Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[CH:3]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][C:6]([CH3:11])=[CH:7][CH:8]=2
Reactant: Cc1ccc2c(c1)C(O)C(Br)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)C=C(Br)C2
Reaction time: 0.33 h

Procedure:
Water (0.6 ml) and N-bromosuccinimide (6.1 g) was added to a solution of 5-methyl-1H-indene (4.4 g) in dimethylsulfoxide (50 ml), and the mixture was stirred for 40 minutes at room temperature. The reaction mixture was poured into ice-cooled water, and extracted with ether. The organic layer was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting crystals were washed with hexane to obtain, by filtration, 2-bromo-6-methylindane-1-ol (4.4 g). To a solution of 2-bromo-6-methylindane-1-ol in toluene (50 ml) was added p-toluene sulfonic acid monohydrate (0.1 g), and the mixture was stirred for 20 minutes. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was washed with water, 5% sodium hydrogencarbonate aqueous solution, and saturated saline solution in order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-bromo-5-methyl-1H-indene (1.7 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].C(=O)([O-])[OH:16].[Na+].O>CS(C)=O>[CH:2]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=[O:16]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C=O)c(OC)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.6 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (3.00 g, 11.6 mmol) in dimethyl sulfoxide (16 ml) was added sodium hydrogen carbonate (1.00 g, 13.6 mmol), and the mixture was stirred at 50° C. for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (870 mg, 39%) as a colorless oil.
Reaction SMILES: C1COCC1.[C:6]([C:9]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:12]2[C:13]([CH3:28])([CH3:27])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[C:23](=[O:24])[C:11]=2[CH:10]=1)=[CH:20][CH:19]=[C:18]([C:25]#[N:26])[CH:17]=4)(=[O:8])[CH3:7].Cl[C:38]([CH3:42])([CH3:41])[C:39]#[CH:40].C(N(CC)CC)C>[Cu]Cl.O>[C:6]([C:9]1[C:30]([N:31]2[CH2:32][CH2:33][N:34]([C:38]([CH3:42])([CH3:41])[C:39]#[CH:40])[CH2:35][CH2:36]2)=[CH:29][C:12]2[C:13]([CH3:28])([CH3:27])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[C:23](=[O:24])[C:11]=2[CH:10]=1)=[CH:20][CH:19]=[C:18]([C:25]#[N:26])[CH:17]=4)(=[O:8])[CH3:7]
Reactant: CC(=O)c1cc2c(cc1N1CCNCC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C#CC(C)(C)N1CCN(c2cc3c(cc2C(C)=O)C(=O)c2c([nH]c4cc(C#N)ccc24)C3(C)C)CC1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To the anhydrous THF solution (0.5 mL) of 9-acetyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound H8-5, 25 mg, 0.06 mmol), 3-chloro-3-methyl-but-1-yne (0.013 mL, 0.12 mmol), copper (I) chloride (0.6 mg, 0.006 mmol) and triethylamine (0.017 mL, 0.12 mmol) were added at room temperature. After stirring for 30 min, the mixture was added with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by amino silica gel column chromatography (dichloromethane/methanol) to obtain the title compound (white solid, 9.8 mg, 35%).
