Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH2:27][CH2:26]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
Cis-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate (4.0 g, 0.0079 mol) was triturated in anhydrous dichloromethane (75 mL) and the reaction mixture was cooled to 0° C. Trifluoroacetic acid (10 mL) was added dropwise and the resulting solution was warmed up to ambient temperature and stirred under an atmosphere of nitrogen for 1.5 hours. The solvents were removed under reduced pressure, the residue suspended in water (70 mL) and basified with saturated aqueous sodium bicarbonate solution. It was extracted with dichloromethane (3×150 mL), the combined organic extracts were dried with magnesium sulfate and the solvent was removed under reduced pressure to yield cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.0 g, 0.00739 mol) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=O.P(Br)(Br)([Br:20])=O>>[Br:20][C:1]1[C:2]2[C:3]([N:8]=[C:9]3[C:17]=1[CH:16]=[CH:15][CH:14]=[C:10]3[CH3:11])=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1ccccc1Nc1ccccc1C(=O)O
Reactant: O=P(Br)(Br)Br
Product: Cc1cccc2c(Br)c3ccccc3nc12
Temperature: 120 °C
Yield: 83.5 %

Procedure:
2-(2′-Methylphenylamino)benzoic acid 7 (1.0 g, 4.4 mmol) was suspended in 11.0 g (38 mmol) of phosphorus oxybromide, and the mixture was heated to 120° C. for 2 hours. Excess phosphorus oxybromide was removed by distillation and the residual solution was poured into a 1:1 mixture of aqueous ammonium hydroxide:CH2Cl2. The CH2Cl2 solution was separated, dried, filtered, and the combined organic layers were dried in vacuo to give 9 (1.0 g, 85%) as a yellow powder. 1H-NMR δ=2.94 (s, 3H), 7.53 (dd, J=8.5 Hz, J=8.8 Hz, 1H), 7.59-7.69 (m, 2H), 7.78 (ddd, J=1.4 Hz, J=8.5 Hz, J=8.5 Hz, 1H), 8.28 (dd, J=8.5 Hz, J=8.5 Hz, 2H), 8.43 (dd, J=1.4 Hz, J=8.8 Hz, 1H). 13C-NMR δ=19.48, 126.37, 128.49, 128.76, 129.07, 129.28, 129.72, 130.95, 131.15, 131.88, 135.87, 138.12, 148.43, 148.71. Anal. calcd. for C14H10NBr: C, 61.79; H, 3.70; N, 5.15. Found: C, 61.40; H, 3.72; N, 5.05.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccccc1Cl
Yield: 91.1 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (45 mg, 0.12 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2-chloro-phenylboronic acid (27 mg, 0.17 mmol) and Pd[PPh3]4 (13 mg, 0.012 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (46 mg, 94%). LC-MS m/e 421.27 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].CN1CCOCC1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([C:34](=[O:37])[CH2:35][CH3:36])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CCC(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cc[nH]n2)cc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43.4 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-pyrazol-3-yl)-propionamide (prepared in example 2, 100 mg, 0.25 mmol) was dissolved in methylene chloride (2 mL). N-Methyl-morpholine (31 μL, 0.28 mmol) was added followed by propionyl chloride (26 μL, 0.28 mmol). The reaction stirred at 25° C. for 2.5 h. The solution was diluted with ethyl acetate (25 mL), washed with water (2×15 mL), saturated aqueous saturated aqueous brine solution (2×15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-propionyl-1H-pyrazol-3-yl)-propionamide (49 mg, 43%) as a white powder: ESI-LRMS m/e calcd for C21H26ClN3O4S [M+] 451.1, found 452.2 [M+H+], 396.0 [M−COCH2CH3+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.24 (m, 2H, CH2), 1.27 (t, J=7.3 Hz, 1H, CH3), 1.44-1.97 (m, 8H, 4×CH2), 2.14-2.32 (m, 1H, CH), 2.99 (q, J=7.3 Hz, 2H, CH2), 3.27 (s, 3H, SO2CH3), 3.57 (t, J=7.5 Hz, 1H, CH), 6.98 (d, J=2.1, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.5 Hz. 1H, Ar), 7.59 (d, Jm=1.5 Hz, 1 H, Ar), 7.81 (s, 1H, NH), 8.10-8.15 (m, 2H, Ar).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19]SC)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][Cl:25])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CSCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(OCCl)cc2C1
Reaction time: 1 h

Procedure:
To a solution of 7-methylthiomethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (9.6 g) in methylene chloride (100 ml) was added a solution of sulfuryl chloride (2.75 ml) in methylene chloride (30 ml) under an argon atmosphere and with ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The solvent was evaporated and toluene was added to the obtained residue to filter off insoluble material. The solvent was evaporated and dried under reduced pressure to give the title compound (7.4 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:5]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1>O1CCOCC1>[Cl:51][C:48]1[N:47]=[CH:46][C:45]([CH2:44][NH:43][C:2]2[N:3]=[C:4]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:5]=[C:6]([NH:8][N:9]=[CH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)[N:7]=2)=[CH:50][CH:49]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Fc1ccc(Nc2nc(Cl)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2nc(NCc3ccc(Cl)nc3)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
{4-Chloro-6-[N′-(4-trifluoromethoxybenzylidene)hydrazino]-1,3,5-triazin-2-yl}-(4-fluoro-3-trifluoromethylphenyl)amine (XXI) (2.54 g, 5.14 mmol) was dissolved in dioxane (25 mL). To this solution was added diisopropylethylamine (1.8 mL, 10.3 mL) followed by 3-aminomethyl-6-chloropyridine (0.52 mL, 5.17 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was removed under vacuum and the residue dissolved in ethyl ether (40 mL). This solution was rinsed with brine, dried over magnesium sulfate, filtered and concentrated to give a dark yellow oil which was purified by column chromatography (silica, gel, hexane/EtOAc), to afford desired product 2 (0.93 g, 32% yield).
