Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[S:26][CH:27]=[C:28]([CH3:30])[N:29]=4)=[O:3])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1csc(N)n1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1csc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)n1
Yield: 17.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-methylthiazole (38.8 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methylthiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (11.5 mg).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]([N:26]([CH3:28])[CH3:27])[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[C:11]([O:13][C:14]([CH3:19])([CH3:18])[CH2:15][O:16][CH3:17])=[O:12])=[O:4].[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:29]1([CH2:2][C:3]([NH:5][C:6]2[N:7]=[C:8]([N:26]([CH3:28])[CH3:27])[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[C:11]([O:13][C:14]([CH3:19])([CH3:18])[CH2:15][O:16][CH3:17])=[O:12])=[O:4])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[CH:30]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COCC(C)(C)OC(=O)c1c(NC(=O)CBr)nc(N(C)C)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCC(C)(C)OC(=O)c1c(NC(=O)Cn2cnc3ccccc32)nc(N(C)C)n1-c1ccccc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
2-Methoxy-1,1-dimethylethyl 4-[(bromoacetyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate (35 mg, 1 eq), synthesized in an analogous manner/method as described for example 90), benzimidazole (2.5 eq) and K2CO3 (22 mg, 2 eq) were dissolved in DMF (5 mL). The reaction was stirred for 1 h at 75° C. The solvent was evaporated off and to the residue was added K2CO3(aq) (1 M, 50 mL) and extracted with ether. The organic phases were pooled, dried (MgSO4.H2O), filtered and evaporated. Eventually the crude material was purified by preparatory HPLC, which gave the desired pure product. Yield: 41%. 1H-NMR d (CDCl3): 1.29 (s, 6H), 2.68 (s, 6H), 3.27 (s, 2H), 3.31 (s, 3H), 5.3-5.9 (s, 2H), 7.24-7.32 (m, 4H), 7.41 (m, 4H), 7.80 (d, 1H), 8.02 (s, 1H), 9.50 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([CH2:24][S:25]([CH2:28][CH2:29][OH:30])(=[O:27])=[O:26])[CH:21]=[C:20]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[N:19]=2)=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[OH:30][CH2:29][CH2:28][S:25]([CH2:24][C:22]1[CH:21]=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:17][CH:16]=2)[N:23]=1)(=[O:26])=[O:27]
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)CCO)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)CCO)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.6 %

Procedure:
Phenyl chloroformate (0.046 mL, 0.36 mmol) was added to 2-[[2-(4-aminophenyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]ethanol (0.143 g, 0.36 mmol) and sodium bicarbonate (0.046 g, 0.55 mmol) in dioxane (20 mL) at RT under air. The resulting slurry was stirred at RT for 2 hours. Water was added and the mixture extracted with DCM three times. The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give the desired material as a yellow solid (0.228 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18](O)=[O:19])[N:10]=[C:9]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[C:8]=2[C:7]1=[O:31].Cl.CN.C[CH2:42][N:43](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN=C=NCCCN(C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:18]([NH:43][CH3:42])=[O:19])[N:10]=[C:9]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[C:8]=2[C:7]1=[O:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(=O)O)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](CC(C)C)Nc1nc(-c2cnn(C)c2)c2c(c1F)CN(Cc1ccc(OC)cc1OC)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of (R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanoic acid (48 mg, 0.094 mmol), methylamine hydrochloride (31.7 mg, 0.469 mmol) and DIPEA (49.2 μL, 0.281 mmol) in DMF (1 mL) was stirred at RT for 10 min. HATU (71.4 mg, 0.188 mmol) was added and the mixture was stirred at RT for 1 h, after which HPLC showed about 80% starting material remained. Additional methylamine (58.4 μL, 0.469 mmol, 33% in EtOH) was added, which resulted in little conversion of the starting material. The solvent was stripped off and the residue was dissolved in DMF (1 mL). To this solution was added EDCI hydrochloride (54.0 mg, 0.281 mmol), HOBT monohydrate (43.1 mg, 0.281 mmol), and methylamine hydrochloride (31.7 mg, 0.469 mmol). The reaction mixture was heated to 60° C. for 4 h. HPLC subsequently showed the reaction mixture contained 95% of desired product. The reaction mixture was allowed to cool to RT. Water (50 mL) was added and the mixture was extracted with DCM (3×50 mL). The organic layers were collected, dried over Na2SO4, filtered, and the solvent was stripped to dryness via rotary evaporation to yield the title compound, which was used without further purification. [M+H] calc'd for C27H33FN6O4, 525. found, 525.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][C:45]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH2:47][CH2:46]1>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:51][S:48]([C:45]3([CH3:44])[CH2:47][CH2:46]3)(=[O:50])=[O:49])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 58.1 %