Reaction SMILES: O.[OH:2]OS([O-])=O.[K+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C@H:34]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]2)[C:19](=[O:33])[NH:20][C:21]2[S:22][C:23]([S:26][C:27](C)(C)[C:28]([OH:30])=[O:29])=[CH:24][N:25]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C@H:34]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]2)[C:19](=[O:33])[NH:20][C:21]2[S:22][C:23]([S:26]([CH2:27][C:28]([OH:30])=[O:29])=[O:2])=[CH:24][N:25]=2)=[CH:12][CH:11]=1
Reactant: O=S([O-])OO
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CCN(C(=O)Nc2ncc(S(=O)CC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Temperature: 25 °C

Procedure:
To Montmorinonite (415 mg) was added H2O (98 μL) the mixture was stirred for 10 min before DCM (0.5 mL), oxone (428 mg, 0.70 mmol) and 2-{2-[3-[2-(4-methoxy-phenyl) -ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid (129 mg, 0.278 mmol) suspended in DCM (2.6 mL) was added in seqence. The mixture was stirred at rt for 1.5 hs. LCMS showed a 1:1 mixture of the sulfoxide and sulfone. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated in vacuo. The mixture was purified by HPLC to give37 mg of {2-[3-[2-(4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfinyl}-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[C:25]([CH3:32])=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[N:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[N:24]=[C:25]([CH3:32])[C:26]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1nn(-c2ccc(F)cc2)c2c1NCCC2
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Product: Cc1nn(-c2ccc(F)cc2)c2c1N(C(=O)Cn1nc(C(F)(F)F)c(Cl)c1C)CCC2
Yield: 41 %

Procedure:
The title compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid and 1-(4-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 75 mg (41%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.47 (m, 0.8H), 7.40 (m, 1.2H), 7.14 (m, 2H), 5.11 (s, 1.2H), 5.01 (s, 0.8H), 3.81 (m, 2H), 2.85 (m, 2H), 2.29-2.40 (m, 6H), 2.07 (m, 2H); MS: (ES) m/z calculated for C20H19ClF4N5O [M+H]+ 456.1, found 456.1.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To 720 g of polyphosphoric acid (116.5%) heated at 89° C. were added 120 g of 2,5-di(4-chloroanilino)terephthalic acid over a period of approximately 45 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The reaction mixture was held at 113° C. for five hours and then cooled to 95° C. To this mixture was added 89.4 g of phosphoric acid (75%) dropwise over a period of 20 minutes. The resultant melt was allowed to stir for 15 minutes at 92° C. and then poured slowly into 1240 g of methanol, the temperature being maintained below reflux by adjustment of the addition rate. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 102 g of 2,9-dichloroquinacridone as a magenta pigment.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C([Li])(C)(C)C.[Br:18][C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[N:28]([C:31]1[N:36]=[C:35]([C:37](OC)=[O:38])[CH:34]=[C:33]([CH3:41])[N:32]=1)[CH2:29][CH3:30]>CCOCC.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[N:28]([CH2:29][CH3:30])[C:31]1[N:36]=[C:35]([C:37]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][CH:8]=[CH:7]3)=[O:38])[CH:34]=[C:33]([CH3:41])[N:32]=1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCN(c1nc(C)cc(C(=O)c2ccc3[nH]ccc3c2)n1)c1ccc(C(C)C)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a suspension of potassium hydride (35% in oil, 0.16 g, 1.4 mmol), washed with hexanes and decanted twice, in anhydrous ether (5 mL), cooled to 0° C. under a nitrogen atmosphere was added a solution of 5-bromoindole (0.27 g, 1.4 mmol) in anhydrous ether. After being stirred for 30 min., the reaction mixture was cooled to −78° C. and transferred via cannula to a pre-cooled (−78° C.) mixture of t-butyl lithium (1.7 M in pentane, 1.6 mL, 2.7 mmol) in dry ether (5 mL). The resulting white suspension was stirred at −78° C. for 30 min and a solution of