Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[N:9]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1)=[C:10]=[S:11]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:10]([NH:9][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1)=[S:11]
Reactant: Cc1ccc(Cn2c(CC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: Nc1ccncc1N
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(CC3CCN(CCNC(=S)Nc4cnccc4N)CC3)nc3ccccc32)cc1
Yield: 100 %

Procedure:
A mixture of 5.2 parts of 3,4-pyridinediamine, 19 parts of 2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-1-[(4-methylphenyl)methyl]-1H-benzimidazole and 225 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 24 parts (100%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[1-[(4-methylphenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]thiourea (405).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29](Br)[CH3:30]>O1CCCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]([N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:30]
Reactant: CC(Br)c1ccccc1Br
Reactant: c1cncc(Nc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ccccc1Br)N(c1cccnc1)c1cccnc1
Reaction time: 0.5 h
Yield: 237.5 %

Procedure:
To a cooled solution (−78° C.) of N-pyridin-3-ylpyridin-3-amine (0.886 g, 5.23 mmol) in dry tetrahydrofuran (20 mL) was added LDA (3.8 mL of a 1.5 M solution, 5.75 mmol) to form a light yellow suspension. After stirring for 30 min, 1-bromo-2-(1-bromoethyl)benzene (3-1) (1.38 g, 5.23 mmol) was added in one portion. The reaction was stirred for 30 min at −78° C. then allowed to warmn to 0° C. and quenched with NH4Cl sat. solution (6 mL). The mixture was diluted with water and extracted with THF (2×20 mL), washed with brine and the organic layer was dried over Na2SO4. The solution was then filtered, concentrated, and dried under vacuum to give crude N-(1-(2-bromophenyl)ethyl)-N-(pyridin-3-yl)pyridin-3-amine (3-2) as a light brown solid (4.40 g): Analytical LCMS: (214 nm), 2.043 min. m/e (m+1): 356.1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]2[CH:25]=[CH:24][C:12]([C:13]([NH:15][C@H:16]([C:21](O)=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])=[C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=2)[CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:44][S:45]([NH:48][C:21](=[O:22])[C@H:16]([CH2:17][CH2:18][S:19][CH3:20])[NH:15][C:13](=[O:14])[C:12]1[CH:24]=[CH:25][C:9]([CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:47])=[O:46]
Reactant: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)O
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)NS(C)(=O)=O
Temperature: 47.5 °C
Reaction time: 8 h

Procedure:
A solution in THF (5 mL) of [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine (143 mg, 0.32 mmol), prepared as in Example 235, and carbonyldiimidazole (136 mg, 0.84 mmol) was stirred overnight at 45-50° C. A 1.6 mL aliquot of the reaction mixture was removed and to it was added methanesulfonamide (78 mg, 0.82 mmol) and DBU (0.12 mL, 0.80 mmol) and the mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between ethty acetate and pH 4 water. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatographyl on silica gel (98.5:1.5:0.5 chloroform-methanol-acetic acid) gave [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine methylsulfonyl amide. (31 mg after azeotroping and lyophilization). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, 1H), 8.39 (d, 1H), 8.18 (d, 1H), 7.50 (m, 4H), 7.36 (m, 6H), 5.28 (s, 2H), 4.27 (m, 1H), 3.21 (s, 3H), 2.20 (t, 2H), 2.02 (s, 3H), 1.81 (m, 2H). MS (APCI) m/e 514 (M+H)+. Anal calcd for C25H27N3O3S2.1.25H2O: C, 56.01; H, 5.55; N, 7.84. Found: C, 55.72; H, 5.08; N, 8.18.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[Si:3]([O:10][CH:11]1[CH2:12][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:14]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB2) (400 mg, 1.09 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (318 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and then diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 40 to 100% ethyl acetate in isohexane followed by 0-20% methanol in ethyl acetate to afford the product (532 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.83 (9H, s), 2.45 (3H, s), 3.61-3.90 (4H, m), 4.47-4.60 (2H, m), 4.69 (1H, m), 6.22 (1H, m), 7.36-7.48 (3H, m), 7.51-7.57 (1H, m), 8.03 (1H, s), 8.38 (1H, s), 8.50 (1H, s), 9.27 (1H, s), 10.31 (1H, s); m/z (ES+) (M+H)+=595; HPLC tR=2.63 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Yield: 47 %

