Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][S:11]([CH:13]2[N:16]([C:17]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15](=[O:44])[CH:14]2[NH:45][C:46]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11](=[O:12])[C@@H:13]3[CH:14]([NH:45][C:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:15](=[O:44])[N:16]3[C:17]=2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1S(=O)CC(=O)CCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1=C(CCc2ccccc2)CS(=O)[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12

Procedure:
4-(4-phenyl-2-oxobutylsulphinyl)-1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino) azetidin-2-one (200 mg) was refluxed in dry dioxan (5 ml) under nitrogen for 8 hours. The mixture was evaporated to give a foam. The crude foam was chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give t-butyl 3-β-phenylethyl-7-triphenylmethylamino-3-cephem-4-carboxylate-1-oxide as a yellow solid (87 kg.) μmax (CHCl3) 1785, 1720 cm-1This sulphoxide (87 mg) was dissolved in dimethylformamide (1 ml) and cooled to 0°C. Triphenylphosphine (74 mg) and acetyl chloride (33 mg) were added and the mixture stood at 0°-5°C for 4 hours. The mixture was diluted with ethyl acetate (25 ml) and washed successively with dilute sodium bicarbonate solution and brine. The dried (MgSO4) organic layer was evaporated to give a gum. The gum was chromatographed on silica gel to give the desired cephem (XX111) as a solid foam (77 mg) νmax (CHCl3) 1775 cm-1 (ε-lactam); 1715 cm-1 (ester) δppm (CDCl3) 1.51 (5.9H); 2.4-3.2 (m.7H.1 H exchanges with D2O); 4.19 (d.1H. J=5Hz); 4.5-4.9 (m.1H); 7.0-7.9 (Aromatics).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N+:10]([C:13]1[CH:14]=[C:15]([C:19]2[C:23](C#N)=[C:22]([N:26]=[CH:27][N:28]([CH3:30])C)[NH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11]>CO>[Cl:2][C:3]1[CH:4]=[C:5]([NH:6][C:30]2[N:28]=[CH:27][N:26]=[C:22]3[NH:21][N:20]=[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=4)[C:23]=23)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CN(C)C=Nc1[nH]nc(-c2cccc([N+](=O)[O-])c2)c1C#N
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
With the exclusion of air, 172.2 mg (1.05 mmol) of 3-chloro-aniline hydrochloride (see Step 14.4) are added to 199 mg (0.70 mmol) of N'-[3-(3-nitro-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine in 2 ml of methanol and the reaction mixture is boiled under reflux for 19 hours. Cooling, filtering and washing with isopropanol and hexane yield 4-(3-chloro-phenylamino)-3-(3-nitro-phenyl)-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rt=0.55 (methylene chloride:methanol=10:1); HPLC: TRet (Grad20-100)=14.2; 1H-NMR: (DMSO-d6) 9.05 (s, HN), 8.54 (s, 2H), 8.32 (dd, J=8, 2, 1H), 8.22 (d, J=8, 1H), 7.8 (m, 2H), 7.49 (d, J=8, 1H), 7.33 (t, J=8, 1H), 7.10 (dd, J=8, 2, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[C:57]([O:61][C:62]([N:64]1[CH2:67][CH:66]([NH2:68])[CH2:65]1)=[O:63])([CH3:60])([CH3:59])[CH3:58].[OH-].[Na+]>O.ClCCl.C(N(CC)CC)C>[C:57]([O:61][C:62]([N:64]1[CH2:67][CH:66]([NH:68][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:65]1)=[O:63])([CH3:60])([CH3:58])[CH3:59]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CN(C(=O)OC(C)(C)C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a mixture of 0.090 g (0.2 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0764 g (0.2 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 3 mL of dichloromethane, 0.08 mL of triethylamine was added followed by 0.0344 g (0.2 mmole) of 3-amino-azetidine-1-carboxylic acid tert-butyl ester. After 2 hours, 6 mL of dichloromethane, 4 mL of water and 0.2 mL of 1M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (gradient, 60:40-0:100) to give 0.0523 g of 3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-azetidine-1-carboxylic acid tert-butyl ester (I-86).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[CH2:19](B(O)O)[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Reactant: CCCCB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCc1c(C#N)cnc2ccc(C(=O)OCC)cc12

