Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:8][C:7](=[O:9])[CH:6]([O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[O:2][CH3:1])[CH2:10][CH3:11])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CCC(Oc1ccccc1OC)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccccc1OC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 96.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.42 g of (2RS)-2-(2-methoxyphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:7]=2[CH2:6]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH:4]=[C:5]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[O:9][C:8]4[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:7]=4[CH2:6]3)[CH2:32][CH2:33]2)=[CH:24][CH:23]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: Oc1cccc2c1CC(=CCCBr)c1cccnc1O2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(F)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 23 h
Yield: 38.6 %

Procedure:
To a solution of 5-(3-bromopropylidene)-5,11-dihydro-7-hydroxy-[1]benzoxepino[2,3-b]pyridine (2.59 g) in DMF (10 ml) was added 4-(4-Fluorophenyl)-4-hydroxypiperidine (1.02 g) and triethylamine (835 μM). The solution was stirred at room temperature for 23 hours. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel chromatography (87:10:3 ethyl acetate:methanol:triethylamine) to yield 0.9 g (39%) of the title compound. 1H-NMR (DMSO) d: 1.64-1.69 (2H, m), 1.74-1.85 (2H, m), 2.27-2.52 (8H, m), 4.81 (1H, s), 5.16 (2H, brs), 6.08 (1H, t), 6.62-6.71 (3H, m), 7.12 (2H, t), 7.40-7.51 (3H, m), 7.72 (1H, dd), 8.48 (1H, dd), 9.09 (1H, s).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1[C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=2)[N:21]=1>CC(C)=O>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:26]=3)[N:21]=2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(CCS)c1ccccc1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2nc1SCCS(=O)(=O)c1ccccc1
Temperature: 70 °C
Yield: 70 %

Procedure:
206 mg (1.5 mmol) K2CO3 and 303 mg (1.5 mmol) 2-(phenylsulfonyl)ethanethiol were added to a solution of 827 mg (1.0 mmol) 2-chloro-6-(trifluoromethyl)quinoline-3-carboxylic acid (precursor VVV03) in acetone (3 ml) and the mixture was heated for 5 h at 70° C. Then it was filtered and the filtrate was concentrated to small volume under vacuum. The residue was dissolved in water and acidified with a 1N hydrochloric acid. It was then extracted with EE and the organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Crystallisation (DCM/hexane) of the residue yielded 316 mg (0.7 mmol, 72%) 2-(2-(phenylsulfonyl)ethylthio)-6-(trifluoromethyl)quinoline-3-carboxylic acid.
Reaction SMILES: C([O:3][C:4]1[C:5](=[O:39])[C:6](=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[C:18]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:19]=3[N:20]=2)=[CH:11][CH:10]=1)C.Cl.[CH2:41]([NH2:43])[CH3:42].C(O)C.C(N(CC)CC)C>>[CH2:41]([NH:43][CH:6]1[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]4[CH3:37])[C:18]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)[C:4](=[O:3])[C:5]1=[O:39])[CH3:42]
Reactant: CCOc1c(Nc2ccc(-c3nc4c(c(N5CCOC[C@@H]5C)n3)CCN(c3ncccn3)C4)cc2)c(=O)c1=O
Reactant: CCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNC1C(=O)C(=O)C1Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncccn2)C3)cc1

Procedure:
Step 2—Synthesis of compound un: (S)-3-ethoxy-4-(4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenylamino)cyclobut-3-ene-1,2-dione (0.087 g, 0.00016 mol), Ethylamine Hydrochloride (0.0780 g, 0.000956 mol), and Ethanol (8.00 mL, 0.137 mol) were combined then added Triethylamine (0.230 mL, 0.00165 mol) and stirred overnight. The reaction mixture was concentrated, and chromatographed through silica gel (12 g, 0-5% MeOH in dichloromethane). 1H NMR (400 MHz, DMSO) δ 9.83 (s, 1H), 8.44 (d, J=4.7, 2H), 8.31 (d, J=8.7, 2H), 7.72 (s, 1H), 7.53 (d, J=8.5, 2H), 6.69 (t, J=4.7, 1H), 4.90 (d, J=18.7, 1H), 4.75 (d, J=18.6, 1H), 4.14 (t, J=9.3, 2H), 3.85 (dd, J=20.6, 7.2, 2H), 3.74-3.55 (m, 6H), 3.44 (t, J=11.9, 1H), 2.75 (s, 2H), 1.31-1.15 (m, 6H). LC/MS-m/z+527.3 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[NH:4]C[CH2:2]1.[CH2:10](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.BrCC(OCC1C=CC=CC=1)=O>C1COCC1>[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[C@H:6]([CH2:1][CH3:2])[CH3:10]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1
Agent: O=C(CBr)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 318.4 %