Reaction SMILES: [C:1](NC1NC(=O)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC)(=O)C(C)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CO>N1C=CC=CC=1>[S:33]([CH3:1])([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
(see FIG. 8B) N2-Isobutyryl-2′-O-methylguanosine (6) (Inoue et al., Nucleic Acids Res. 1987, 15, 6131-6148, and is incorporated by reference herin in its entirety) (1.6 g, 4.36 mmol) was dissolved in dry pyridine (25 mL) and the solution was cooled to 0° C. while protected from moisture. p-Toluenesulfonyl chloride (1.0 g, 5.23 mmol) was added and the reaction mixture was left at 0-3° C. for 48 h. MeOH (10 mL) was added and the mixture evaporated to a syrup. After standard work up and column chromatography using 1-2% MeOH in CH2Cl2, 7 was obtained as a colorless foam, 1.06 g (47%), 1H NMR δ12.25 (br s, 1H, NH), 9.55 (br s, 1H, NH), 7.83 (d, JH,H=8.3, 2H, Ts), 7.78 (s, 1H, H8), 7.42 (d, JH,H=8.3, 2H, Ts), 5.83 (d, J1′,2′=6.2, 1H, H1′), 4.82 (app t, J2′,3′=5.7, 1H, H2′), 4.64 (m, 1H, H3′), 4.37 (dd, J5′,4′=2.2, J5′,5″=10.3, 1H, H5′), 5.23 (dd, J4′,5″=2.9, J4′,3′=5.2, 1H, H4′), 4.29 (dd, J5″,4′=2.9, J5″,5′=10.3, 1H, H5″), 3.47 (s, 3H), OMe), 2.76 (m, 1H, CH(CH3)2), 2.51 (s, 3H, Ts-Me),1.29 (m, 6H, 2×Me).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:3]=1[CH2:4][CH:5](C(OCC)=O)[C:6](OCC)=[O:7].Cl>C(O)(=O)C>[F:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:2]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:7])[NH:1]2
Reactant: CCOC(=O)C(Cc1c(N)cccc1F)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C1CCc2c(F)cccc2N1
Temperature: 90 °C

Procedure:
To a stirred solution of diethyl 2-(2-amino-6-fluorobenzyl)malonate (146-3; 2.0 g, 0.00706 mol)) in acetic acid (20 mL) was added hydrochloric acid (20 mL). The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was cooled to room temperature and then poured into ice cold water. It was extracted with ethyl acetate (3×40 mL). The combined organic layer was washed with 10% aqueous sodium hydroxide solution, saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to afford the title compound. 1H NMR (400 MHz, DMSO) δ 10.219 (s, 1H), 7.164-7.108 (q, J=7.6 Hz, 1H), 6.769-6.725 (t, J=8.4 Hz, 1H), 6.684-6.664 (d, J=8.0 Hz, 1H), 2.871-2.832 (t, J=7.6 Hz, 2H), 2.472-2.434 (t, J=8.0 Hz, 2H). MS (M+1): 166.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][C:6]2[C:7](=[O:32])[C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[BH4-].[Na+].Cl.N>CO.O>[OH:32][CH:7]1[C:6]2[CH:33]=[C:34]([O:35][CH3:36])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=3)[CH2:17]2)[C:8]1=[O:31]
Reactant: COc1cc2c(cc1OC)CC(N(C)CCCN1CCc3cc(OC)c(OC)cc3C(=O)C1=O)CC2
Agent: Cl
Agent: N
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)CC(N(C)CCCN1CCc3cc(OC)c(OC)cc3C(O)C1=O)CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Here, 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (0.70 g 0.0014 mol) is dissolved in a mixture of methanol/water=(95:5, 21 ml) then sodium borohydride (0.060 g, 0.0016 mol) is added and the mixture is stirred for 20 minutes at ambient temperature. It is then acidified with hydrochloric acid (2 mol/l), made alkaline with methanolic ammonia and extracted with methylene chloride, dried over magnesium sulphate, concentrated by evaporation and the residue is purified over a column [alumina N (50 g), activity II, eluant: methylene chloride and then with increasing amounts of ethanol (up to 3%)]. The residue is dissolved in acetone and mixed with ethereal hydrochloric acid. The precipitate obtained is suction filtered, washed with ether and dried. Yield: 0.18 g. Mp: 141°-143° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:12])[CH3:2].C1(=O)O[CH2:16][CH2:15][O:14]1>[Br-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:12][CH2:16][CH2:15][OH:14])=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cccc(C=O)c1O
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCOc1cccc(C=O)c1OCCO
Temperature: 140 °C
Yield: 70 %

Procedure:
