Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9](O)[CH3:10].FC(F)(F)C(O)=O.[NH:19]=[N+:20]=[N-:21]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:19]=[N+:20]=[N-:21])[CH3:10]
Reactant: CC(O)c1c(F)cccc1F
Reactant: [N-]=[N+]=N
Solvent: O=C(O)C(F)(F)F
Product: CC(N=[N+]=[N-])c1c(F)cccc1F
Reaction time: 24 h

Procedure:
10 g (63 millimoles) of 1-(2,6-difluorophenyl)ethanol are dissolved in 150 ml of hydrazoic acid (1.2N in toluene). To this solution are added 22.8 g (200 millimoles) of trifluoroacetic acid and the reaction mixture is allowed to stand for 24 hours at room temperature. After dilution with 300 ml of hexane, the reaction solution is washed first with water, then with sodium bicarbonate solution until free of acid and dried over sodium sulfate. The solvent is subsequently removed at 40°-50° C. under reduced pressure. The residue is dissolved in 100 ml of hexane and the solution is filtered through 50 g of silica gel and concentrated by evaporation once more, affording 1-(2,6-difluorophenyl)ethyl azide as a colourless oil.
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:19][C:14]2[C:15]([O:17][CH3:18])=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(C(CF)CF)CC2

Procedure:
5-Chloro-N(2)-[3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N(4)-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was prepared from 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 308c. Product isolated as a white foam (60 mg, 30%). LCMS (m/e) 589 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.29 (d, 1H, J=8.7 Hz), 8.14 (s, 1H), 8.04 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 5.52 (d, 1H, J=8.7 Hz), 4.75-4.67 (m, 2H), 4.63-4.56 (m, 2H), 3.94 (s, 3H), 3.93-3.89 (m, 4H), 3.88 (s, 3H), 3.2-3.10 (m, 5H), 2.93-2.79 (m, 8H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.[CH2:21]([O:23][C:24](=[O:38])[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[CH2:27]Br)[CH3:22]>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][CH2:27][C:26]([O:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)=[CH:25][C:24]([O:23][CH2:21][CH3:22])=[O:38])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1ccc(OC)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C=C(CN[C@@H](CC(C)C)C(=O)OC)Oc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.64 g, 3.56 mmol) in acetonitrile (8.9 mL) was treated with N,N-diisopropylethylamine (0.57 mL, 3.49 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.57 mL, 3.49 mmol) and acetonitrile (8.9 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (1.02 g, 3.23 mmol) in acetonitrile (8.09 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 20-30% ethyl acetate/hexanes) afforded (S)-2-[3-ethoxycarbonyl-2-(4-methoxy-phenoxy)-allylamino]-4-methyl-pentanoic acid methyl ester (0.84 g, 68%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H), 1.30-1.50 (m, 2H), 1.63-1.81 (m, 1H), 3.60 (s, 3H), 3.77 (s, 3H), 3.88 (dd, J=6.5, 3.2 Hz, 1H), 3.96 (d, J=6.9 Hz, 1H), 4.01 (d, J=6.9 Hz, 1H), 4.61 (s, 1H), 7.02 (s, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]OS(C)(=O)=O)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[ClH:39].CO>CC(C)=O>[ClH:39].[ClH:39].[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: CN1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)CC1
Temperature: 15 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
The solid from Step 8 (assume 0.232 mol) was dissolved in acetone (700 mL) and this solution was added over 45 mins to a cooled (internal temp 15-17° C.) suspension of K2CO3 (48 g) and N-methylpiperazine (50 mL, 0.45 mol) in acetone (330 mL). The suspension was stirred at 15° C. for 3 h (complete removal of starting material by tlc) when the solution was evaporated to a small volume and the residue partition between EtOAc (1000 mL) and a mixture of water (500 mL) and saturated brine (50 mL). The organic phase was washed with a mixture of water (500 mL) and saturated brine (150 mL) and finally washed with saturated brine (300 mL). The solution was dried (MgSO4) and filtered and to this solution was added 1M-HCl in MeOH (430 mL, 0.43 mol). The suspension was cooled (0° C. for 30 mins) and the solid removed by filtration which was washed with EtOAc and then heptane on the sinter and the solid dried (oil-pump, RT 72 h) to give crop 1 of the title compound 66.34 g (65%) as a colourless solid. 1H NMR (400 MHz, Me-d3-OD): 7.64-7.51 (m, 2H), 7.51-7.29 (m, 6H), 5.23 (s, 2H), 4.79 (dd, J=16.2, 6.1 Hz, 4H), 4.49 (s, 2H), 3.66 (s, 8H), 3.03 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].C([N-]C1CCCCC1)(C)C.[Li+].[I:25]I>C1COCC1>[I:25][C:5]1[O:1][C:2]([P:6]([O:7][CH2:8][CH3:9])(=[O:10])[O:11][CH2:12][CH3:13])=[CH:3][CH:4]=1
Reactant: II
Reactant: CCOP(=O)(OCC)c1ccco1
Agent: CC(C)[N-]C1CCCCC1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(I)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of diethyl 2-furanphosphonate (prepared as described in Step A, Example 1) (1 mmol) in 2 mL THF was cooled to −78° C. and added to a solution of lithium isopropylcyclohexylamide (LICA) (1 mmol) in 2 mL THF at −78° C. over 20 min. The resulting mixture was stirred −78° C. for 20 min and added into a solution of iodine (1 mmole) in 1 mL TIF at −78° C. over 20 min. The mixture was then stirred at −78° C. for 20 min. Extraction and chromatography provided diethyl 5-iodo-2-furanphosphonate as a yellow oil.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:25])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:26]=[S:27]1(=[O:41])[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:41]=[S:27]1(=[O:26])[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:14]4[CH:15]=[C:10]([NH:9][C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:8])[CH:11]=[CH:12][C:13]=4[Cl:25])=[CH:17][CH:18]=3)=[O:23])=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: O=C(O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CN2CCS(=O)(=O)CC2)cc1)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reaction time: 18 h
Yield: 21.6 %