Procedure:
Similar procedure as described in example 46d was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester, butylboronic acid, sodium carbonate and POPd to give 3-cyano-4-butyl-quinoline-6-carboxylic acid ethyl ester as a clear oil. LC-MS m/e 283 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:13](=O)[CH3:14])[C:6]#[N:7].[NH2:22][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][C:25]#[N:26].CC(C)([O-])C.[K+]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:16]3[S:17][CH:18]=[C:19]([CH3:21])[N:20]=3)=[C:13]([CH3:14])[NH:22][C:23]([C:27]([F:30])([F:29])[F:28])=[C:24]2[C:25]#[N:26])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: COc1cc(C#N)ccc1C=C(C(C)=O)c1nc(C)cs1
Reactant: N#CC=C(N)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C(F)(F)F)NC(C)=C1c1nc(C)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.335 mmol) of the compound from example 6A, 46 mg (0.335 mmol) of 3-amino-4,4,4-tri-fluorobut-2-enenitrile [preparation in analogy to U.S. Pat. No. 3,635,977 and K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 5.6 mg (0.05 mmol) of potassium tert-butoxide are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 119 mg (82% of theory) of the title compound are obtained.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(OC(NC1(C(O)=O)CC1)=O)(C)(C)C.ClC1C=C(OC)C=CC=1OC1C=CC(CN)=CC=1.[F:62][C:63]([F:74])([F:73])[C:64]1[CH:65]=[N:66][CH:67]=[C:68]([CH:72]=1)[C:69]([OH:71])=O.[Cl:75][C:76]1[CH:96]=[C:95]([O:97][CH3:98])[CH:94]=[CH:93][C:77]=1[O:78][C:79]1[CH:92]=[CH:91][C:82]([CH2:83][NH:84][C:85]([C:87]2([NH2:90])[CH2:89][CH2:88]2)=[O:86])=[CH:81][CH:80]=1>CN(C=O)C>[Cl:75][C:76]1[CH:96]=[C:95]([O:97][CH3:98])[CH:94]=[CH:93][C:77]=1[O:78][C:79]1[CH:92]=[CH:91][C:82]([CH2:83][NH:84][C:85]([C:87]2([NH:90][C:69](=[O:71])[C:68]3[CH:72]=[C:64]([C:63]([F:62])([F:74])[F:73])[CH:65]=[N:66][CH:67]=3)[CH2:88][CH2:89]2)=[O:86])=[CH:81][CH:80]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(Cl)c1
Reactant: O=C(O)c1cncc(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1ccc(Oc2ccc(CN)cc2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncc(C(F)(F)F)c4)CC3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
102 μL (0.73 mmol) of triethylamine and 117 mg (0.36 mmol) of TBTU were added to a solution of 73.7 mg (0.37 mmol) of 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid in 6 mL DMF and the mixture was stirred for 5 min at RT. Then 96.6 mg (0.37 mmol) of 4-(2-chloro-4-methoxy-phenoxy)-benzylamine was added and the mixture was stirred overnight at ambient temperature. The reaction mixture was filtered through Alox B, washed with DMF and the filtrate was evaporated down. 10 ml of dichloromethane/trifluoroacetic acid=1/1 were added to the residue and this was shaken for 1 h at RT. The reaction mixture was evaporated down and the residue was purified by chromatography (reversed phase). The corresponding fractions were freeze-dried. 35 mg (0.18 mmol) of 5-(trifluoromethyl)nicotinic acid was dissolved in 2 ml DMF and combined with 52 μL (0.37 mmol) of triethylamine and 59 mg (0.18 mmol) of TBTU and stirred for 10 min at RT. Then the freeze-dried 1-amino-cyclopropanecarboxylic acid-4-(2-chloro-4-methoxy-phenoxy)-benzylamide was added and the mixture was stirred overnight at RT. The reaction mixture was purified directly by chromatography (reversed phase).