A mixture of 40 g of 3-ethoxysalicylaldehyde, 22 g of ethylene carbonate and 40 g of tetraethylammonium bromide was heated at 140° C. for 4 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture, the solid substance was filtered off, the filtrate was washed with water and the organic phase was dried over magnesium sulphate and evaporated. The residue was distilled under reduced pressure. Yield 70%. Boiling point 0.1 140°-145° C.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:21])=[C:14]([NH:16][C:17]([NH:19][CH3:20])=[S:18])[CH:15]=1>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:21])=[C:14]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH3:20])[C:17]2=[S:18])[CH:15]=1
Reactant: CNC(=S)Nc1cc(Cl)ccc1C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1N1C(=O)C(=O)N(C)C1=S
Yield: 72.2 %

Procedure:
Ethyl chlorooxoacetate (16.3 g; 0.128 mol) was added dropwise to the solution N-(5-chloro-2-methylphenyl)-N′-methylthiourea (10.7 g; 0.05 mol) in chloroform (200 mL). The mixture was heated at reflux for 4 hours then evaporated to dryness. The residue was treated with ether (200 mL). The precipitated solid was collected by filtration and dried to give 9.7 g of 1-(5-chloro-2-methylphenyl)-3-methyl-2-thioxo-4,5-imidazolidinedione, m.p. 171–173° C. Mass spectrum; (El, M.+) m/z268/270. 1H-NMR (DMSO-d6; 300 MHz): δ 7.50–7.47 (m, 1H), 7.42–7.40 (m, 2H), 3.31 (s, 3H), and 2.15 ppm (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C@@H:24]([NH:26][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:15][CH:14]=2)[CH3:25])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc([C@H](C)N)c1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc([C@H](C)NC(=O)c2ccc(-c3ccncc3)cc2)c1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A mixture of 4-(pyridin-4-yl)benzoic acid (0.970 g, 4.87 mmol), (S)-1-(3-methoxyphenyl)ethanamine (0.884 g, 5.84 mmol), DIEA (1.7 ml, 9.8 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.87 g, 5.82 mmol) in DMF (10 ml) was stirred overnight, diluted with EtOAc, washed with 1N NaOH, sat NaHCO3, and brine, dried (Na2SO4), and chromatographed (20-85% EtOAc/dichloromethane) and triturated (Et2O) to give the title compound (1.075 g, 3.23 mmol) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:42])[CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)[C:12](=[O:43])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+].[CH3:45][N:46]=[C:47]=[O:48].C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:45][NH:46][C:47]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:42])[CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)[C:12](=[O:43])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=[O:48]
Reactant: CN=C=O
Reactant: O=C(Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g of the raw product of Step A of Example 1 was added under nitrogen to a mixture of 5 ml of dimethylformamide and 0.5 ml of methyl isocyanate at 5° C. and 0.5 ml of methyl isocyanate was added thereto. After 30 minutes at 5° C., another 0.5 ml of methyl isocyanate was added and after stirring 2 hours at room temperature, the mixture was poured into 75 ml of an aqueous 6% NaHCO3 solution. The mixture was extracted with ethyl acetate and the extracts were washed with sodium bicarbonate solution. The combined aqueous phases were added to ethyl acetate and the mixture was acidified with 6 N hydrochloric acid to a pH of 2. The mixture was decanted and the aqueous phase was extracted with ethyl acetate. The organic extracts were washed with water, dried and concentrated to dryness and the residue was empasted with isopropyl ether and was vacuum filtered. The product was taken up with methylene chloride and the solution was treated with activated carbon and was vacuum filtered. The filtrate was evaporated to dryness and the residue was crystallized from isopropyl ether to obtain 331 mg of 3-methylcarbamoyloxymethyl-7β-[2-(2-tritylamino-4-thiazolyl)-acetamido]-ceph-3-eme-4-carboxylic acid melting at about 210° C. Thin layer chromatography: Rf=0.42 (80-15-5-ethyl acetate-acetic acid-water).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:6]=1.[Br:17]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:14])[F:15])=[N:5][N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nnc(-c2ccccc2C(F)(F)F)s1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1-c1nnc(CBr)s1
