Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.C(O)(C)C.C([O-])=O.[NH4+]>O.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:22])[C:7](=[O:21])[N:8]2[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21
Temperature: 75 °C
Yield: 77.7 %

Procedure:
84.3 g (0.26 mol) of 6-chloro-1-(ethoxycarbonylmethyl)-7-nitro-2,3(1H,4H)-quinoxalinedione were suspended in 1.5 1 of isopropanol, and 194.2 g (3.1 mol) of ammonium formate dissolved in 500 ml of water, and 8.5 g of palladium/carbon (10%) were successively added. The mixture was heated at 75° C. for 4 h and, after cooling, filtered, and the filter cake was extracted three times with 800 ml of dimethylformamide. The combined dimethylformamide phases were concentrated under reduced pressure, and the residue was washed with water to yield 53.2 g (79%) of the product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18])[CH3:2].[O:19]=[S:20]1(=[O:35])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[N:21]1[CH2:30][CH2:31][CH2:32][CH2:33]Br.C(OCC)C>O>[O:19]=[S:20]1(=[O:35])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:29])[N:21]1[CH2:30][CH2:31][CH2:32][CH2:33][N:15]1[CH2:16][CH2:17][CH:12]([N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:3]([CH2:1][CH3:2])[C:4]2=[O:18])[CH2:13][CH2:14]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reactant: CCn1c(=O)n(C2CCNCC2)c2ccccc21
Solvent: CCOCC
Solvent: O
Product: CCn1c(=O)n(C2CCN(CCCCN3C(=O)c4ccccc4S3(=O)=O)CC2)c2ccccc21

Procedure:
From 4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine and 1,1-dioxido-2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one (prepared as shown in Example 21) using the procedures described in Example 1 there was obtained a white solid as the freebase (from diethyl ether), melting point 124-25° C. Analysis calculated for C25H30N4O4S.0.4 H2O: C, 61.30; H, 6.34; N, 11.44; found: C, 61.34; H, 6.18; N, 11.47. The NMR was consistent with the structure.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N+](CCCC)(CCCC)CCCC)CCC.[C:24](=[O:32])([S:29][CH2:30][CH3:31])[O:25][CH:26](Cl)[CH3:27]>O1CCCC1>[C:24](=[O:32])([S:29][CH2:30][CH3:31])[O:25][CH:26]([O:5][C:1](=[O:6])[CH:2]([CH3:4])[CH3:3])[CH3:27]
Reactant: CC(C)C(=O)[O-]
Reactant: CCSC(=O)OC(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCSC(=O)OC(C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of tetrabutylammonium isobutyrate (5) (382 mmol) in tetrahydrofuran (500 mL) was added compound (2) (49 g, 288 mmol). The mixture was stirred at ambient temperature for 16 h then the solvent removed in vacuo. The residue was dissolved in diethyl ether (600 mL), washed with water (3×300 mL) and the organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation (60° C./240 mTorr) to afford the product (7) as a colorless liquid (40 g, 63%). 1H NMR (CDCl3, 400 MHz): δ 1.2 (d, 6H), 1.35 (t, 3H), 1.5 (d, 3H), 1.55 (m, 1H), 2.85 (dq, 2H), 6.95 (q, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([CH2:7][O:8][C:9]2[CH2:10][S:11][C@@H:12]3[C@H:32]([NH:33]C(=O)CC4C=CC=CC=4)[C:31](=[O:43])[N:13]3[C:14]=2[C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4][O:3]1.CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:33][C@@H:32]1[C:31](=[O:43])[N:13]2[C:14]([C:15]([O:17][CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[C:9]([O:8][CH2:7][C:5]3[CH2:4][O:3][C:2](=[O:1])[CH:6]=3)[CH2:10][S:11][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OCC3=CC(=O)OC3)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OCC3=CC(=O)OC3)CS[C@H]12
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Diphenylmethyl 3-(2,5-dihydro-2-oxofuran-4-ylmethyl oxy)-7β-phenylacetamidoceph-3-em-4-carboxylate (958 mg) was dissolved in dichloromethane (13 ml) whilst under an inert atmosphere. The solution was cooled to -20° C. before treating with N-methylmorpholine (352 μl) followed by a solution of phosphorous pentachloride in dichloromethane (12.5 ml of 40 mg ml-1 solution). After stirring for 30 min. at -20° C. the solution was treated with methanol (3.2 ml) and then allowed to warm to RT. After a further 30 min. water (4.3 ml) was added and the reaction was stirred vigorously for 60 min. Solvent was removed by evaporation in vacuo and the residue dissolved in ethyl acetate/water. The pH of the mixture was adjusted to 6.5 with 1.0M aqueous ammonia. Separation of the organic phase was followed by washing with water and brine before drying over anhydrous magnesium sulphate. Purification was accomplished by chromatography of the crude material on silica gel (Keiselgel) eluting with ethyl acetate. The title compound was finally isolated as a foam (565 mg). υmax (CH2Cl2) 1780, 1755 and 1730cm-1 ; δH(CDCl3) 3.34 (1H, d, J 17.7Hz), 3.54 (1H, d, J 17.7Hz), 4.51-4.58 (2H, m), 4.70 (2H, bs) 4.75 (1H, d, J 4.7Hz), 4.97 (1H, d, J 4.7Hz), 5.93 (1H, s), and 7.26-7.40 (10H, m). [Mass spectrum: FAB +ve ion (3NOBA/Na+) MNa+ 501].
Reaction SMILES: CCOP(OCC)([CH2:6][C:7]#[N:8])=O.[H-].[Na+].O=[C:15]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:7]([CH:6]=[C:15]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]1)#[N:8]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CC(=CC#N)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
Diethyl cyanomethyl phosphonate (0.86 ml, 4.4 mmol) was dissolved in dry THF (50 ml) and the solution cooled to 0° C. Sodium hydride (205 mg of a 60% suspension in parrafin oil, 5.1 mmol) was then added cautiously and the reaction stirred for 30 min. The reaction mixture was then cooled to −78° C. and a solution of 1-tert-butyl 2-methyl (25)-4-oxo-1,2-pyrrolidinedicarboxylate (1.0 g, 4.1 mmol) in dry THF (5 ml) was added dropwise. The reaction was then allowed to reach room temperature. Saturated aqueous ammonium chloride solution (15 ml) was then added, followed by ethyl acetate (100 ml). (The organic layer was removed, and the aqueous washed with ethyl acetate (3×5 ml). The combined organic layers were dried with brine and magnesium sulfate before filtering and removal of solvent. Silica gel chromatography, eluting with 35% ethyl acetate in hexanes gave the desired compound (860 mg, 80%) as an off-white wax.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([Cl:19])[C:13]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:13]2[C:12]([Cl:11])=[CH:17][C:16]([CH3:18])=[CH:15][C:14]=2[Cl:19])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)c(OCCc2ccc(Br)cc2)c(Cl)c1
Temperature: 80 °C

