Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[NH2:16][C:17](=O)[C@@H:18]([NH:37][C:38]([C:40]1([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:39])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[N:30]([CH3:36])[CH2:29]3)=[CH:22][CH:21]=1>ClCCl>[C:17]([C@@H:18]([NH:37][C:38]([C:40]1([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:50])[CH3:52])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:39])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[N:30]([CH3:36])[CH2:29]3)=[CH:22][CH:21]=1)#[N:16]
Reactant: CN1Cc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)ccc2C1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CN1Cc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.8 %

Procedure:
Burgess' reagent (638 mg) was added to (S)-tert-butyl 4-(1-amino-3-(4-(2-methyl-1-oxoisoindolin-5-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 31, step (iv), 718 mg) in dichloromethane (25 mL) at 20° C. under nitrogen. The resulting solution was stirred at room temperature for 17 h. The reaction mixture was diluted with dichloromethane, and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude material. The crude product was purified by chromatography on silica eluting with methanol/ethyl acetate (0:100 to 5:95) to afford sub-titled compound (436 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-(4-Chlorophenoxy)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., and then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(4-chlorophenoxy)pheny]carbamate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:4]=[C:5]([O:21][C:22](=[O:36])[N:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:6]2[N:7]=[CH:8][N:9]([C:19]=2[N:20]=1)[C@@H:10]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]1[OH:12].[CH3:37][O:38][C:39]1[CH:60]=[CH:59][C:42]([C:43](Cl)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)=[CH:41][CH:40]=1.C1(C)C=CC=CC=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:51][O:50][C:47]1[CH:46]=[CH:45][C:44]([C:43]([O:17][CH2:16][C@H:15]2[O:18][C@@H:10]([N:9]3[C:19]4[N:20]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([O:21][C:22](=[O:36])[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:6]=4[N:7]=[CH:8]3)[C@H:11]([OH:12])[C@@H:13]2[OH:14])([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:42]2[CH:59]=[CH:60][C:39]([O:38][CH3:37])=[CH:40][CH:41]=2)=[CH:49][CH:48]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Compound 5 (0.51 g, 1.05 mmol, 1.0 eq) and 4,4′-dimethoxytritylchloride (0.39 g, 1.14 mmol, 1.09 eq) were azeotroped three times with toluene for ˜15 h. To the dried compound 5, anhydrous pyridine (5 mL) was added. The mixture was stirred at room temperature under Ar atmosphere for 4 h. 4-Dimethylaminopyridine (0.09 g, 0.7 mmol, 0.7 eq) was subsequently added and stirring was continued for 17 h. The reaction was quenched with methanol (1 mL) and evaporated to dryness. The crude residue was dissolved in 50 mL of dichloromethane and washed with 5% sodium bicarbonate followed by saturated sodium chloride. The organic layer was dried over sodium sulfate and filtered. The product was then purified via silica gel chromatography using a solvent mixture of 90% dichloromethane, 9% methanol, 1% triethylamine to give 11 as a light yellow crystalline solid (0.56 g, 67%). TLC (CH2Cl2:MeOH, 9:1 v/v): Rf=0.4; 1H NMR (CD3OD, 400 MHz) 2.71 (br.s, 1H), 2.98-3.03 (q, 1H), 3.21 (d, J=3.2 Hz, 3H), 3.25-3.27 (m, 1H), 3.29-3.32 (m, 1H), 3.60 (d, J=4.8 Hz, 6H), 3.66 (m, 1H), 4.07-4.10 (m, 1H), 4.45 (m, 1H), 4.83 (m, 1H), 5.87 (d, J=4.8 Hz, 1H), 6.64-6.69 (m, 5H), 7.05-7.38 (m, 18H), 8.0 (s, 1H); 13C NMR ((CD3)2SO, 500 MHz) 28.8, 55.6, 72.2, 74.9, 82.3, 85.3, 87.7, 113.8, 114.0, 126.3, 127.8, 128.5, 128.7, 129.1, 129.2, 129.3, 129.9, 130.2, 130.4, 131.2, 141.2, 149.2, 159.9; ESI-MS (ES+) calculated for C45H42N6O8 794.3064, found 795.7 (M+H+), 303.4 ([(MeO)2Tr]+).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH:12]1([C:18]([O:20][CH:21]([O:23][C:24](ON2C(=O)CCC2=O)=[O:25])[CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC(OC)(C)C.CC(C)=O.O>[CH:12]1([C:18]([O:20][CH:21]([O:23][C:24]([NH:11][CH2:10][C@H:2]2[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]2)=[O:25])[CH3:22])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C1CCCCC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (780 mg, 5.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl cyclohexanecarboxylate (700 mg, 2.2 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 22 (200 mg, 26% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.99 (m, 2H), 1.20-1.44 (br. m, 11H), 1.58-1.81 (m, 7H), 1.89-1.92 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.27-2.35 (m, 1H), 2.79-2.90 (m, 2H), 6.66 (q, J=5.6 Hz, 1H), 7.48 (t, J=6.0 Hz, 1H), 12.05 (br. s, 1H). MS (ESI) m/z 378.13 (M+Na)+; 354.15 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23]C)=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C(=O)O)nc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)picolinate (200 mg, 0.60 mmol) was stirred at rt in THF/MeOH (1:1, v/v). 3N NaOH (0.2 mL, 0.60 mmol) was added and the resulting mixture was stirred at rt for 5 h. TLC indicated the reaction was complete. Most of the volatile solvent was evaporated under reduced pressure. The residue was acidified with 3N aq. HCl to pH˜5, and extracted with DCM (2×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)picolinic acid as a white semi-solid (200 mg, quantitative).
Reaction SMILES: [CH2:1]([C:3]1([C:13]([OH:15])=O)[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([C:3]1([C:13]([Cl:18])=[O:15])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)O)CCc2ccccc2C1
Reactant: O=S(Cl)Cl
Product: CCC1(C(=O)Cl)CCc2ccccc2C1
Reaction time: 120 h