Procedure:
A mixture of 5′-(cyclohexanecarbonyl-amino)-2′-chloro-biphenyl-4-carboxylic acid (100 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (67 mg), triethylamine (0.098 ml) and HBTU (159 mg) in dry DMF (5 ml) was stirred at 20 C for 18 h. The mixture was then evaporated to dryness and purified via reversed-phase preparative HPLC (eluting with acetonitrile/water) to afford the title compound as an orange solid (35 mg).
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.C(N(C(C)C)CC)(C)C.N1C2[C:39](=[CH:40][CH:41]=CC=2)[CH2:38][CH2:37]1>C(#N)C>[CH3:26][C:13]1[S:12]/[C:11](=[N:10]\[C:8]([N:5]2[C:4]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:7][CH2:6]2)=[O:9])/[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:14]=1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: c1ccc2c(c1)CCN2
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)N2CCc3ccccc32)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (62 mg, 0.13 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (28 μL, 0.16 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added indoline (17 mg, 0.14 mmol) dissolved in acetonitrile (0.7 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[C:10](=[O:20])[CH:9]=2)[CH:7]=1.[NH:23]1[C:27]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)=[N:26][N:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][CH3:19])[C:15]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([C:27]4[NH:26][N:25]=[N:24][N:23]=4)=[CH:29][CH:30]=3)=[O:17])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: CCC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CCC(C(=O)Nc1ccc(-c2nnn[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
212 mg (purity 60%, 0.4 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) (Example 3.1C) and 31 mg (0.19 mmol) of 4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1. Yield: 143 mg (77% of theory)
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([N+:34]([O-])=O)[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:34][C:32]1[CH:31]=[CH:30][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:33]=1
Reactant: CN(CCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1)C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 107 %