Procedure:
2-(4-Bromophenyl)ethanol (1 eq.) and 2,6-dichloro-4-methylphenol (1.5 eq.) were taken up in freshly deoxygenated toluene (0.1 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 80° C. for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→10:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: N#N.[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15](Cl)=[O:16])[N:14]=1)(=[O:5])[CH3:4].[N-:21]=[N+:22]=[N-:23].[Na+]>CC(C)=O.O>[C:3]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15]([N:21]=[N+:22]=[N-:23])=[O:16])[N:14]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)c1cccc(Cc2nc(C(=O)Cl)co2)c1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cccc(Cc2nc(C(=O)N=[N+]=[N-])co2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of the crude 2-(3-acetyl-benzyl)-oxazole-4-carbonyl chloride in dry acetone (13.5 mL) was cooled to 0° C. and a solution of sodium azide (210 mg, 3.20 mmol) in H2O (1.7 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was concentrated under reduced pressure (coevaporation with toluene) then dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 02: tR=0.91 min [M+AcCN+H]+=312.31.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[C:25]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=2)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([NH:23][C:24]1[C:25]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=2)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSc1ccc(C(=O)O)c(OCCNC(=O)OC(C)(C)C)c1
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCCNC(=O)OC(C)(C)C)c1
Yield: 79 %

Procedure:
Using a procedure analogous to Example 1-G, 2-(2-tert-butoxycarbonylaminoethoxy)-4-(methylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the desired product as a solid (4.0 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][CH2:25][C:26](=[O:28])[CH3:27].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(O)(=O)C>[O:28]=[C:26]([CH3:27])[CH2:25][NH:24][C:20](=[O:22])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)CNC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
t-Butyloxycarbonyl-p-nitrophenylalanine (4.42g, 14.26 mmol, aminoacetone hydrochloride (1.56 g, 14.26 mmol), triethylamine (1.44 g, 14.26 mmol), 1-hydroxybenzotriazole (1.69 g, 12.55 mmol), were dissolved in ethyl acetate (400 ml). 1,3-Dicyclohexylcarbodiimide (3.23 g, 15.68 mmol) in ethyl acetate (25 ml) was added and the solution allowed to stir for 18 hours. Glacial acetic acid (0.2 ml) was added and the solution was filtered. The filtrate was extracted with saturated salt solution (100 ml), lN HCl solution (3×100 ml), and saturated salt solution (100 ml), 5% bicarbonate solution (3×100 ml), and saturated salt solution (100 ml). The organic phase was dried over MgSO4 , filtered and concentrated to 50 ml. Petroleum ether (50 ml) was added and the solution was cooled to 0° C. for 12 hours. The precipitated product was collected and dried under vacuum.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=2)[NH:24][C:23]1=[O:28])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1ccc2c(c1)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-methoxy-2-oxindole to give 0.3 g of 3-(3,5-Diisopropyl-4-methoxybenzylidene)-5-methoxy-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][O-:15].[Na+].Cl>CS(C)=O>[Br:1][C:2]1[CH:10]=[C:9]([O:15][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C[O-]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C(=O)O)c(Br)c1