methyl 2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate (Example 18) (0.5 g, 1.25 mmol) in anhydrous ether (5 mL) was added dropwise. After quenching the reaction mixture as in Example 87; it was extracted three times with ethyl acetate, followed by two washings of the combined organic layers with a saturated NaHCO3 solution, drying over MgSO4, filtration and concentration in vacuo to give a dark brown oil. Column chromatography (ethyl acetate: hexanes::1:4) afforded the title product, a light brown solid (140 mg, 24% yield, Rf 0.2): mp 77-79° C.; NMR (DMSO-d6, 400 MHz, 90° C.): 11.6-11.35 (br s, 1H), 8.30 (s, 1H), 7.75 (dd, 1H, J=8, 1), 7.55 (d, 1H, J=1), 7.4-7.35 (m, 2H), 7.35-7.25 (m, 2H), 6.9 (s, 1H), 6.60-6.55 (m, 1H), 4.1-3.7 (m, 2H), 2.95-2.8 (m, 1H), 2.4 (br s, 3H), 1.25-1.1 (m, 9H); Anal (C25H25BrN4O): C, 62.90; H, 5.28; N, 11.74; Br, 16.74; Found: C, 63.13; H, 5.60; N, 11.37; Br, 16.80.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](O[C:14](=[O:28])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]4OCO[C:22]=4[CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1.[C:29]([O-:32])(=[O:31])C.[NH4+:33]>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([NH:33][C:14](=[O:28])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]4[O:32][CH2:29][O:31][C:22]=4[CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1
Reactant: CC(=O)[O-]
Reactant: [NH4+]
Reactant: O=C1OC(=O)C(c2c[nH]c3cc4c(cc23)OCO4)=C1c1c[nH]c2ccccc12
Solvent: O
Product: O=C1NC(=O)C(c2c[nH]c3cc4c(cc23)OCO4)=C1c1c[nH]c2ccccc12
Yield: 51.3 %

Procedure:
0.8 g (2.1 mmol) 2-(1H-indol-3-yl)-3-(5,6-methylenedioxy-1H-indol-3-yl)-maleic acid anhydride, together with 20 g ammonium acetate, are heated for 1 hour to 140° C. (melt). After cooling, the reaction mixture is mixed with water and the red-brown precipitate obtained is filtered off with suction. For purification, it is chromatographed on silica gel with dichloromethane/ethyl acetate (3:1 v/v) as elution agent. There is obtained 0.40 g (45% of theory) 2-(1H-indol-3-yl)-3-(5,6-methylenedioxy-1H-indol-3-yl) -maleinimide in the form of red crystals; m.p. 150° C. (decomp.); RF=0.4 (methylene chloride/ethyl acetate 3:1 v/v).
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH:31]([NH:34][CH2:35][CH2:36][CH2:37][NH2:38])([CH3:33])[CH3:32]>>[CH:31]([NH:34][CH2:35][CH2:36][CH2:37][NH:38][C:8](=[O:30])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29])([CH3:33])[CH3:32]
Reactant: CC(C)NCCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCNC(C)C)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-isopropyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCI, m/z): 460 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:21]=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:21][OH:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C=O)c1ccc(OCc2ccccc2)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCOC(=O)C(CO)c1ccc(OCc2ccccc2)c(OC)c1
Yield: 115.1 %

Procedure:
A solution of ethyl 2-(4-benzyloxy-3-methoxyphenyl)-3-oxo-propionate (1.356 g; 3.47 mmol; from step (ii) above) in MeOH:CH2Cl2 (3:1, 20 mL) was cooled to −15 to −5° C., and NaBH4 (0.264 g; 6.95 mmol) was added in portions. The cooled reaction mixture was stirred, whereafter it was allowed to attain room temperature. Water was added, and the mixture was partially concentrated. After extraction with EtOAc (2×25 mL), washing of the organic phase with brine, drying (Na2SO4) and evaporation, 1.32 g (97.1%) of the sub-title compound was obtained.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1.[Cl:35][C:36]1[N:41]=[C:40](Cl)[C:39]([F:43])=[CH:38][N:37]=1>>[Cl:35][C:36]1[N:41]=[C:40]([NH:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[C:39]([F:43])=[CH:38][N:37]=1