Procedure:
A mixture of 2-ethyl-1,2,3,4-tetrahydro-2-naphthoic acid (22,0 g) and thionyl chloride is boiled for 5 days. The acid chloride is distilled. B.p. 110°-115° C./0.2 mmHg. Yield 21.6 g, 90%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH2:24][N:25]1[C:30](=[O:31])[CH2:29][N:28]([S:32]([CH:35]=[CH:36][C:37]2[S:38][C:39]([Cl:42])=[CH:40][CH:41]=2)(=[O:34])=[O:33])[CH2:27][C@@H:26]1[C:43]([CH3:51])([CH3:50])[O:44][SiH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])=O)(C)(C)C>C(Cl)Cl>[C:46]([SiH2:45][O:44][C:43]([CH3:51])([CH3:50])[C@@H:26]1[N:25]([CH2:24][C:16]2[NH:15][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH:17]=2)[C:30](=[O:31])[CH2:29][N:28]([S:32]([CH:35]=[CH:36][C:37]2[S:38][C:39]([Cl:42])=[CH:40][CH:41]=2)(=[O:33])=[O:34])[CH2:27]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)n1c(CN2C(=O)CN(S(=O)(=O)C=Cc3ccc(Cl)s3)C[C@@H]2C(C)(C)O[SiH2]C(C)(C)C)cc2cnccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CC(=O)N1Cc1cc2cnccc2[nH]1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.25 mL) is added to a solution of 2-{2-(R)-(tert-butyl-dimethyl-silanyloxymethyl)-4-[2-(5-chloro-thiophen-2-yl)-ethenesulfonyl]-6-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.025 g, 0.037 mmol) in CH2Cl2(0.5 mL) at room temperature. The reaction mixture is stirred for 2 h then concentrated to dryness. The residue is diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product (0.019 g, 0.033 mmol) is used in the subsequent step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](I)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27][C:28]1[N:33]=[C:32]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH:30][N:29]=1.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:30]3[CH:31]=[CH:32][N:33]=[C:28]([S:27][CH3:26])[N:29]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Reactant: Fc1ccc(-c2nc3c(OCc4ccccc4)cccn3c2I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(OCc4ccccc4)cccn23)n1
Temperature: 110 °C
Yield: 38.7 %