Procedure:
Using the procedure described in Example 5 and Example 17, L-homoproline-L-isoleucine benzylamide (43 mg, 0.13 mmol), was treated with triethylamine (91 uL, 0.65 mmol, 1.5 eq), and benzyl 2-bromoacetate (41 uL, 0.26 mmol, 2.0 eq) in THF (2.5 mL). Purification by HPLC provided 54.3 mg of L-isoleucine, N-[1-(2-(carbobenzyloxymethylene)-2-oxoethyl)-L-homoprolyl] benzylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][NH:10][C:9](=[O:19])[CH2:8][C:7]=2[CH:20]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:10]1[C:9](=[O:19])[CH:8]([CH2:12][C:6]2[CH:7]=[CH:20][CH:3]=[CH:4][CH:5]=2)[C:7]2[CH:20]=[C:3]([O:2][CH3:1])[C:4]([O:21][CH3:22])=[CH:5][C:6]=2[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NNC(=O)C2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)C(=O)N(Cc1ccccc1)N=C2c1ccccc1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 7,8-dimethoxy-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIaa (200 mg, 0.67 mmol) in DMF (10 ml), under an inert atmosphee, add NaH in oil (50 mg, 1.25 mmol). Then add dropwise benzyl bromide (150 μl, 1.26 mmol). After 2 hours at room temperature, evaporate the DMF. Take up the residue in CH2Cl2, wash twice with water. Dry the organic phases on Na2SO4. Purify by silica gel column chromatography (AcOEt/hexane, 4:1). Yield: 79%. 1H-NMR (200 MHz, CDCl3): d 3.35–3.56 (m, 2H, CH2Ph), 3.70 (s, 3H, OCH3), 3.80 (m, 1H, CH), 3.97 (s, 3H, OCH3), 4.87 (d, J=10.2, 1H, NCHPh), 5.30 (d, J=10.2, 1H, NCHPh), 6.61 (s, 1H, Ar), 6.93 (s, 1H, Ar), 7.06–7.42 (m, 13H, Ar), 7.59 (d, J=4.8, 2H, Ar). SM: 477 (M+H), 500 (M+H+Na).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]([CH2:24][CH:25]=[CH:26][Cl:27])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Cl:27][CH2:26][CH:25]1[C:2]2[C:11]3[CH:10]=[C:9]([S:12]([CH3:15])(=[O:13])=[O:14])[CH:8]=[CH:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:16]([C:17]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:23])[CH2:24]1
Reactant: CC(C)(C)OC(=O)N(CC=CCl)c1ccc2ccc(S(C)(=O)=O)cc2c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1ccc(S(C)(=O)=O)cc21
Yield: 66 %

Procedure:
A solution of 204 (1.60 g, 3.37 mmol) in dry benzene (30 mL) was treated with Bu3SnH (0.91 mL, 3.38 mmol) followed by AIBN (0.1 g, 0.6 mmol). The mixture was stirred under N2 at reflux for 2 h, then concentrated under reduced pressure. The residue was dissolved in EtOAc, and the solution was diluted with hexane and refrigerated. The resulting semisolid was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (19:1), and the product was triturated with i-Pr2O/hexane to give tert-butyl 1-(chloromethyl)-8-(methylsulfonyl)-1,2-dihydro-3H-benzo[e]indole-3-carboxylate (205) (0.88 g, 66%) as an amorphous solid: 1H NMR [(CD3)2SO] δ 8.41 (d, J=1.6 Hz, 1H), 8.2 (v br, 1H), 8.17 (d, J=8.6 Hz, 1H), 8.03 (d, J=8.9. Hz. H), 7.80 (dd, J=8.6, 1.8 Hz, 1H), 4.42-4.33 (m, 1H), 4.21 (t, J=10.4 Hz, 1H), 4.12 (dd, J=11.6, 2.9 Hz, 1H), 4.07 (dd, J=11.2, 3.4 Hz, 1H). 3.89 (dd, J=11.2, 7.1 Hz; 1H), 3.33 (s, 3H), 1.55 (s, 9H). Anal. (C19H22ClNO4S.½i-Pr2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: Cc1cccnc1C(=O)CBr
Product: CCOC(=O)n1c(C(=O)c2ncccc2C)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromoacetyl-3-methylpyridine (step 1). 1H-NMR (CDCl3) δ: 8.36 (1 H, dd, J=1.1, 4.8 Hz), 8.14 (1 H, d, J=1.8 Hz), 7.64 (1 H, ddd, J=0.7, 1.5, 7.0 Hz), 7.51 (1 H, dd, J=0.7, 8.4 Hz), 7.24 (1 H, d, J=1.8, 8.8 Hz), 7.22 (1 H, d, J=7.7 Hz), 6.05 (2 H, br s), 3.78 (2 H, q, J=7.3 Hz), 2.63 (3 H, s), 1.01 (3 H, t, J=7.3 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:32]([C:36]1[CH:60]=[CH:59][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52](/[C:55](=[N:57]/O)/[NH2:56])=[CH:51][CH:50]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[C:32]([C:36]1[CH:60]=[CH:59][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55](=[NH:56])[NH:57][O:14][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)=[CH:53][CH:54]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@H](Cc1ccc(/C(N)=N/O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCCCOc1ccc(C(=O)ONC(=N)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reaction time: 2 h