Reaction SMILES: [N:1](=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([OH:8])=O)[OH:2].Cl.Cl.[CH:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:19])[CH3:18]>>[CH:17]([N:20]1[CH2:25][CH2:24][N:23]([C:6](=[O:8])[CH2:5][CH2:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:1][OH:2])[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: O=C(O)CCC(=NO)c1ccccc1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Product: CC(C)N1CCN(C(=O)CCC(=NO)c2ccccc2)CC1

Procedure:
Using coupling method A, 4-hydroximino-4-phenylbutyric acid (500 mg, 2.6 mmol) and 1-isopropylpiperazine dihydrochloride (521 mg, 2.6 mmol) afforded, after purification (SiO2: 10% isopropylamine in EtOAc), 730 mg (89%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:71])[C@@H:12]([NH:24][C:25]([C@H:27]1[NH:45][C:44](=[O:46])[C@H:43]([CH2:47][CH2:48][CH2:49][NH:50]C(OC(C)(C)C)=O)[NH:42][C:41](=[O:58])[C@@H:40]([NH:59]C(OC(C)(C)C)=O)[CH2:39][C:38]2[CH:67]=[C:34]([CH:35]=[CH:36][C:37]=2[OH:68])[C:33]2=[CH:69][C:29](=[C:30]([OH:70])[CH:31]=[CH:32]2)[CH2:28]1)=[O:26])[CH2:13][CH2:14][CH2:15][NH:16]C(OC(C)(C)C)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:59][C@H:40]1[CH2:39][C:38]2[CH:67]=[C:34]([CH:35]=[CH:36][C:37]=2[OH:68])[C:33]2=[CH:69][C:29](=[C:30]([OH:70])[CH:31]=[CH:32]2)[CH2:28][C@@H:27]([C:25]([NH:24][C@H:12]([C:11]([NH:10][CH2:9][CH2:8][NH2:7])=[O:71])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:26])[NH:45][C:44](=[O:46])[C@H:43]([CH2:47][CH2:48][CH2:49][NH2:50])[NH:42][C:41]1=[O:58]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1)C(=O)NCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@H](NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](CCCN)C(=O)N1)C(=O)NCCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
29.7 mg (0.029 mmol) of tert-butyl(2-{[(2S)-5-[(tert-butoxycarbonyl)amino]-2-({[(8S,11S,14S)-14-[(tert-butoxycarbonyl)amino]-11-{3-[(tert-butoxycarbonyl)amino]propyl}-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-8-yl]carbonyl}amino)pentanoyl]amino}ethyl)carbamate (Example 167A) are dissolved in 3.0 ml of 4N hydrogen chloride in dioxane and stirred at room temperature for 2 h. The solvent is evaporated in vacuo and the remaining solid is converted by preparative HPLC (Reprosil ODS-A, mobile phase acetonitrile/0.2% aqueous trifluoroacetic acid 5:95→95:5) into the tetra(hydrotrifluoroacetate).
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH3:18])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N:25]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:17]([CH:13]([C:14]([NH2:16])=[O:15])[C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:31])=[O:5])=[CH:12][CH:11]=2)[CH3:18])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
One hundred milligrams (0.237 mmol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid-tert.butyl ester in 5 ml of benzene were heated together with some crystals of p-toluene-sulfonic acid hydrate to reflux temperature for half a day. According to the thin layer chromatogram no starting product could be then detected; however, according to the Rf -value and mass spectrum the desired product was formed.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2/[C:14](=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:15][O:16][C@H:10]12)(C(C)(C)C)(C)C.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.C(O)C>[OH:8][C@H:9]1[C@H:10]2[O:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C@H:11]2[O:12][CH2:13]1
Reactant: CCOC(=O)/C=C1\CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1CO[C@@H]2[C@H](O)CO[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 20 mL vessel was charged ethyl(2E)-2-[(3R,3aS,6aR)-3-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-ylidene]acetate (45 mg, 0.137 mmol), nickel chloride hexahydrate (32.6 mg, 0.137 mmol) and ethanol (1 mL). Sodium borohydride (51.8 mg, 1.37 mmol) was added slowly and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (0.5 mL) and partitioned between water (4 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic phases were dried over MgSO4, filtered and concentrated to afford the title compound. LC-MS: calculated for C1OH16O5, [M+Na]+Calc: 239.1. Found: 239.1, Rt=0.22 min (4 min run).