Procedure:
To a 3 ml of methylene chloride solution of 772 mg of N-tert-butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol synthesized in Step A, a 3 ml of trifluoroacetic acid was dropwise added under ice cooling. The resultant mixture was stirred at room temperature for 2 hours, then adjusted by 10% aqueous sodium hydroxide solution to pH=9 to 10 and extracted with ether. The extract was dried, filtered, then concentrated under reduced pressure to give a residue, which was then recrystallized from ether/methylene chloride to give 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine in an amount of 250 mg (yield 47%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:45][O:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C>[CH3:45][O:46][CH:47]1[CH2:52][CH2:51][N:50]([C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]([CH3:15])[CH3:14])[CH2:49][CH2:48]1
Reactant: COC1CCNCC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC1CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-methylbutanoic acid (2.0 g, 9.21 mmol) and TBTU (2.96 g, 9.21 mmol) were mixed in DMF (20 mL). The mixture was cooled to 0° C. and NMM (1.518 mL, 13.81 mmol) was dropwise added. After stirring for 10 min was 4-methoxypiperidine (1.272 g, 11.05 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (50 mL). The organic layer was washed with HCl (1M aq. solution, 100 mL), NaHCO3 (saturated, 2×100 mL) and brine (100 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (isocratic; DCM/MeOH, 95:5, KP-SIL 100 g column). The solvent was removed under reduced pressure to give the title compound (1.75 g, 60%). 1H NMR (400 MHz, CD3OD) δ 0.69-1.09, 1.24-1.71, 1.72-2.10, 3.09-3.27, 3.36, 3.39-3.60, 3.60-4.15, 4.20-4.49. Total no of protons: 30.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@@:9]1([CH3:30])[C@H:14]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:12]2([CH3:13])[C:11](=[O:29])[CH2:10]1)[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3)[CH3:8].[Cl-].[NH4+]>O1CCCC1>[CH3:8][CH2:7][C@:9]1([CH3:30])[C@H:14]2[C@H:15]3[C@H:24]([CH2:25][CH2:26][C@:12]2([CH3:13])[C@H:11]([OH:29])[CH2:10]1)[C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=1[CH2:17][CH2:16]3
Reactant: CC[C@]1(C)CC(=O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC[C@@]1(C)C[C@@H](O)[C@@]2(C)CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.3 %

Procedure:
Lithium aluminum hydride (58 mg; 0.31 mmol) was added to a solution of the 15β-ethyl-15β-methyl ketone (5) (100 mg; 0.31 mmol) in dry tetrahydrofuran (2 ml) at 0°C. The solution was stirred at 0° C. for 5 min. Saturated aqueous ammonium chloride was added and the mixture was filtered. Standard work-up of the filtrate gave 15β-ethyl-3-methoxy-15α-methylestra-1,3,5(10)-trien-17β-ol (13) (92 mg; 90%), as an oil, [α]D +70° (c 1.0); νmax 3604 cm-1 (OH); δH 0.88 (3H, t, J 7.2 Hz, 15β-CH2CH3), 0.90 (3H, s, 15α-Me), 1.10 (3H, s, 13β-Me), 1.51 obsc (2H, m, 15α-CH2CH3), 1.73 obsc (2H, m, 16α- and 16β-H), 2.84 (2H, m, 6-H2), 3.74 (1H, dd, J 9.9 and 8.2 Hz, 17α-H), 3.78 (3H, s, 3-OMe), 6.63 (1H, d, J 2.8 Hz, 4-H), 6.71 (1H, dd, J 8.4 and 2.8 Hz, 2-H), and 7.21 (1H, d, J 8.4 Hz, 1-H); δc 8.6 (C-15 2), 13.9 (C-18), 25.9 (C-151), 28.6 (C-11), 29.0 (C-7), 29.9 (C-6), 30.3 (C-12), 36.8 (C-8), 39.0 (15α-Me), 40.0 (C-15), 45.2 (C-9), 45.5 (C-4), 55.2 (3-OMe), 59.6 (C-13), 79.5 (C-16), 80.0 (C-17), 111.4 (C-2), 113.6 (C-4), 126.2 (C-1), 133.0 (C-10), 137.7 (C-5), and 157.5 (C-3).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH3:39])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH:22]2[CH2:37][OH:38])(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[C:12]1([CH3:39])[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH:22]2[CH2:37][O:38][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CC(CO)N(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CC(OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a cooled solution of 1.83 g (9.6 mmoles) 4-toluenesulfonyl chloride in 10 mL pyridine at +10° C. was added 3.40 g (8 mmoles) of 1-(4-toluenesulfonyl)-2-hydroxymethyl-4-(4-toluenesulfonyloxy)-pyrrolidine and the mixture was stirred 18 hours. The solution obtained was then poured into 50 mL ice-cooled 2N hydrochloric acid. The precipitate was filtered, washed with water and ether. The crystalline product was purified in boiling water and ether. The crystalline product was purified in boiling ethanol to give 3.94 g of titled compound. MP 153° C. [α]D =+46.7° (c=1.9,acetone)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][CH2:19][CH3:20])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:21][S:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:23]>>[O:17]=[C:16]1[NH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])/[C:12]/1=[C:4]1/[NH:5][C:6]2[C:11]([C:2]([C:30]3[CH:31]=[C:26]([NH:25][S:22]([CH3:21])(=[O:23])=[O:24])[CH:27]=[CH:28][CH:29]=3)=[CH:3]/1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CCCC1=NNC(=O)/C1=C1/C=C(c2cccc(NS(C)(=O)=O)c2)c2ccccc2N1