Procedure:
Prepared using General Procedure 5: To a solution of 4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6 mL) were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31 mmol). After stirring for 2 h, (S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N′-hydroxycarbamimidoyl)phenyl)-propanoate, INT-2 (673.3 mg, 1.69 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, partitioned between saturated aqueous NaHCO3 (15 mL) and EA (15 mL), and concentrated under reduced pressure to afford the intermediate (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy)carbamimidoyl)phenyl)propanoate. The intermediate was dissolved in DMF (10 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EA (10 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was extracted with water (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated. The brown oil was purified by chromatography (EA/hexanes) to afford 710 mg (77%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate as a white solid. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.3; no m/z observed, tR=12.80 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2, 8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H), 7.18 (d, J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3 Hz, 2H), 3.67 (s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08 (s, 4H), 1.74 (dd, J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz, 2H), 1.30 (d, J=14.5 Hz, 9H), 0.88 (t, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 174.05, 170.87, 133.81, 165.14, 161.43, 153.21, 140.51, 129.70, 128.85, 128.78, 126.06, 125.84, 123.93, 123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32, 33.47, 30.06, 29.74, 27.33, 27.24, 24.23, 20.89, 12.80.
Reaction SMILES: O[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:14])[N:3]=1.P(Cl)(Cl)([Cl:17])=O>O>[Cl:17][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[C:5]([C:6]#[N:7])=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1nc(O)c([N+](=O)[O-])c(C)c1C#N
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(C)c1C#N
Temperature: 100 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A mixture of 6-hydroxy-2,4-dimethyl-5-nitronicotinonitrile (step 2, 3.2 g, 16.6 mmol) and phosphorus oxychloride (20 mL) was stirred at 100° C. for 16 h. After cooling, the mixture was poured in water (100 mL). The resulting mixture was extracted with dichloromethane (3×100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated to afford 2.3 g (66%) of the title compound as brown solids: 1H-NMR (DMSO-d6) δ 2.82 (3H, s), 2.52 (3H, s).
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:35])[N:21]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[Pd].[OH-].[OH-].[Pd+2]>[CH2:31]([NH:30][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]([OH:29])=[C:19]([C:14]2[NH:13][C:12]3[CH:36]=[CH:37][C:9]([OH:8])=[CH:10][C:11]=3[S:16](=[O:17])(=[O:18])[N:15]=2)[C:20]1=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: C1CCOC1
Product: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Yield: 101.9 %