Reaction SMILES: Br[C:2]1([CH2:20][C:21]([OH:23])=[O:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:9]([O:18][CH3:19])=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3]1.[N+:24]([O-:29])([N+]([O-])=O)=[O:25]>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]1[C:9]([O:18][CH3:19])=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3][C:2]1([N+:24]([O-:29])=[O:25])[CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: COC1=C2C=CC=C2OC(Br)(CC(=O)O)C1c1ccccc1F
Product: COC1=C2C=CC=C2OC(CC(=O)O)([N+](=O)[O-])C1c1ccccc1F

Procedure:
Using the method of Example 17, 2-bromo-3-(2-fluorophenyl)-4-methoxy-7-benzofuranacetic acid is reacted with dinitrogen tetroxide to provide 3-(2-fluorophenyl)-4-methoxy-2-nitro-7-benzofuranacetic acid. Recrystallization of the acid from benzene provides yellow crystals, m.p. 185°-195° C.
Reaction SMILES: C(OC(NC(C1NC(C2C=CC=C3C=2N=C(NCC(F)(F)F)C(C)=N3)=CC=1C(OCC)=O)C)=O)(C)(C)C.Br[CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=[O:41].[C:59]([O:63][C:64]([NH:66][CH2:67][C:68](=[O:75])[CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:65])([CH3:62])([CH3:61])[CH3:60].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCO>[C:59]([O:63][C:64]([NH:66][CH2:67][C:68](=[O:75])[CH:69]([CH2:39][C:40]([C:42]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]2[C:43]=1[N:44]=[C:45]([NH:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:46]([CH3:53])=[N:47]2)=[O:41])[C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:65])([CH3:61])([CH3:62])[CH3:60]
Reactant: CCOC(=O)CC(=O)CNC(=O)OC(C)(C)C
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC(C)(C)C
Agent: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC(C)(C)C)nc12)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
This compound (873 mg, 34% yield) as a yellow foam was prepared according to the procedure described for intermediate 293b, using 2-bromo-1-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (605) (1.81 g, 5.11 mmol), ethyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (601) (1.50 g, 6.13 mmol) and K2CO3 (1.77 g, 12.77 mmol) in DMF (17 mL) was stirred at RT for 6 h, followed by the subsequent treatment of the resulting ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (296a) (1.43 g, 2.76 mmol, 54% yield, m/z (ESI, +ve) 519.2 (M+H)+) with NH4Oac (3.15 g, 40.9 mmol) in 12 mL of EtOH and AcOH (6 mL). 1H NMR (400 MHz, CDCl3) δ ppm 7.63 (dd, J=8.80, 5.67 Hz, 1H), 7.34 (dd, J=4.60, 2.45 Hz, 1H), 7.21 (dd, J=11.64, 8.90 Hz, 1H), 4.94 (s, 1H), 4.62 (d, J=5.87 Hz, 2H), 4.34 (q, J=7.24 Hz, 2H), 2.54 (s, 3H), 1.69 (s, 9H), 1.43 (s, 9H), 1.38-1.42 (m, 3H). 19F NMR (376 MHz, CDCl3) δ ppm −107.37 (s, 1F). m/z (ESI, +ve) 500.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:6][CH:5]2O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:6][CH2:5]2
Reactant: Cc1ccccc1C1CC(O)c2cc(Br)ccc2O1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C1CCc2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-bromo-2-o-tolyl-chroman-4-ol (11.9 g, 37.3 mmol) in dichloromethane (130 ml) at 0° C. triethylsilane (29.6 g, 255 mmol, 6.8 eq) and trifluoroacetic acid (75 ml, 27 eq) were added. The solution was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure and the residue separated between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water and saturated aqueous solution of sodium hydrogencarbonate, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; ethyl acetate/heptane gradient). 6-Bromo-2-o-tolyl-chroman was obtained as a pale yellow oil (7.10 g, 63%).