Procedure:
To a suspension of 99 (30 mg, 0.058 mmol) in EtOH (1.6 ml) and water (0.6 ml) was added ammonium chloride (3 mg, 0.9 eq, 0.053 mmol) and Fe (28 mg, 8.5 eq, 0.49 mmol) and the reaction mixture was heated to reflux for 45 min. The reaction mixture was cooled to RT, filtered through celite then concentrated to afford title compound 100 (30 mg, 100% yield). MS (m/z): 484.1 (M+H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][N:31]([CH3:38])[C:32](=[O:37])[CH2:33][CH2:34][NH:35][CH3:36]>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:35]([CH3:36])[CH2:34][CH2:33][C:32]([N:31]([CH3:38])[CH3:30])=[O:37])[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CNCCC(=O)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)CCC(=O)N(C)C)nc2c1C#N

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.84 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.16 ml, 0.94 mmol) and N,N-dimethyl-3-(methylamino)propionamide (I-149) (0.11 g, 0.84 mmol) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[CH:10]=[C:9]2[OH:17]>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11](=[O:16])[C:10]([N+:1]([O-:4])=[O:2])=[C:9]2[OH:17]
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=c1oc2ccc(Cl)cc2c(O)c1[N+](=O)[O-]

Procedure:
Red fuming nitric acid (10 mL) was added to a stirred suspension of 6-Chloro-4-hydroxy-chromen-2-one (2.0 g, 10.17 mmol) in chloroform (200 mL) at 0° C. The resultant solution was stirred at 0° C. for 1.5 h, quenched with water (80 mL), the organics separated and treated with saturated NaHCO3 when a thick yellow solid fell out of solution. The solid was filtered and the filtrate acidified with 3N HCl (pH 2) and extracted with chloroform. The organic extracts were dried to a yellow powder and all solids were combined and identified as 6-chloro-4-hydroxy-3-nitro-chromen-2-one. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.78 (d, 1H), 7.55 (dd, 1H), 7.23 (d, 1H).
Reaction SMILES: [CH2:1]1[CH:6]2[CH:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:5]2[C:4]([C:21]([OH:23])=[O:22])=[C:3]([Cl:24])[CH2:2]1.O.Cl.OC1C=CC(C(OCC)=O)=CC=1>C(O)C>[CH:17]1[CH:16]=[CH:15][C:14]([C@@H:13]([NH2:20])[C:11]([NH:10][C@@H:7]2[C:8](=[O:9])[N:5]3[C@@H:6]2[CH2:1][CH2:2][C:3]([Cl:24])=[C:4]3[C:21]([OH:23])=[O:22])=[O:12])=[CH:19][CH:18]=1
Reactant: N[C@@H](C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CCC12)c1ccccc1
Agent: CCOC(=O)c1ccc(O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.2 %