Reactant: NCc1cccnc1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Fc1cnc(Cl)nc1NCc1cccnc1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-pyridylmethylamine (162 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) were reacted to give 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine. Then 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) reacted to give 5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 43%). 1H NMR (CD3OD): δ 4.71 (s, 2H), 6.38 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 6.88 (ddd, J=0.9, 2.1 and 8.1 Hz, 1H), 7.00 (t, J=8.1 Hz, 1H), 7.14 (t, J=2.4 Hz, 1H), 7.37 (dd, J=4.8 and 7.8 Hz, 1H), 7.73 (d, J=3.6 Hz, 1H), 7.87 (dt, J=2.1 and 7.5 Hz, 1H), 8.39 (dd, J=1.2 and 7.8 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ−170.99; LCMS: ret. time: 8.82 min.; purity: 92.90%; MS (m/e): 312.05 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C@@:17]3([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)[C:16]3[C:11](=[N:12][CH:13]=[C:14]([Br:24])[CH:15]=3)[O:10][C:7]2=[CH:8][CH:9]=1)=[N+]=[N-].[B-].[Na+].[BH4-].[Na+].O>CO.CCOC(C)=O>[Br:24][C:14]1[CH:15]=[C:16]2[C@:17]3([CH2:22][CH2:21][O:20][C:19]([NH2:23])=[N:18]3)[C:6]3[C:7](=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)[O:10][C:11]2=[N:12][CH:13]=1
Reactant: [N-]=[N+]=Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Br)cnc1O2
Agent: [B-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncc(Br)cc12
Reaction time: 1 h

Procedure:
(S)-7-azido-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (200 mg, 0.517 mmol) was dissolved in MeOH (2 mL) and sodium borohydrate (195 mg, 5.17 mmol) was added at rt. After 1 h, additional MeOH (2 mL) and 10 equiv of NaBH4 were added at rt. The reaction mixture was allowed to stir overnight. Additional MeOH (2 mL) and 10 equiv of NaBH4 were added and the reaction was allowed to stir for 1 h. Water was added, followed by EtOAc. The organic phase was separated, dried over MgSO4. The solvent was removed under reduced pressure to give (S)-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine as a light-yellow solid. The compound was used in the next step without further purification. MS m/z=362.8 [M+H]+. Calculated for C15H13BrN4O2: 361.19.
Reaction SMILES: CCCCCC.[C:7]([O:11][C:12](=[O:22])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1Br)([CH3:10])([CH3:9])[CH3:8].[CH:23](=[O:25])[CH3:24].[Cl-].[NH4+]>C1COCC1.O>[C:7]([O:11][C:12](=[O:22])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH:23]([OH:25])[CH3:24])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1Br
Reactant: CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(O)c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
At −78° C. under nitrogen 1.6 M butyllithium solution in hexane (4.89 ml, 7.8 mmol) were added dropwise to [2-bromo-4-chloro-phenyl]-carbamic acid tert-butyl ester (1.09 g, 3.56 mmol) in THF (20 ml). The reaction was stirred for 15 minutes at −78° C. and acetaldehyde (235 mg, 5.33 mmol) was added dropwise. After stirring for 15 minutes at −78° C. saturated aqueous ammonium chloride solution was added and the reaction was allowed to warm to room temperature. The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated to yield the crude product which was purified by column chromatography (heptane:ethyl acetate=4:1). The product was isolated as a colorless viscous oil (525 mg, 54%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][O:20][CH3:21])[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=1)=[O:7].[NH2:22][CH:23]1[C:43](=[O:44])[N:25]2[C:26]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])=[CH:27][CH2:28][S:29][C@H:24]12.C[Si](CC(N)=O)(C)C>C(Cl)Cl.CN(C)C=O>[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][O:20][CH3:21])[C:16]([NH:22][CH:23]2[C:43](=[O:44])[N:25]3[C:26]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=4)=[O:31])=[CH:27][CH2:28][S:29][C@H:24]23)=[O:18])[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CON=C(C(=O)O)c1cccc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1cccc(NC=O)n1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A mixture of N,N-dimethylformamide (3 ml.) and phosphoryl chloride (460 mg.) was stirred at 