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid etherate (105 mg, 0.177 mmol) and 1-methyl-cyclopropanesulfonic acid amide (31 mg, 0.23 mmol, prepared as described above). Flash chromatography (2% methanol/methylene chloride) gave 73 mg (58%) of [18-(isoquinolin-1-yloxy)-4-(1-methyl-cyclopropanesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: LC-MS (Method A, retention time: 3.50 min), MS m/z 710 (M++1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([OH:14])[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7].C(N(CC)CC)C.Cl.[C:24]1([C:30](=N)OCC)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C.CCCCCC>ClCCCl.C(O)C>[C:24]1([C:30]2[O:14][C@@H:5]([C:4]([O:3][CH3:2])=[O:15])[C@H:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccccc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)[C@@H]1OC(c2ccccc2)=N[C@H]1c1ccccc1
Reaction time: 0.17 h

Procedure:
(2R,3S)-3-Phenylisoserine methyl ester hydrochloride salt (5.76 g, 24.9 mmoles) was dissolved in 1,2-dichloroethane (75 ml). Triethylamine (2.77 g, 27.3 mmoles) was added and the resulting mixture was stirred for 15 minutes before the addition of the benzimidate prepared in step (a) above (4.62 g, 24.9 mmoles) in one portion. The mixture was stirred for 10 minutes, then heated to reflux. TLC after 4½ hours of reflux showed the reaction to be complete. (1:1 ethyl acetate/hexane, PMA/ethanol, U.V.)
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[N:10]([CH:12]=[N:13][N:14]=2)[CH:11]=1)C.C1C(=O)N(Br)C(=O)C1.[CH2:29]([NH:32][C:33]([NH2:35])=[S:34])[CH2:30][CH3:31]>O1CCOCC1.O>[C:15]1([C:8]2[C:9]3[N:10]([CH:12]=[N:13][N:14]=3)[CH:11]=[C:6]([C:5]3[S:34][C:33]([NH:32][CH2:29][CH2:30][CH3:31])=[N:35][CH:4]=3)[CH:7]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCNC(N)=S
Reactant: CCO/C=C\c1cc(-c2ccccc2)c2nncn2c1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1ncc(-c2cc(-c3ccccc3)c3nncn3c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A solution of (Z)-6-(2-ethoxyvinyl)-8-phenyl-[1,2,4]triazolo[4,3-a]pyridine (13 mg, 0.049 mmol) in 1,4-dioxane (1 mL) and water (1 mL) was added NBS (9.4 mg, 0.054 mmol) and stirred at rt for 1 h. The mixture was then added 1-propylthiourea (6.4 mg, 0.054 mmol), heated to 85-90° C. for 10 h, then cooled and concentrated. The residue was dissolved in a mixture of 20% MeOH in dichloromethane and purified by 500 μm silica gel prep plate using 75% ethyl acetate in hexanes as an eluent. The product was collected (4.5 mg, 27.4% yield). LCMS: 336.55 (M+H), Tr 2.98 min, (Conditions A).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)([CH3:34])([CH3:33])[CH3:32]>C1COCC1>[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12](=[O:13])[C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:15]=4)=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:43][CH:44]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CNC(=O)OC(C)(C)C)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 47.8 %

Procedure:
charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added (4-Amino-benzyl)-carbamic acid tert-butyl ester (55.3 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 48% (0.072 g, 0.119 mmol) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29](O)=[O:30])[C:26]([C:32]3[CH:33]=[N:34][N:35]([CH2:38][C:39]4([CH2:46][CH2:47][O:48][CH3:49])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[C:36]=3[CH3:37])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:50][S:51]([NH2:54])(=[O:53])=[O:52].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[CH:24]=[CH:25][C:26]([C:32]3[CH:33]=[N:34][N:35]([CH2:38][C:39]4([CH2:46][CH2:47][O:48][CH3:49])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]4)[C:36]=3[CH3:37])=[C:27]([C:29](=[O:30])[NH:54][S:51]([CH3:50])(=[O:53])=[O:52])[N:28]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COCCC1(Cn2ncc(-c3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2C)CCCCCC1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCC1(Cn2ncc(-c3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)NS(C)(=O)=O)c2C)CCCCCC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 134G (50 mg) in dichloromethane (2 mL) was added methanesulfonamide (7.4 mg), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (28 mg) and 4-dimethylaminopyridine (18 mg). The mixture was stirred overnight. The mixture was loaded on a silica gel column and eluted with 5% methanol in dichloromethane to give the pure product. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 8.03 (d, 1H), 7.79 (d, 1H), 7.60 (s, 1H), 7.41 (m, 5H), 7.30 (s, 1H), 7.00 (d, 1H), 4.96 (s, 2H), 3.94 (m, 2H), 3.83 (s, 2H), 3.42 (t, 2H), 3.41 (s, 3H), 3.27 (s, 3H), 3.21 (m, 3H), 3.11 (m, 2H), 2.12 (s, 3H), 1.45 (m, 16H)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=CCCCCC(=O)O)cc1
Agent: [Pd]
Product: CCOc1ccc(CCCCCCC(=O)O)cc1
Yield: 96.7 %