Procedure:
The tile compound was synthesized from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 3-(methylsulfonamido)phenylboronic acid using Suzuki coupling conditions. The final compound was purified by LC-MS. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.33 Hz, 3H) 1.71 (td, J=14.53, 6.82 Hz, 2H) 2.94 (t, J=7.33 Hz, 2H) 3.09 (s, 3H) 7.33 (d, J=7.83 Hz, 1H) 7.41 (d, J=1.77 Hz, 2H) 7.50-7.61 (m, 2H) 7.69 (s, 1H) 7.77-7.83 (m, 2H) 7.99 (d, J=8.34 Hz, 1H) 10.04 (s, 1H); ESI-MS: m/z calc'd for C22H22N4O3S 422.5. found 423.3 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][CH2:35][CH2:36][Mg]Br.O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]([OH:33])[CH:35]([CH3:36])[CH3:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCC[Mg]Br
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (100 mg) in tetrahydrofuran (3 mL) was added (2-methylethyl)magnesium bromide (1M tetrahydrofuran solution, 650 μL), and the mixture was stirred at −20° C. for 30 min and then overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (40.0 mg, yield 37%) as a pale-yellow amorphous solid. MS: 509 (MH+).
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=[O:2].[CH3:8][C:9]([CH3:79])([CH3:78])[C@H:10]([NH:71][C:72](=[O:77])[C@@H:73]([NH:75][CH3:76])[CH3:74])[C:11]([N:13]1[C@H:17]([C:18](=[O:30])[NH:19][C@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)[CH2:16][C@H:15]([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][C@@H:36]([C:58]([NH:60][C@H:61]4[C:70]5[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=5)[CH2:64][CH2:63][CH2:62]4)=[O:59])[N:37]([C:41](=[O:57])[C@@H:42]([NH:50][C:51](=[O:56])[C@@H:52]([NH:54][CH3:55])[CH3:53])[C:43]([S:46]CCO)([CH3:45])[CH3:44])[CH2:38]3)=[CH:33][CH:32]=2)[CH2:14]1)=[O:12]>>[CH3:79][C:9]([CH3:8])([CH3:78])[C@H:10]([NH:71][C:72](=[O:77])[C@@H:73]([NH:75][CH3:76])[CH3:74])[C:11]([N:13]1[C@H:17]([C:18](=[O:30])[NH:19][C@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)[CH2:16][C@H:15]([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][C@@H:36]([C:58](=[O:59])[NH:60][C@H:61]4[C:70]5[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=5)[CH2:64][CH2:63][CH2:62]4)[N:37]([C:41](=[O:57])[C@@H:42]([NH:50][C:51](=[O:56])[C@@H:52]([NH:54][CH3:55])[CH3:53])[C:43]([S:46][CH2:3][C:1]([OH:7])=[O:2])([CH3:44])[CH3:45])[CH2:38]3)=[CH:33][CH:32]=2)[CH2:14]1)=[O:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)SCCO)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)SCC(=O)O)[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
A solution of TFA (20% in CH2Cl2, 1.06 mmol) was added to Compound F of Example 28 (13 mg, 0.011 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The crude oil was purified by preparative HPLC to give the title compound (2.5 mg, 18%) as a white solid after lyophilization. MS (ESI+) m/z 1021.6 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][CH:15]2[C:40](=[O:41])[N:17]3[C:18]([C:24]([O:26]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)(=[O:4])=[O:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][CH:15]2[C:40](=[O:41])[N:17]3[C:18]([C:24]([OH:26])=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)(=[O:3])=[O:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (4.5 g) in methylene chloride (30 ml) and anisole (4.6 g) was added 2,2,2-trifluoroacetic acid (16.8 g) under ice-cooling, and the solution was stirred at ambient temperature for an hour. After evaporation of the reaction mixture, thereto were added water and ethyl acetate, followed by adjusting to pH 7 with 1N aqueous solution of sodium hydroxide. To the separated aqueous layer were added ethyl acetate and tetrahydrofuran, followed by adjusting to pH 2 with 10% hydrochloric acid. After the organic layer was separated out, it was washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain 7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (1.5 g).
Reaction SMILES: [C:1]([NH:8][NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=O.S(Cl)(Cl)=O>ClCCCl.C(Cl)Cl>[CH2:6]([O:5][C:3]([C:1]1[O:20][C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)=[N:9][N:8]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(=O)NNC(=O)c1ccc(OCC)cc1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1nnc(-c2ccc(OCC)cc2)o1
Yield: 77.2 %