37° to 40° C. for 30 minutes. To the solution were added methylene chloride (3 ml.) and 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (669 mg.) at -20° to -25° C. and stirred at -10° to -15° C. for one hour. A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (670 mg.) and trimethylsilylacetamide (2 g.) in methylene chloride (200 ml.) was added to the above solution at -10° to -15° C., and then stirred at the same temperature for 30 minutes. After the solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue. The ethyl acetate layer was separated, washed with an aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give 4-nitrobenzyl 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (730 mg.), mp. 195° to 200° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[CH:13][C:14]=2[C:15](Cl)=[O:16])[CH:11]=1)(=[O:5])=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:24]>N1C=CC=CC=1>[CH3:39][C:38]1[CH:37]=[CH:36][C:22]([C:23](=[O:24])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[CH:21][C:20]=1[NH:19][C:15]([C:14]1[CH:13]=[N:12][N:10]2[CH:11]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:18])[CH3:1])[CH:7]=[CH:8][C:9]=12)=[O:16]
Reactant: CN(C)S(=O)(=O)c1ccc2c(C(=O)Cl)cnn2c1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1N
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cnn2cc(S(=O)(=O)N(C)C)ccc12

Procedure:
6-Dimethylsulfamoyl-pyrazolo[1,5-a]pyridine-3-carbonyl chloride (200 mg, 0.35 mmol) and 3-amino-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide are reacted in 2 ml dry pyridine at r.t. for 18 hrs. The solvent is removed under reduced pressure. The product is isolated by automated column chromatography and is dried at the high vacuum pump, yielding the title compound as a white solid.
Reaction SMILES: [NH:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1O)C(C)=O.[C:20](=[O:23])([O-])[O-].[K+].[K+].[C:26](=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:5]1[C:14]2[C:9](=[CH:10][C:11]([S:15]([OH:18])(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:23][CH2:20][CH3:26]
Reactant: CC(=O)Nc1c(O)ccc2cc(S(=O)(=O)O)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOc1ccc2cc(S(=O)(=O)O)ccc2c1N
Temperature: 120 °C
Yield: 190.3 %

Procedure:
6.42 kg (62% pure=4 kg of 100% pure) of 1-acetamino-2-hydroxy-naphthalene-6-sulphonic acid, prepared according to Example 4, 0.98 kg of potassium carbonate and 0.75 kg of sodium carbonate are introduced into a 150 l autoclave. After flushing the autoclave with nitrogen, 22 kg (28 l) of ethanol are added to the mixture. The autoclave is closed and heated to 120° C., whilst stirring thoroughly. 7 kg (6.5 l) of 2 N potassium hydroxide solution and 2.75 kg (about 3 l) of ethyl chloride are now pumped into the autoclave in the course of 1 to 2 hours. The entire reaction mixture is stirred for a further 5 hours at 120° C. After cooling the reaction mixture to room temperature, the autoclave is let down and flushed twice with nitrogen. The contents of the autoclave are then introduced into a 250 ml V4A steel kettle. The autoclave is rinsed out with 5 kg of 80% pure ethanol and the rinsing solution is likewise introduced into the steel kettle. The mixture in the steel kettle is heated to the boiling point, about 20 kg of alcohol being distilled off. 13 kg of water are then allowed to run slowly into the boiling solution and the mixture is distilled until no further alcohol passes over. After adding 4.3 kg of 50% strength sodium hydroxide solution, the mixture is stirred at 100° C. for 4 hours. The mixture is then cooled to 20° C. and the product which has precipitated is filtered off and washed with 25 kg of sodium chloride solution. After drying, 3.6 kg of 1-amino-2-ethoxy-naphthalene-6-sulphonic acid (content: 84.2% pure, corresponding to 3.03 kg of 100% pure=80% of theory, relative to 1-acetamino-2-hydroxy-naphthalene-6-sulphonic acid, or 61.6% of theory, relative to 2-hydroxy-naphthalene-6-sulphonic acid) are obtained.