Procedure:
2-Bromo-4-nitrobenzoic acid (3 g, 12.2 mmol) was reacted with sodium methoxide (6 g, 111 mmol) in dry DMSO (250 mL) at 80° C. After completion of reaction mixture was poured over crushed ice, acidified with 1:1 HCl and extracted with EtOAc (3×150 mL). The organic layer was concentrated to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])C(=O)C(F)(F)F)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH2:39]([O:46][C:47]1[CH:48]=[C:49]([CH:59]=[C:60]([O:63][CH2:64][CH3:65])[C:61]=1I)[CH2:50][C:51]1[C:52]([NH2:58])=[N:53][C:54]([NH2:57])=[N:55][CH:56]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.CN(C)C=O>[CH2:39]([O:46][C:47]1[C:61]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][CH3:15])=[CH:6][CH:7]=2)=[C:60]([O:63][CH2:64][CH3:65])[CH:59]=[C:49]([CH2:50][C:51]2[C:52]([NH2:58])=[N:53][C:54]([NH2:57])=[N:55][CH:56]=2)[CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CN(C(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCc2ccccc2)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCc2ccccc2)c1-c1ccc(NC)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
N-(4-Bromo-phenyl)-2,2,2-trifluoro-N-methyl-acetamide (2.68 g; 9 mmol), bis(pinacolato)diboron (2.51 g; 9.9 mmol), potassium acetate (2.65 g; 27 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (PdCl2(dppf)) (936 mg; 0.81 mmol) are suspended in dimethoxyethane (90 ml; dried over a molecular sieve), and four times the suspension is evacuated with vigorous stirring to remove the oxygen ester and ventilated with argon. The mixture is then stirred at a bath temperature of 80° C. for 24 hours. After cooling to room temperature, dimethylformamide (170 ml), tetrakis-triphenylphosphine-palladium (936 mg; 0.81 mmol), 5-(3-benzyloxy-5-ethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (3.42 g; 7.2 mmol) and a 2 M aqueous potassium phosphate solution (36 ml) are added to the reaction mixture. The reaction mixture is stirred for approx. 17 hours under argon at 90° C. (bath temperature), cooled to room temperature and filtered with suction and the filtrate is concentrated. Water (100 ml) is added to the residue obtained and the mixture is extracted with methylene chloride (150 ml). The organic phase is washed successively with water (100 ml and a saturated aqueous sodium chloride solution (100 ml), dried over magnesium sulphate, filtered with suction and concentrated. The residue is chromatographed over silica gel (600 g) with methylene chloride/methanol/NH4OH 19/1/0.05. 2.30 g (47%) 5-(6-benzyloxy-2-ethoxy-4′-methylamino-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine are obtained as a light-brown powder, which is employed directly in the next stage.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC#N>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1ccc2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a solution of 7-nitro-1H-indole (0.5 g, 3.08 mmol) in dry CH3CN (20 ml), K2CO3 (0.511 g, 3.70 mmol) was added at room temperature. After 10 minutes, methyl 2-bromoacetate (0.343 ml, 3.70 mmol) was added dropwise, and the reaction was refluxed for 24 hours. Additional K2CO3 (0.511 g, 3.70 mmol) and methyl 2-bromoacetate (0.343 ml, 3.70 mmol) were added, and the stirring was prolonged for further 16 hours. The reaction was cooled at room temperature and the solvent was evaporated under vacuum. The resulting crude was partitioned between water and DCM; the organic phase was dried over sodium sulfate and evaporated under vacuum. The crude was purified by flash column chromatography on silica gel (hexane:ethyl acetate=9:1) affording methyl 2-(7-nitro-1H-indol-1-yl)acetate that crystallizes on standing (0.37 g, 1.580 mmol, 51% yield). MS/ESI+ 234.9 [MH]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[CH2:10][O:11]S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][P:22]([O-])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[CH2:1]([O:8][C:9](=[O:16])[CH2:10][O:11][P:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: CS(=O)(=O)OCC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(OCC(=O)OCc1ccccc1)OC(C)(C)C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of methanesulfonyloxy-acetic acid benzyl ester (2.50 g, 10.24 mmol) in THF (20 mL) was added the tetrabutylammonium salt of di-tert-butylphosphate (4.61 g, 10.24 mmol). The reaction was stirred overnight, concentrated, and purified directly by MPLC (SiO2, 10-30% gradient elution, Hexane: EtOAc) to give 1.42 g (39%) of (di-tert-butoxy-phosphoryloxy)-acetic acid benzyl ester. 1H NMR (400 MHz, CDCl3): δ 7.37-7.35 (m, 5H), 5.21 (s, 2H), 4.55 (d, 2H), and 1.48 (s, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[C:21]([Cl:24])=[N:22][CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1.[NH4+].[Cl-]>[NH2:16][C:11]1[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]2[C:5]([NH:17][C:18]3[CH:19]=[C:20]([NH:25][S:26]([N:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])[C:21]([Cl:24])=[N:22][CH:23]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Reactant: CN(C)S(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2Nc2cnc(Cl)c(NS(=O)(=O)N(C)C)c2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
To a 100-mL round-bottomed flask was added 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 356, Step 1; 960 mg, 4.01 mmol), N′-(5-amino-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (1004 mg, 4.01 mmol) and lithium bis(trimethylsilyl)amide (Aldrich; 3352 mg, 20.03 mmol) in tetrahydrofuran (20 mL) at 0° C. After the addition, the reaction mixture was stirred at 0° C. for 20 min. The reaction mixture was diluted with satd NH4Cl (30 mL) and extracted with CH2Cl2 (3×200 mL). The organic extract was washed with satd NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 5% MeOH/CH2Cl2 to give N′-(5-((3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chloro-2-pyridinyl)amino)-2-chloro-3-pyridinyl)-N,N-dimethylsulfamide (1.29 g, 2.74 mmol, 68.5% yield) as a yellow solid. m/z (ESI, +ve ion) 470.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 2.61 (s, 3H) 2.95 (s, 6H) 5.48 (br. s., 2H) 6.80 (s, 1H) 8.31 (d, J=2.74 Hz, 1H) 8.38 (d, J=2.54 Hz, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.85 (d, J=2.74 Hz, 1H) 12.35 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12](Br)[C:13]([O:19][CH3:20])=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([S:15]([CH3:18])(=[O:16])=[O:17])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1c(Br)cc2c(c1S(C)(=O)=O)CCN(C(C)=O)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1S(C)(=O)=O)CCN(C(C)=O)CC2