Procedure:
This compound was synthesized from 7-(p-ethoxyphenyl)-6-heptenoic acid (1.24 g, 5 mmol) and Pd/C (125 mg) by a hydrogenation reaction. Crystallization (petroleum ether) afforded the product (1.21 g, 97%) as white crystals (mp 65°-66° C.). IR: 3400-2500, 1715 cm-1 ; 1H-NMR: 1.32 (m, 7H), 1.55 (m, 5H), 2.30 (t, 2H), 2.50 (t, 2H), 3.95 (q, 2H), 6.90 (q, 2H), 10.20 (bs, 1H). Anal. Calcd. for C15H22O3 : C, 71.97, H, 8.86%; Found: C, 71.91, H, 8.87%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2([F:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:11](I)=[CH:10][N:9]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>[Pd].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.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.CC#N>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2([F:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:11]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:10][N:9]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CNc2cc(Cl)ncc2I)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cnc(Cl)cc2NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 48.1 %

Procedure:
MeCN (0.72 mL) and 0.5M aqueous sodium carbonate (0.24 mL, 1.5 eq.) were added to a mixture of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (37 mg, 0.079 mmol), 4-methoxyphenylboronic acid (11.97 mg, 0.079 mmol), and tetrakis(triphenylphosphine) palladium(0) (4.55 mg, 3.94 μmol) in a 0.5 mL microwave reaction vial. The sealed vial was heated at 100° C. for 20 mins by microwave irradiation. The volatiles were removed in vacuo. The residue was dissolved in dichloromethane and loaded onto a 12+S Biotage silica column. Chromatography, eluting with a gradient of EtOAc in hexanes, gave tert-butyl 4-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (17 mg, 0.038 mmol, 48%) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:25])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][C:3]=1[N+:26]([O-])=O>[Pd]>[NH2:26][C:3]1[CH:4]=[C:5]([C:8]2([OH:25])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1N
Yield: 98 %

Procedure:
A solution of 3-(4-amino-3-nitrophenyl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (10 g, 26.6 mmol) in a mixture of terahydrofuran-ethyl acetate (1:1, 20 mL) was hydrogenated over 10% Pd—C (100 mg) at 40 psi for 18 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford 3-(3,4-diaminophenyl)-3-hydroxy-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-one (9.0 g, 98%) as a brown powder. MS (EI) for C21H19N3O2: 368 (MNa+).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:37][CH3:38])=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([S:15][CH2:16][CH2:17][CH2:18][C:19]1[C:35]([OH:36])=[CH:34][C:22]3[CH2:23][CH:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:21]=3[CH:20]=1)[CH:9]=2)([O:3]C)=[O:2].CO.[OH-].[Na+]>>[C:1]([C:5]1[C:6]([O:37][CH3:38])=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([S:15][CH2:16][CH2:17][CH2:18][C:19]1[C:35]([OH:36])=[CH:34][C:22]3[CH2:23][CH:24]([CH2:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:25][C:21]=3[CH:20]=1)[CH:9]=2)([OH:3])=[O:2]
Reactant: COC(=O)c1cc2ccc(SCCCc3cc4c(cc3O)CC(CCc3ccccc3)O4)cc2nc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc2cc(SCCCc3cc4c(cc3O)CC(CCc3ccccc3)O4)ccc2cc1C(=O)O
Temperature: 75 °C
Yield: 21 %

