; 15 mL). The vessel was capped with a septum, flushed with Argon and phosphorous tribromide (1.32 mL, 14.0 mmol) was added by syringe. The septum cap was replaced by a Teflon cap and the mixture was stirred for 20 min at 120° C. The mixture was cooled to room temperature, neutralized with a 3M NaOH solution and extracted with toluene (3×). The combined organic phases were dried over anhydrous MgSO4 and concentrated under vacuum to give 2.00 g of the desired 2-bromo-3-methyl-5-nitropyridine product as an orange solid (99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11].C([N-]C(C)C)(C)C.[Li+].Cl>O1CCCC1>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:4]1[C:3]([F:8])=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(Br)c1F
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (2.0 g, 11.42 mmol) and trimethylsilyl chloride (5.79 ml, 45.69 mmol) in dry tetrahydrofurane (30 ml) at −78° C., under nitrogen, lithium diisopropylamide (2 M in hexane, 28 ml, 12.56 mmol) was added dropwise. The mixture was stirred for 1 h and then brought to ambient temperature. 10% Hydrochloric acid (100 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethyl acetate/isooctane, 1:1) to give the title compound (2.3 g). MS m/z (rel. intensity, 70 eV) 248 (M+, 22), 246 (20), 151 (96), 105 (bp), 75 (64).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:38]([CH3:39])=[CH:37][C:36]2=[N:40][C:33]3=[CH:34][N:35]2[C:12]=1[N:13]1[CH2:44][CH2:43][C:16]([CH3:45])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([F:42])=[CH:28][C:29]=2[CH2:30][NH:31][C:32]3=[O:41])[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].CO.O[Li].O>O>[C:1]([O:5][C@@H:6]([C:11]1[C:38]([CH3:39])=[CH:37][C:36]2=[N:40][C:33]3=[CH:34][N:35]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:45])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([F:42])=[CH:28][C:29]=2[CH2:30][NH:31][C:32]3=[O:41])[CH2:43][CH2:44]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCCCOc1ccc(F)cc1CNC3=O
Agent: [Li]O
Solvent: O
Solvent: CO
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCOc1ccc(F)cc1CNC3=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
To a solution of methyl(2S)-2-(tert-butoxy)-2-{15-fluoro-4,26-dimethyl-10-oxo-19,25-dioxa-1,7,11,31-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetate (22 mg, 0.035 mmol, 1 equiv) in 9:1 MeOH:water (1 mL) was added LiOH.H2O (44 mg, 1.06 mmol, 30 equiv). The reaction was heated to 60° C. for 1 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (10.2 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ 8.72-8.62 (m, 1H), 8.01 (s, 1H), 7.29-7.18 (m, 2H), 7.05 (dd, J=8.4, 2.9 Hz, 1H), 6.97 (dd, J=8.7, 4.4 Hz, 1H), 5.91 (br. s., 1H), 4.31 (br. s., 2H), 4.08-3.95 (m, 2H), 3.86-3.79 (m, 2H), 3.50-3.40 (m, J=5.2 Hz, 2H), 2.95 (d, J=7.9 Hz, 1H), 2.60 (d, J=7.6 Hz, 1H), 2.38 (s, 3H), 1.89-1.60 (m, 10H), 1.21 (s, 3H), 1.17 (s, 9H); LCMS (ESI, M+1): 611.5. —OH
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:22]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2cc(NC(=O)N3CCCC3)ncn2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
N-(6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl)pyrrolidine-1-carboxamide (0.320 g, 0.921 mmol) was dissolved in a mixture of 3:1 ethanol/water (8 ml). Then iron (0.276 g, 4.95 mmol) and ammonium chloride (0.0281 g, 0.525 mmol) was added to the mixture with stirring. The mixture was placed in a pre-heated oil bath (80° C.) for 1 hour. The oil bath was removed to allow the mixture to cool to ambient temperature. The mixture was filtered through a filter diskette. The flask was rinsed with methanol (3×10 ml) and filtered through diskette. Combined organic solution was concentrated in-vacuo. Then water was added to the mixture with stirring. The precipitate was collected by filtration and washed with hexanes. The solid was dried in a reduced-pressure oven to give the desired product N-(6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl)pyrrolidine-1-carboxamide (0.240 g, 0.756 mmol, 82% yield) as a yellow solid. MS (ESI pos. ion) m/z: 318 (MH+). Calc'd exact mass for C15H16FN5O2: 317. 1HNMR (300 MHz, CDCl3): 1.91-2.05 (s, 4H), 3.41-3.54 (t, 4H), 6.41-6.52 (m, 2H), 6.92-7.01 (t, 1H), 7.21 (s, 1H), 7.63 (s, 1H), 8.36 (s, 1H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(OCC)(=O)C.[Pd]>[NH2:18][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC2CCCCC2)c(N)c1

Procedure:
A solution of compound 45 (2.03 g, 7.29 mmol) in a mixture of methanol (25 mL) and ethyl acetate (25 mL) was hydrogenated over 10% palladium on carbon (0.20 g) at 25 psi for 15 h. The reaction mixture was filtered and concentrated to afford compound 46 as a crude grey-brown oil (1.99 g, 100%). ESI-MS m/e 249.3 (M+1).