Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N:29]1[CH:34]=[CH:33][C:32]([CH2:35]Cl)=[CH:31][CH:30]=1>O1CCCC1>[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:12]2[C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:11]2)=[CH:31][CH:30]=1
Reactant: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: ClCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1c2cccnc2c(-c2cccc([N+](=O)[O-])c2)nn1Cc1ccncc1
Yield: 26.9 %

Procedure:
To a solution of 8-(3-nitrophenyl)-pyrido[2,3-d]pyridazin-5-one (0.16 g, 0.6 moles) in tetrahydrofuran (50 ml) was added potassium carbonate (0.19 g, 7.1 moles), potassium iodide (1.0 g, 6.0 moles) and 4-picolyl chloride (0.98 g, 6.0 mmoles). The mixture was stirred and refluxed under an inert atmosphere for 18 hours. The solvent was removed under vacuum. The residue was partitioned in methanol/ethyl acetate (1:1), chromatographed in 100% hexane followed by 100% ethyl acetate. The remaining solvent was removed yielding 0.58 g of crude 6-(4-pyridylmethyl)-8-(3-nitrophenyl)pyrido[2,3-d]pyridazin-5-one, which was recrystallized from methanol yielding 0.08 g of the pure compound (37.1%), mp. 167°-168° C.
Reaction SMILES: [C@@H:1]1([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[O:12][C@H:6]([CH:7]([C:9]([OH:11])=[O:10])[OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].S(=O)(=O)(O)O.C(N([CH2:33][CH3:34])CC)C>C(O)CCCCC>[CH2:1]([O:10][C:9]([CH:7]([OH:8])[C@H:6]1[O:12][C@@H:1]([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[C@H:2]([OH:3])[C@@H:4]1[OH:5])=[O:11])[CH2:2][CH2:4][CH2:6][CH2:33][CH3:34]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(=O)O)[C@@H](O)[C@H]1O
Reactant: CCN(CC)CC
Agent: O=S(=O)(O)O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 48 %

Procedure:
5 g of adenosine-5'-carboxylic acid are dissolved in 200 ml of n-hexanol and 2 ml of concentrated sulfuric acid and heated to 100° C. for 3 hours. After cooling, the reaction mixture is neutralized with triethylamine and left to stand overnight, the desired n-hexyl ester and triethylamine sulfate thereby crystallizing out. After filtering off with suction, the triethylamine sulfate is washed out with water and the remaining ester is recrystallized from methanol. There are obtained 3.1 g (48% of theory) of adenosine-5'-carboxylic acid n-hexyl ester, which has a melting point of 145°-147° C.
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][NH:15][CH3:16])C=1C#N.Cl.[CH2:18]([OH:20])[CH3:19]>O>[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][NH:15][CH3:16])[C:19]=1[C:18]([OH:1])=[O:20]
Reactant: CCO
Reactant: [OH-]
Reactant: CNCCOc1cccc(N)c1C#N
Agent: Cl
Agent: [K+]
Solvent: O
Product: CNCCOc1cccc(N)c1C(=O)O
Temperature: 90 °C

Procedure:
Sodium hydride (8.81 g, 220.38 mmol) was added portionwise to 2-(methylamino)ethanol (16.55 g, 220.38 mmol) in THF (500 mL) at 0° C. over a period of 10 minutes under an atmosphere of argon. The resulting solution was stirred at 0° C. for 1 hour and then 2-amino-6-fluorobenzonitrile (20 g, 146.92 mmol) was added in one portion and the mixture heated at 85° C. for 2 hours. The mixture was quenched with water and then evaporated. The residue was dissolved in EtOAc (300 mL), and the mixture washed sequentially with water (2×300 mL), and then with a saturated solution of NaCl (300 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-10%, of a 7M solution of NH3 in MeOH, in CH2Cl2. Fractions containing product were evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzonitrile (12.08 g, 43% yield); Mass spectrum: m/z (ESI+) (M+H)+=192.43. b) Potassium hydroxide (32 g, 570.35 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzonitrile (16 g, 83.67 mmol) in ethanol (160 mL). The resulting mixture was heated at 90° C. for 2 days. The mixture was then diluted with water (1000 mL) and acidified to ˜pH1 with 2M HCl. The mixture was loaded onto an SCX column and the product was eluted first using MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzoic acid which was used without further purification. c) HATU (35.0 g, 92.04 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzoic acid (17.59 g, 83.67 mmol) and DIPEA (15.92 mL, 92.04 mmol) in DMF (200 mL) and the resulting solution was stirred for 1 hour. The mixture was evaporated and the residue dissolved in EtOAc (500 mL). The mixture was washed sequentially with a saturated solution of Na2CO3 (500 mL), water (500 mL), and finally with a saturated solution of NaCl (500 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford 6-amino-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (1.635 g, 10% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.09 (s, 3H), 3.44 (t, 2H), 4.20 (t, 2H), 5.74 (br s, 2H), 6.22 (dd, 1H), 6.52 (dd, 1H), 7.08 (appt t, 1H); Mass spectrum: m/z (ESI+) (M+H)+=193.41.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:30][C:31]1[CH:36]=[CH:35][N:34]2[C:37]([C:40](OC)=[O:41])=[CH:38][N:39]=[C:33]2[CH:32]=1.CO.C(Cl)Cl>C1COCC1>[Br:30][C:31]1[CH:36]=[CH:35][N:34]2[C:37]([C:40]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:41])=[CH:38][N:39]=[C:33]2[CH:32]=1
Reactant: COC(=O)c1cnc2cc(Br)ccn12
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a solution of 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (197.8 mg, 0.784 mmol) in anhydrous THF (3 ml) was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.6 mL) under a nitrogen atmosphere at ambient temperature. The resulting mixture was stirred at ambient temperature for 10 minutes, then added dropwise to a chilled (ice-water bath) solution of methyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (200 mg, 0.784 mmol) in anhydrous THF (3 mL). The cold bath was removed, and the reaction mixture was allowed to warm to ambient temperature, and quenched with water. The resulting suspension was extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 8% MeOH/DCM as the eluent to afford 255.6 mg of desired product as a yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:27])[N:14]=[CH:15][C:10]=3[CH:9]=[CH:8][C:7]2=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2ccc(=O)n(C3CCCC3)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(C3CCCC3)c2n1