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:20]1[CH:24]=[C:23]([C:25]2[C:26]3[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=3[N:28]=[CH:29][N:30]=2)[CH:22]=[N:21]1)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)#[N:2].Cl.O1CCOCC1>C(Cl)Cl>[N:6]1([CH2:5][CH:4]([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:3][C:1]#[N:2])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCCNCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of tert-butyl 4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-1,4-diazepane-1-carboxylate (6.4 g, 11 mmol;) in DCM (10 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (22 mL, 88 mmol). The reaction solution was stirred at room temperature for 90 minutes. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with 1.0 N NaOH solution. The aqueous was extracted with ethyl acetate. The combined extracts were dried over MgSO4, filtered, and concentrated to give the desired product as a brown sticky gum (4.1 g, 77%). LCMS calculated for C24H37N8OSi(M+H)+: m/z=481.2.
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19].C(OCC)C>C1(C)C=CC=CC=1>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:18]2[S:19][CH2:15][CH2:16][N:17]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: S=C=NCCCl
Reactant: CCCCCCc1ccc(N)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(NC2=NCCS2)cc1
Temperature: 50 °C

Procedure:
A 2 liter, 3-neck round bottom flask fitted with magnetic stirrer, addition funnel, argon gas inlet and thermometer was charged with 4-hexylaniline (65.0 g, 0.367 m) dissolved in 500 ml reagent toluene. To this stirred solution, was added dropwise a solution of β-chloroethylisothiocyanate (53.5 g, 0.441 m, 1.2 eq.) in 175 ml toluene at room temperature. No significant exotherm was noted. After the addition was completed, the reaction mixture was warmed to 50° C. for 19 hours. The reaction was cooled to room temperature and the toluene removed on the rotary evaporator to give an orange, semi-solid residue which was stirred with 900 ml diethyl ether (Et2O). The resulting slurry of off-white solid was cooled in an ice water bath and the solid filtered, washed with cold Et2O, and dried (filter suction, desiccator) to give the slightly impure hydrochloride salt of the desired aminothiazoline. The HCl salt was neutralized by adding the salt to a cold, stirred solution of sodium hydroxide (14.7 g, 0.367 m) in 1200 ml water layered with Et2O. After neutralization, the ether layer was separated and the aqueous layer was extracted with Et2O four times. The combined Et2O extracts were washed with water twice and with a saturated NaCl solution once, dried (MgSO4), and evaporated under vacuum to afford 90.0 g of crude, freebase product as a waxy, off-white solid. The crude material was recrystallized from 900 ml hexane to give 73.0 g (76%) product in two crops as small, off-white platelets. m.p. 77°-79° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCN1CCNCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN3CCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-(piperazin-1-yl)ethanamine. MS obsd. (ESI+) [(M+H)+] 466, 1H NMR (400 MHz, DMSO-d6) ppm 7.925 (d, J=8.0 Hz, 1 H), 7.806 (d, J=7.2 Hz, 1 H), 7.516-7.575 (m, 2 H), 7.359-7.395 (m, 2 H), 7.238 (m, 1 H), 5.98 (s, 1 H), 5.10 (s, 2 H), 4.49 (brs, 2 H), 3.538 (m, 2 H), 3.542 (m, 2 H), 3.44 (t, J=6.57 Hz, 2 H), 3.32 (s, 2 H), 2.89 (t, J=4.80 Hz, 4 H), 2.71 (t, J=6.57 Hz, 2 H), 2.56 (brs, 4 H), 2.37 (s, 3 H).