Procedure:
A solution of 22 g of 1-ethoxalyl-2-(4-ethoxybenzoyl)-hydrazine and 28 g of thionyl chloride in 157 ml of anhydrous 1,2-dichloroethane is heated under reflux, whilst stirring vigorously, until the evolution of gas has ceased (that is to say about 4 hours). The solvent and excess thionyl chloride are driven off in vacuo (50° C., 20 mm Hg). The residue is taken up in 150 ml of methylene chloride and the methylene chloride solution is successively washed with 2×30 ml of water, then with 30 ml of a 20% strength potassium bicarbonate solution and then with 2×30 ml of water. It is dried over anhydrous sodium sulphate. The solvent is driven off under reduced pressure (20 mm Hg, 50° C.). The solid residue is then recrystallized from isopropanol. 15.9 g of 2-ethoxycarbonyl-5-(4-ethoxyphenyl)-1,3,4-oxadiazole, which melts at 93° C., are obtained. The structure is confirmed by infrared spectrography.
Reaction SMILES: Cl[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH2:12][CH3:13])=[N:7][C:6]=2[N:14]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:12]([S:11][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:2]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=3)=[N:14][C:6]=2[N:7]=1)[CH3:13]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCSc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Temperature: 150 °C

Procedure:
7-chloro-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidine (6-3) (0.80 g, 2.66 mmol) was combined with 4-formylphenylboronic acid (1.0 g, 6.64 mmol), cesium carbonate (4.30 g, 13 mmol), and bis(tri-t-butylphosphine)palladium (0.136 g, 0.266 mmol) in dioxane (10 mL) and heated in a microwave reactor at 150° C. for 60 min. The reaction mixture was diluted with water and extracted with CH2Cl2. he combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (35% EtOAc in hexane) to give 4-[2-(ethylthio)-6-phenylpyrido[2,3-d]pyrimidine-7-yl]benzaldehyde. LRMS m/z (M+H) Calcd: 372.5, found: 372.5
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])OC(C)(C)C)#[N:2].Cl.N1C=CC=CC=1.[C:34]([O:37][C:38](C)([CH3:42])[C:39](Cl)=O)(=[O:36])[CH3:35]>>[C:34]([O:37][C:38]([CH3:42])([CH3:39])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:3]=1[C:1]#[N:2])=[O:19])(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)C(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
To a solution of tert-butyl 6-(2-cyano-3-nitrophenoxy)hexylcarbamate (333 mmol, 121 mg) (Example 277c) in dixoane (2 mL) was added con. HCl (1 mL). After 15 minutes, the solution was concentrated in vacuo and dried on high vacuum. The crude HCl salt was suspended in DCM (dry, 10 mL) and treated with pyridine (2.664 mmol, 215 μL) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (1.332 mmol, 193 μL). The reaction mixture was refluxed under a nitrogen atmosphere until clear (6 h), then cooled to room temperature and the volatiles removed in vacuo. The residue was purified on silica gel (40% to 100% EtOAc in hexanes) to give the product (117 mg, 90%) as a light yellow heavy oil. MS 392 (MH+).