Procedure:
A solution of 8-cyclopentyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (10), (3.5 mmol) and MCPBA (5.25 mmol) in CH2Cl2 was stirred at room temperature for about 12 h. After completion of the reaction, the reaction mixture was washed with saturated NaHCO3. The organic layer was dried over Na2SO4, filtered away from the drying agent, and concentrated to give the desired product (11) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[OH-].[K+].Br[CH:20]([Cl:22])[CH3:21]>CCO>[Cl:22][CH2:20][CH2:21][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:16])([CH3:1])[NH:13][C:12]([CH3:15])([CH3:14])[CH2:11]2)[NH:8][C:7]1=[O:9]
Reactant: CC1(C)CC2(CC(C)(C)N1)NC(=O)NC2=O
Reactant: CC(Cl)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC2(CC(C)(C)N1)NC(=O)N(CCCl)C2=O
Reaction time: 6 h

Procedure:
A mixture of 7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (5, 22.2 mmol) and KOH (1.24 g, 22.2 mmol) in EtOH was refluxed for 10 min and bromochloroethane (6.35 g, 44.4 mmol) was added and refluxing continued for additional 6 h. Filtered and concentrated to get the crude chloroethylated product which was used as such for the next step (5.5 g). LCMS—[M+H] m/z 228.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O.[Ag]=O>[CH2:19]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: COc1ccc(C2CCCNC2)cc1OC
Agent: O=[Ag]
Solvent: CC(C)=O
Product: C=CCN1CCCC(c2ccc(OC)c(OC)c2)C1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
2.8 g of silver oxide were added to a solution of 5.6 g of 3-(3',4'-dimethoxyphenyl)-piperidine in 28 ml of acetone and then 2.3 ml of allyl bromide were added dropwise thereto with slow cooling. The mixture was stirred at 20° C for 30 minutes and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 6-3-1 cyclohexane-chloroform-triethylamine mixture yielded 5.55 g of N-allyl-3-(3',4'-dimethoxyphenyl)-piperidine.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][C:7](=[O:9])[O:6][C:4]1=[O:5])[CH3:2].[CH3:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH2:23][O:24][C:25]3[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=3)[NH2:28])=[N:20]2)=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH2:23][O:24][C:25]3[CH:26]=[C:27]([NH:28][C:7](=[O:9])[CH2:8][C:3]([CH2:10][CH3:11])([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])[CH:29]=[CH:30][CH:31]=3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc2ccc(COc3cccc(N)c3)nc2c1
Reactant: CCC1(CC)CC(=O)OC1=O
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(C)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-diethylsuccinic acid anhydride and 3-(7-methyl-2-quinolinylmethoxy)aniline; colourless crystals of m.p. 162°-163°.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13]>[OH-].[Na+].O>[C:5]([OH:6])(=[O:14])[CH2:7][CH2:8][CH2:1][CH3:3].[C:9]([OH:14])(=[O:2])[CH2:10][CH2:11][CH2:12][CH3:13].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(=O)O
Reaction time: 1 h

Procedure:
Hydroquinone (45.6 g) was dissolved in a solution of sodium hydroxide (33.2 g) in water (332 ml) and to the resulting solution was added dropwise valeryl chloride (100 g), while maintaining the temperature at 3° to 6° C. The reaction was allowed to proceed at 15° C. for 1 hour. After reaction, the mixture was extracted with benzene and the benzene extract was washed with dil. sodium hydroxide solution to remove unreacted hydroquinone. The solvent was removed from the extract and the residue was distilled under a reduced pressure to give crude crystals (40 g) which were recrystallized from ethanol to give hydroquinone divalerate (36 g). b.p. 155°-157° C./1 mmHg.
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:38])=[O:37])=O.[F:45][C:46]([F:58])([F:57])[C:47]1[CH:48]=[C:49]([NH:53][C:54]([NH2:56])=[O:55])[CH:50]=[CH:51][CH:52]=1.[C:59]([O:65][CH2:66][CH:67]=[CH2:68])(=[O:64])[CH2:60][C:61]([CH3:63])=O>CC(OC)(C)C>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH:26]2[C:60]([C:59]([O:65][CH2:66][CH:67]=[CH2:68])=[O:64])=[C:61]([CH3:63])[N:53]([C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([C:46]([F:57])([F:58])[F:45])[CH:48]=3)[C:54](=[O:55])[NH:56]2)=[C:29]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:30]=1)#[N:33]
Reactant: C=CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)c(S(=O)(=O)c2ccccc2)c1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOP(=O)(OCC)OCC
Solvent: COC(C)(C)C
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)c1ccccc1
Temperature: 90 °C