Procedure:
A mixture of 3-acetyl-8-bromo-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (3.7 g, 0.01 m) and 10% palladium-on-carbon (0.37 g) in methanol (50 ml) is stirred in an atmosphere of hydrogen (60 psi) until uptake is complete. The mixture is degassed, filtered and concentrated in vacuo to give 3-acetyl-7-methoxy-6-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:36])[C:26]([C:33]([OH:35])=[O:34])=[CH:27][N:28]3[CH2:31][CH3:32])=[CH:23][C:22]=2[F:37])[CH2:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:38]=O>C(O)=O>[CH2:1]([O:13][CH2:14][CH:15]1[N:20]([CH3:38])[CH2:19][CH2:18][N:17]([C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:36])[C:26]([C:33]([OH:35])=[O:34])=[CH:27][N:28]3[CH2:31][CH3:32])=[CH:23][C:22]=2[F:37])[CH2:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=O
Reactant: CCCCCCCCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1
Solvent: O=CO
Product: CCCCCCCCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1C

Procedure:
A 300 mg portion of 7-[3-[(dodecyloxy)methyl]-1-piperazinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in a mixture of 1.2 ml of 37% formaldehyde and 1.5 ml of 90% formic acid, heated on a steam bath for 45 minutes and then evaporated in vacuo. A 5 ml portion of water was added, the solution neutralized with aqueous sodium hydroxide and the solid collected, washed with water and dried, giving 260 mg of the desired product, mp 166°-168° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:20][N:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[CH:10][CH:11]=1
Reactant: Cn1ccnc1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Dissolve [4-(1-methyl-1H-imidazol-2-yl)-benzyl]-carbamic acid tert-butyl ester (500 mg, 1.7 mmol) in DCM (20 mL) and trifluoroacetic acid (5 mL). Stir the mixture for 1 h at ambient temperature. Concentrate in vacuo and purify by SCX chromatography to obtain the title compound (240 mg, 74%). MS (ES+) m/z: 188 (M+H)+.