Procedure:
The product of Example 322B (0.045 g, 0.087 mmol) in tetrahyrofuran (8 mL) was reacted with a catalytic amount of palladium hydroxide on carbon, a catalytic amount of 5% palladium on carbon, and ammonium formate (0.03 g, 0.48 mmol) at 60° C. for 4 hours. The warm reaction mixture was filtered through celite® (diatomaceous earth) and the filtrate was evaporated under reduced pressure to give the title compound (0.038 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([OH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.CCOC(C)=O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:22])[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C(O)c3ccccn3)cc2OCc2ccccc2)S1(=O)=O
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C(=O)c3ccccn3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
To a solution of 5-[2-benzyloxy-4-(hydroxypyridin-2-yl-methyl)-phenyl]1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (45 mg, 0.085 mmol) in acetic acid (2 mL) is added iron powder (24 mg, 0.43 mmol) and the mixture is refluxed for 2 h. The reaction is diluted with EtOAc and filtered. The solvent is removed under reduced pressure and the crude material is purified by flash chromatography using a gradient of 0-50% EtOAc/hexane to afford the title compound as a yellow oil: (M+H)+=524.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=[O:31])/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([CH:23]1[C:22](=[O:31])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1NC(c2ccc(F)cc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccccc1
Product: O=C1Oc2[nH]c(-c3ccc(F)cc3F)nc2C(c2ccccc2)C1Cc1ccccc1
Reaction time: 72 h
Yield: 62 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,4-difluorophenyl)-1H-imidazol-5(4H)-one and trans-cinnamaldehyde. After 72 h, the unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 5i as an off-white solid (78 mg, 62%). Analytical data for 5i: 1H NMR (500 MHz, CDCl3) δ 9.43 (d, J=7.1 Hz, 1H), 8.15 (td, J=9.0, 6.4 Hz, 1H), 7.35-7.27 (m, 5H), 7.26-7.23 (m, 1H), 7.11-7.05 (m, 2H), 7.01-6.92 (m, 3H), 6.83 (ddd, J=12.4, 8.4, 2.5 Hz, 1H), 4.09 (d, J=7.1 Hz, 1H), 3.61 (ddd, J=10.1, 6.9, 4.6 Hz, 1H), 3.34 (dd, J=14.9, 4.6 Hz, 1H), 2.42 (dd, J=14.8, 10.1 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 169.0, 162.6 (dd, JCF=252.4, 12.8 Hz), 159.4 (dd, JCF=247.4, 11.2 Hz), 148.8, 137.9, 137.2, 136.7, 129.7 (dd, JCF=9.3, 4.8 Hz), 129.2, 129.0, 128.6, 128.3, 128.0, 126.8, 113.7 (dd, JCF=10.6, 3.5 Hz), 112.8 (dd, JCF=21.7, 3.1 Hz), 110.2 (d, JCF=3.5 Hz), 104.2 (t, JCF=26.3 Hz), 47.3, 38.4, 32.7; IR (film) cm−1 1771, 1632, 1597, 1535, 1494, 1448, 1267, 1138, 1124, 1105, 1090, 909, 850, 732, 697; LRMS (ESI): Mass calcd for [M+H]+ C25H19F2N2O2: 417.1. found 417.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel AD-H; 10% IPA/hexanes 1.0 mL/min, 280 nm), Rt1 (minor)=25.4 Rt2 (major)=30.9 min; er=98:2.
Reaction SMILES: [C:1]([NH2:9])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].O=C1CCC(=O)N1[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:20]=1>>[CH3:2][C:1]([NH:9][C:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:21][CH:20]=1)=[O:17])([CH3:3])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)NC(C)(C)CC(C)(C)C)cc1)c1ccccc1

Procedure:
The title product was prepared from tert-octylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester, preparative HPLC (method C) (26%, white crystals). HPLC-MS m/z=383.5 (M+1), Rt: 4.67 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-piperidin-4-yl-morpholine using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as an off white solid (50% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography to give 336 as an off white solid (21% yield). NMR (CDCl3, 400 MHz), 1.60-1.67 (2H, m), 1.86 (2H, d, J=12.2), 2.14 (2H, t, J=10.6), 2.17-2.23 (1H, m), 2.57-2.59 (4H, m), 3.05 (2H, d, J=11.7), 3.73-3.75 (4H, m), 3.83 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=497
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:24])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26].ClC1C=C(C=CC=1)C(OO)=[O:32].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:24])(=[O:32])=[O:23])[C:17]=3[CH:25]=2)[C:3]1=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)=O)c3c2)c1=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)(=O)=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-methyl-3-{3-[(methylsulfinyl)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.480 g, 1.24 mmol) and 3-chloroperoxybenzoic acid (0.600 g, 60%, 2.10 mmol) in methylene chloride is stirred at room temperature for four hours, washed with 5% sodium carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Flash column chromatography of the solid using silica gel and a 10% diethyl ether in methylene chloride solution gives the title product as a white solid which is identified by NMR spectral analyses.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[N:10][C:11]([Cl:17])=[CH:12][CH:13]=2)[N:8]=1.C(N(CC)CC)C.C(OC(C)C)(C)C>C(Cl)Cl>[Cl:17][C:11]1[N:10]=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])=[N:8]2)=[CH:13][CH:12]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: C=CC(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ccc(Cl)nc2n1
Yield: 8.3 %

Procedure:
Acryloyl chloride (42 g) is added with stirring in the course of 30 minutes to a solution of 2-amino-7-chloro-1,8-naphthyridine (54 g) and triethylamine (115 g) in methylene chloride (1875 cc). The solution obtained is heated for 1 hour under reflux and then poured into isopropyl ether (5000 cc). The precipitate obtained is filtered off, washed with isopropyl ether (3×200 cc) and then water (3×200 cc) at 40° C. and dried in the air. The crude product obtained is purified by flash chromatography (under 50 kPa) on a column 60 mm in diameter containing silica (500 g; 0.04-0.06 mm), eluting with a mixture (99:1 by volume) of methylene chloride and methanol and collecting 100-cc fractions. After concentration of fractions 5 to 10 to dryness at 40° C. under reduced pressure (4 kPa), N-(7-chloro-1,8-naphthyridin-2-yl)acrylamide (5.85 g), m.p. 200° C., is obtained.