Procedure:
To a mixture of 8-(benzyloxy)-2-(4-fluorophenyl)-3-iodoimidazo[1,2-a]pyridine (0.15 g, 0.35 mmol) and dichlorobis(triphenylphosphine)palladium(II) (30 mg, 0.0035 mmol) in toluene (3 mL) was added 2-(methylsulfanyl)-4-(tributylstannyl)pyrimidine (0.19 g, 0.46 mmol). The mixture was heated to 110° C. in a sealed tube for 16 hours. The reaction was allowed to cool and was diluted with ethyl acetate before being poured into a 10% aqueous potassium fluoride solution. The mixture was extracted with ethyl acetate. The organic phase was concentrated and the residue purified by silica chromatography, eluting with dichloromethane and then 5% acetone in dichloromethane to yield 60 mg (39%) of 8-(benzyloxy)-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)pyrimidin-4-yl]imidazo[1,2-a]pyridine. 1H NMR (CDCl3): δ 9.18 (d, 1H), 8.33 (d, 1H), 7.68 (dd, 2H), 7.54 (2H), 7.41 (m, 3H), 7.16 (t, 2H), 6.83 (m, 2H), 6.70 (d, 1H), 5.46 (s, 2H), 2.67 (s, 3H). MS m/z 443 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[CH2:14]([O:16][C:17](=[O:37])[N:18]([C:26]1[CH:31]=[C:30](Br)[N:29]=[C:28]([NH2:33])[C:27]=1[N+:34]([O-:36])=[O:35])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:15]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:14]([O:16][C:17](=[O:37])[N:18]([C:26]1[CH:31]=[C:30]([C:8]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:11]=[CH:10][N:9]=2)[N:29]=[C:28]([NH2:33])[C:27]=1[N+:34]([O-:36])=[O:35])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:15]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: C[Si](C)(C)CCOCn1ccnc1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(-c2nccn2COCC[Si](C)(C)C)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (201 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (200 mg) and palladium bis(triphenylphosphine)dichloride (71 mg), giving the product (174 mg) as a yellow gum.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[Na+].[N+:17](CC)([O-])=O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:17]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C#N)c(O)c1
Temperature: 0 °C
Yield: 85.9 %

Procedure:
A mixture of the 2-hydroxy-4-methoxybenzaldehyde (20 g, 128.8 mmol), sodium acetate (35.05 g, 257.6 mmol) and nitroethane (19 mL, 257.6 mmol) in glacial acetic acid (100 mL) was heated at gentle reflux for 12 h. The reaction mixture was then poured into ˜1000 mL of ice water (1:1 ratio of ice and water). The product was extracted with ethyl acetate (3×200 mL). The organic extracts were washed with sodium bicarbonate solution until the aqueous layer had pH ˜8. The organic layers were then dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 2-hydroxy-4-methoxy-benzonitrile as a yellow oil (16.5 g, 86%). It was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[C@@H:4]([NH:13][C:14]([C:16]1[N:17]=[C:18]([CH2:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[C:21]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[CH:20]=2)=[O:15])[CH2:5][C:6]1[S:7]C(C=C)=[CH:9][CH:10]=1.O.C[N+]1([O-])CC[O:49]CC1.C(OCC)(=O)C.[CH3:59][C:60]([CH3:62])=[O:61]>[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:43])[C@@H:4]([NH:13][C:14]([C:16]1[N:17]=[C:18]([CH2:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[C:21]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[CH:20]=2)=[O:15])[CH2:5][C:6]1[S:7][C:59]([CH:60]([OH:61])[CH2:62][OH:49])=[CH:9][CH:10]=1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc(C[C@H](NC(=O)c2cc3ccc(Oc4ccc(C(C)(C)C)cc4)cc3c(CC3CCCC3)n2)C(=O)OC)s1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(C(O)CO)s1)NC(=O)c1cc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2c(CC2CCCC2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-vinylthiophen-2-yl)-propionic acid methyl ester (prepared in Example 9) (0.650 g, 1.09 mmol) in acetone:water was added methylmorpholine-N-oxide (0.340 mL) and osmium tetroxide (2 crystals). The solution was stirred at 0° C. for 1.5 h. Ethyl acetate was added and extracted with a solution of Na2S2O4(satd), brine, dried (Na2SO4), and concentrated under reduced pressure to give 0.600 g of 2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(1,2-dihydroxy-ethyl)-thiophen-2-yl]-propionic acid methyl ester.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:28](=[O:29])[O:27][C:8]2=[N:9][C:10]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)=[CH:11][CH:12]=[C:7]2[CH:6]=1)=O.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CCO>[S:32]1[CH:33]=[CH:34][N:35]2[CH:2]=[C:3]([C:5]3[C:28](=[O:29])[O:27][C:8]4=[N:9][C:10]([N:13]5[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:15][CH2:14]5)=[CH:11][CH:12]=[C:7]4[CH:6]=3)[N:30]=[C:31]12
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3cc(C(=O)CBr)c(=O)oc3n2)CC1
Reactant: Nc1nccs1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3cc(-c4cn5ccsc5n4)c(=O)oc3n2)CC1
Yield: 49.1 %