Procedure:
A mixture of 6-[3-(3-carbomethoxy-2-methoxyquinolin-7-yl)thiopropyl]-5-hydroxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E26, (794 mg; 1.5 mmoles), methanol (12 mL) and 1N sodium hydroxide (12 mL) was heated in an oil bath at 75° C. and under nitrogen atmosphere for 45 minutes. The mixture was concentrated in vacuo to remove most of the methanol and the residue was neutralized with excess 25% ammonium acetate solution. The mixture was extracted with ethylacetate, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel using 65:30:5 hexane:ethylacetate:acetic acid as eluent to yield 165 mgs (21%) of 6-[3-(3-carboxy-2-methoxyquinolin-7-yl)thiopropyl]-5-hydroxy-2-(2-phenylethyl)-2,3-dihydrobenzofuran, E27, m.p. 157°-161° C.
Reaction SMILES: OO.[CH2:3]([O:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[C:21]#[N:22])=[N:18][C:17]([O:23][CH3:24])=[CH:16][CH:15]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].C(OCC)(=[O:29])C>CO.[O-2].[O-2].[Mn+4]>[CH2:3]([O:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:22])=[O:29])=[N:18][C:17]([O:23][CH3:24])=[CH:16][CH:15]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2ncc(OCc3ccccc3)c(C#N)c2n1
Reactant: CCOC(C)=O
Agent: [Mn+4]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncc(OCc3ccccc3)c(C(N)=O)c2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
30% Hydrogen peroxide (17.2 mmol, 5.0 eq) is added dropwise at room temperature to a stirred suspension of 3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-carbonitrile (1.0 g, 3.43 mmol, 1.0 eq) and sodium hydroxide (69 mg, 0.17 mmol, 0.05 eq) in methanol (100 mL). After 1 hour stirring at 70° C., a catalytic amount of manganese dioxide is added to the reaction mixture that is concentrated to give a crude that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 1:1, v/v) to afford 3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-carboxylic acid amide as a white solid (800 mg, 75% yield).
Reaction SMILES: O.O.O.[C:4]([O-:7])(=[O:6])[CH3:5].[C:8]([O-:11])(=[O:10])[CH3:9].[Pb+2].[CH3:13][C@@H:14]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26](O)[CH2:27][C@@H:28]2[OH:36])=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)[CH2:15]O.O>CN(C)C=O.C(OC(=O)C)(=O)C>[C:4]([O:7][C@H:26]1[CH2:27][C@H:28]([OH:36])[C@@:29]2([CH3:30])[C:24](=[CH:23][CH2:22][C@@H:21]3[C@@H:31]2[CH2:32][CH2:33][C@@:34]2([CH3:35])[C@H:20]3[CH2:19][CH2:18][C@@H:17]2[C@H:14]([CH3:15])[CH2:13][O:10][C:8](=[O:11])[CH3:9])[CH2:25]1)(=[O:6])[CH3:5]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h
Yield: 41.7 %

Procedure:
To a solution of 2.4 g of lead diacetate-trihydrate in 180 ml of dimethylformamide and 24 ml of acetic anhydride was added 4.6 g of (20S)-20-methylpregn-5-ene-1α,3β,21-triol. After standing at room temperature for 24 hr., the mixture was poured onto 1 kg of a 3:1 water--ice mixture and then extracted with ether. The ether extract was washed with water, dried (Na2SO4) and evaporated by means of a water aspirator. The residue was chromatographed on 100 g of silica gel. Elution with 1:1 hexane--ether afforded 1.14 g (20%) of (20S)-3β,21-diacetyloxy-20-methylpregn-5-en-1α-ol, mp 148°-149°. Elution with ether gave first 0.24 g (4.6%) of (20S)-3β-acetyloxy-20-methylpregn-5-ene-1α,21-diol, mp 202°-203° and then 2.94 g (57%) of (20S)-21-acetyloxy-20-methylpregn-5-ene-1α,3β -diol, mp 121°-121°. Finally, elution with ethyl acetate afforded 0.79 g (17%) of starting triol.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([CH2:11][O:12][C:13]3[C:14]([F:23])=[C:15]([C:19]([F:22])=[CH:20][CH:21]=3)[C:16]([NH2:18])=[O:17])=[N:10][C:5]2=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[F:23][C:14]1[C:13]([O:12][CH2:11][C:9]2[S:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=3)=[CH:21][CH:20]=[C:19]([F:22])[C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)c1c(F)ccc(OCc2nc3ccc(Br)nc3s2)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc3ccc(-c4ccccc4)nc3s2)c1F
Temperature: 120 °C
Yield: 41.1 %

Procedure:
To a solution of 3-(5-bromo-thiazolo[5,4-b]pyridin-2-ylmethoxy)-2,6-difluoro-benzamide (0.20 g, 0.49 mmol) in 4 ml of DMF and water (2.0 ml) was added phenyl boronic acid (0.12 g, 0.99 mmol) and potassium phosphate (0.13 g, 0.59 mmol). The reaction mixture was degassed for 10 minutes followed by addition of dichlorobis(tri phenyl phosphine) palladium (II) (0.070 g, 0.099 mmol). The reaction mixture was heated at 120° C. for 2 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 60% EtOAc-Hexane) to get the desired product (0.080 g, 41%) as a beige solid. 1H NMR (DMSO-d6, 400 MHz): δ 5.74 (s, 2H), 7.10 (m, 1H), 7.41-7.56 (m, 4H), 7.85 (m, 3H), 8.19 (m, 1H), 8.71 (br s, 1H) and 8.98 (br s, 1H). MS ES+ (398.09), HPLC (method I) Rt=16.07 min.