Temperature: 25 °C

Procedure:
172 mg (0.70 mmol) of the compound from Example 72A together with 251 mg (1.41 mmol) of N-bromosuccinimide and 12 mg (0.07 mmol) of 2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride were heated under reflux for 8 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 33 mg (15% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:13]([NH2:23])=[CH:12][N:11]=3)[C:6]=2[CH:24]=1.[C:25]1([CH2:31][C:32](O)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH:16][CH:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[C:13]([NH:23][C:32](=[O:33])[CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:12][N:11]=3)[C:6]=2[CH:24]=1
Reactant: Nc1cnc(-n2cnc3ccc(F)cc32)nc1NC1CCOCC1
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: O=C(Cc1ccccc1)Nc1cnc(-n2cnc3ccc(F)cc32)nc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To the solution of 10 mg (0.030 mmol) 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-N4-(tetrahydro-2H-pyran-4-yl) pyrimidine-4,5-diamine in 1 mL acetonitrile was added 16 mg (0.12 mmol) of phenylacetic acid and 20 mg (excess) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The solution was stirred for 1 hr at room temperature. Solvent was removed under vacuum and column chromatography with 5% MeOH in DCM provided 10 mg (75%) pale yellow solid as the desired amide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]([CH:20]([F:22])[F:21])[S:18][CH:19]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:21][CH:20]([F:22])[C:17]1[S:18][CH:19]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:16]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: FC(F)c1cc(Br)cs1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2csc(C(F)F)c2)C1=O
Yield: 8.4 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 4-bromo-2-difluoromethyl-thiophene (179.6 mg, 0.8474 mmol), 1,4-dioxane (5 mL), copper iodide (16.14 mg, 0.08474 mmol), trans-1,2-diamino cyclohexane (29.1 mg, 0.2542 mmol) and potassium phosphate (539.59 mg, 2.542 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 22 mg of the product (8.5% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH2:10][CH2:11][C:12](=[CH2:25])[CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1.CC([O-])=O.[Na+].[Na+].[I-:39].CC1C=CC(S(NCl)(=O)=O)=CC=1>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH:12]([CH2:25][I:39])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Reactant: [I-]
Agent: B
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Solvent: C1CCOC1
Product: O=C(CCC(CI)CCC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
Compound B4 (176 mg, 0.5 mmol) was dissolved in anhydrous THF (0.5 mL). The solution was cooled to 0° C. and BH3-THF (2.0 M, 0.25 mL, 0.5 mmol) was added via a syringe. The solution was then stirred at room temperature for 1 h. Methanolic NaOAc (3.0 mL, 1.0 M, 3.0 mmol), aqueous NaI (3.0 mL, 1.0 M, 3.0 mmol) and methanolic chloramine-T (6.0 mL, 0.5 M, 3.0 mmol) were added sequentially to the organoborane solution at room temperature. The reaction mixture were stirred for 10 min at room temperature and then quenched with aqueous Na2S2O3 (1.0 M). The mixture was partitioned between Et2O (50 mL) and H2O (50 mL) and the organic layer was washed with brine (30 mL) before drying over Na2SO4. The solvent was evaporated and the residue was subjected to silica chromatography (CH2Cl2/hexanes, 2/100 to 7/100) to yield compound 1b (85 mg). The yield was 35%. 1H NMR (200 MHz, CDCl3) δ 7.37 (m, 10H), 5.11 (s, 4H), 3.21 (d, 2H, J=8.0 Hz), 2.37 (m, 4H), 1.68 (m, 4H), 1.20 (m, 1H); 13C NMR (50 MHz, CDCl3) δ 173.2, 136.3, 129.1, 128.8, 66.9, 37.5, 31.8, 29.9, 14.5; MS (MALDI-TOF) calcd (M+Na+) 503.3, found 503.8.