Procedure:
tert-Butyl 4-(3-(2-bromoacetyl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (132 mg, 0.28 mmol) in 5 mL of EtOH was treated with 2-aminothiazole (34.1 mg, 0.34 mmol) at room temperature. The solution was refluxed for 16 hours and concentrated under vacuum. The residue was purified on silica gel to provide tert-butyl 4-(3-(imidazo[2,1-b]thiazol-6-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (64.3 mg, 49%). MS m/z 468 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:47])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([C@@H:34]4[CH2:39][O:38][CH2:37][CH2:36][N:35]4C(OC(C)(C)C)=O)=[O:33])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:47])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([C@@H:34]4[CH2:39][O:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@@H]4COCCN4C(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@@H]4COCCN4)c3)c3ccccc23)cc1
Yield: 59.2 %

Procedure:
A solution of the carbamate (9) (30 mg, 0.04 mmol) in DCM/TFA (1:1 v/v, 2.0 mL) was stirred at RT for 1 hr and was then evaporated in vacuo. the resulting residue was subjected to capture and release on SCX and then triturated from DCM (5.0 mL) and isohexane (5.0 mL) to afford the title compound (Example 11) as a brown solid (15 mg, 63%): m/z 634 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.39 (3H, s), 2.73-2.92 (3H, overlapping m), 3.56-3.64 (4H, overlapping m), 3.82 (1H, m), 5.38 (2H, s), 6.34 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.42 (2H, m), 7.55-7.62 (3H, overlapping m), 7.91 (1H, m), 8.30 (1H, dd), 8.32 (1H, br s), 8.35 (1H, dd), 8.56 (1H, br s), 8.77 (1H, br s) 10.16 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)([C:30]3[CH:35]=CC(OC)=CC=3)S2)=CC=1.CI.[NH:42]1[CH2:47]C[NH:45][CH2:44][CH2:43]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:45]3[CH2:30][CH2:35][N:42]([CH3:47])[CH2:43][CH2:44]3)=[N:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Reactant: C1CNCCN1
Solvent: CI
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3cc(Cl)ccc3Oc3ccccc32)CC1
Temperature: 130 °C
Yield: 67.9 %

Procedure:
A mixture of 8-chloro-10H-dibenzo[b,f][1,4]oxazepin-11-one (189JO29C) (30 mg, 0.069 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (29 mg, 0.040 mmol) in toluene (2 mL) was heated in a capped tube using microwave assisted heating (130° C., 20 minutes). The reaction mixture was cooled to room temperature and MeI (38 μL, 0.29 mmol) was added and the resulting mixture was heated in capped tube using microwave assisted heating (120° C., 20 minutes). The mixture was concentrated the residue was taken up in pyridine (2 mL) and piperazine (24 mg, 0.29 mmol) was added. The resulting mixture was heated in a capped tube at 130° C. over night then heated using microwave assisted heating (160° C., 30 minutes). The mixture was concentrated, diluted with EtOAc and washed with water. The organic phase was dried (Na2SO4), concentrated and flash chromatographed (SiO2, toluene:EtOAc:MeOH, 4:2:0-2:2:1) to give 8.9 mg of the title compound (189JO47). MS (ESI) 328 (MH+). Purity for MH+ (UV/MS) 98/93.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6]2.Br[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:17]1[CH:18]=[C:19]([NH2:20])[CH:21]=[CH:22][CH:23]=1)[CH:7]=[CH:6]2
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
6-methoxy-naphthalene-2-boronic acid (0.140 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.06 g in 75% yield.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[N:4].[C:7]([N:11]=[C:12]=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:3]([C:2]([NH:6][C:12]([NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])([CH3:5])[CH3:1])#[N:4]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(N)C#N
Product: CC(C)(C)NC(=O)NC(C)(C)C#N
Reaction time: 0.08 h

Procedure:
In a nitrogen atmosphere, 24.8 g. (0.3 mole) 2-methyl-2-aminopropionitrile and 30.7 g. (0.3 mole) t-butyl isocyanate, 97%, are combined and stirred for 5 minutes. At the end of this period, the mixture is filtered and 1 ml. of pyridine is added to the filtrate. This mixture is heated in an oil bath for one and one-half hours, keeping the temperature of the bath below 70°. The solid is recrystallized from methanol:water, 60:40, to give N-(1-cyano-1-methylethyl)-N'-(1,1-dimethylethyl)urea, m.p. 204°-5°; Anal. Calcd. for C9H17N3O; C: 58.99, H: 9.35, N: 22.93; Found: C: 59.21, H: 9.26, N: 22.59.