Procedure:
The pH of aqueous loracarbef monohydrate mother liquor (1000 ml, having 9.23 mg/ml of loracarbef monohydrate) was adjusted to 3.6 with HCl. Ethyl p-hydroxybenzoate (ethyl paraben) (4.52g) in ethanol (36 ml) was added dropwise over 15 minutes. After approximately 5 minutes, precipitation occurred, resulting in white crystals. The mixture was stirred overnight (15 hrs) at room temperature, filtered, washed with H2O, and dried under vacuum at 40° C. The yield was 11.72 g having a potency of 73.5% as loracarbef, and the theoretical yield was 8.78 g as loracarbef, resulting in a percent yield of 98.2%. The loracarbef:ethyl paraben exhibited the following X-ray powder diffraction pattern:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:16]C)=[C:10]([O:14]C)[C:11]=2[F:13])[C:6](=[O:18])[C:5]([C:19]([O:21]CC)=[O:20])=[CH:4]1)[CH3:2].B(Br)(Br)Br>ClCCl.CCO>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:16])=[C:10]([OH:14])[C:11]=2[F:13])[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(OC)c(OC)cc2c1=O
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCn1cc(C(=O)O)c(=O)c2cc(O)c(O)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 1-ethyl-8-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (24 g, 74.2 mmol) in Dichloromethane (DCM) (300 mL) was added boron tribromide (35.1 mL, 371 mmol) at −78° C. The mixture was warmed up to rt and stirred at 25° C. overnight. LCMS indicated completion of the reaction. The mixture was diluted with EtOH and concentrated in vacuo. The same procedure was repeated several times to afford 1-ethyl-8-fluoro-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (18 g, 67.4 mmol, 91% yield) as a yellow solid. This product was used in next step reaction without further purification. LCMS (M+H)+: 268.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].Cl[C:26]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[C:28]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]=1>CN(C)C=O>[C:38]1([C:28]2[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:31]=[C:26]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:22])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:27]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g (28.2 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene are dissolved in 225 ml of dimethylformamide under a protective-gas atmosphere, and 1.5 g of NaH, 60% in mineral oil (37.5 mmol), are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (8.5 g, 31.75 mmol) in 75 ml of dimethylformamide is added dropwise. The reaction mixture is then stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene. The yield is 12 g (23 mmol, 83%).
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([S:28]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 0.22 mmol) in CH2Cl2 (4 ml) was treated with butane-1-sulfonyl chloride (56 μl, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, dried (MgSO4) and evaporated. The residue was dissolved in EtOAc (5 ml) and extracted into 2M HCl (10 ml). The aqueous phase was then basified using 2M NaOH to pH=8 and extracted with CH2Cl2 (2×10 ml). The combined organic phases were dried (MgSO4) and evaporated to afford the title compound: RT=3.29 min, m/z (ES+)=351.2 [+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1.CC#N>CN(C=O)C.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[NH2:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(-c3ccc(S(N)(=O)=O)cc3)cc3[nH]ncc23)cs1
Temperature: 135 °C
Reaction time: 18 h
Yield: 6.7 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (101 mg) was dissolved in DMF (0.4 ml) and added to 4-bromobenzenesulfonamide (42.5 mg) in DMF (0.4 ml). Chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (4 mg, heaped microspatula) was added to the reaction which was then heated under microwave irradiation at 135° C. for 20 min. The reaction was loaded onto a C18 SPE pre-conditioned with MeCN:0.1% TFA (aq), eluted with 3 ml MeCN:0.1% TFA (aq) then evaporated to dryness. The residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The residue was then dissolved in IPA (0.3 ml) and 2M NaOH (0.3 ml) was added. The reaction was stirred at RT for 18 h then diluted with DMSO (0.6 ml) and purified by MDAP (method D) to give the title compound (5 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(Cl)(Cl)=O.N1C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: CO
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10 g of 2,6-dimethylbenzoic acid in 22 g thionyl chloride was stirred at reflux temperature for 2 hours. Removal of the excess thionyl chloride afforded the crude acid chloride as a yellow oil. This intermediate was added to a stirred solution of 4 mL of methanol in 10.8 mL pyridine at 65°-70° C. After completion of the addition, the resulting mixture was stirred at room temperature for 2 hours and then poured into 75 mL ice-water. The aqueous layer was extracted with four 50-mL portions of ether and the combined organic extracts were back-washed with saturated sodium bicarbonate solution, 5% aqueous hydrochloric acid, and water. Drying and evaporation of the solvent gave a pale yellow oil which was purified by bulb-to-bulb distillation (40°-50° C., 0.5 mm Hg) to afford 9.5 g of pure 2,6-dimethylbenzoic acid, methyl ester as a colorless liquid; IR (film) 1725 cm-1 ; NMR(CDCl3) δ 2.3 (s, 6H), 3.9 (s, 3H), 7.0-7.4 (m, 3H).