Procedure:
The reaction was carried out under argon. Triethyl phosphate (172 mg, 0.947 mmol) and diphosphorus pentoxide (90 mg) were stirred at 40° C. overnight. The mixture was then diluted with MTBE (9.5 ml), and 4-formyl-3-(phenylsulfonyl)benzonitrile (214 mg, 0.789 mmol), 1-[3-(trifluoromethyl)phenyl]urea (0.161 g, 0.789 mmol) and allyl acetoacetate (0.168 g, 1.18 mmol; 1.5 eq.) were added. The mixture was stirred under reflux for 16 h. The reaction mixture was then concentrated by distillative removal of MTBE and subsequently heated at 90° C. for a further 2 h. For work-up, residual solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (150 ml). The organic phase was washed with saturated sodium chloride solution (2×30 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (230 mg, 33% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[O:32][CH:33]=2)[N:3]=1.O>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:22][OH:21])=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[O:32][CH:33]=2)[N:3]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
400 mg (0.70 mmol) of the compound from Example 46A are initially charged in 17 ml of acetic acid, and 8.6 ml of water are then added carefully. The mixture is stirred at RT for 12 h. After concentration of the reaction mixture on a rotary evaporator, the residue is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2)C.[OH-].[Na+]>CO>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]([CH2:5][C:4]([OH:27])=[O:3])[C:7]=2[CH2:19][CH2:18]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.8 %

Procedure:
tert-Butyl 6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.606 g, 1.63 mmol) is dissolved in MeOH (20 mL) and 1N NaOH (2.44 mL, 2.44 mmol, 1.5 equiv.) is added. The resulting solution is stirred at rt for 3 h. The reaction mixture is concentrated and the residue is partitioned between EtOAc (50 mL) and 10% aqueous citric acid (30 mL). The layers are separated and the aqueous layer is extracted with EtOAc (25 mL). The combined organic layers are washed with water (2×15 mL) and brine (15 mL), dried over MgSO4, filtered and concentrated. Crude (3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetic acid (0.566 g) is obtained in quantitative yield. 1H NMR (300 MHz, CDCl3) δ 1.49, 2.92-2.96, 3.00-3.04, 3.67-3.79, 4.83, 7.14, 7.19-7.20, 7.49; MS (ESI−) for C19H24N2O4 m/z 343.1 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.BrC1C=CC(CBr)=CC=1[F:48]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:22][C:23]=1[F:48]
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Reactant: Fc1cc(CBr)ccc1Br
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)c(F)c1

Procedure:
1-(4-(4-Bromo-3-fluorobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 4-bromo-3-fluorobenzyl bromide. MS(ES+): 387/389.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=O.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21].[S].O>CN(C=O)C>[NH:21]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:22]=[C:1]1[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1n[nH]c2cc(C(=O)O)ccc12
Agent: [S]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Yield: 89.7 %

Procedure:
To 3-formyl-1H-indazole-6-carboxylic acid (2.35 g, 12.42 mmol) in DMF (60 mL) was added 1,2-phenylenediamine (12.42 mmol, 1.34 g) and sulfur powder (1.1 eq, 13.66 mmol). This mixture was then heated to reflux for 6 hours. The reaction was followed by TLC and LC-MS. After cooling, water (50 mL) was added to the reaction and the brown precipitate which formed was filtered and collected to provide 3.1 g (90%) of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid. 1H NMR (DMSO-d6) 14.01 (1H, s), 8.58 (1H, d, J=8.5 Hz), 8.24 (1H, s), 7.87 (1H, d, J=8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Mg]Br.C(OCC)C.O.Cl>C(OCC)C>[F:11][C:10]1[C:2]([CH3:14])=[C:3]([C:7]([F:13])=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: C[Mg]Br
Reactant: O=C(O)c1c(F)cc(F)c(F)c1F
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Cc1c(F)c(F)cc(F)c1C(=O)O
Temperature: -10 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
200 mg of 2,3,4,6-tetrafluorobenzoic acid was dissolved in 10 ml of diethyl ether and cooled to −10° C. in an argon atmosphere. Then 1.72 ml of a methyl magnesium bromide-diethyl ether solution (3 moles/liter) was added dropwise. After completion of dropwise addition, the reaction mixture was heated to room temperature and stirred at room temperature for 17 hours. The reaction mixture was added to about 50 ml of cold water and adjusted to pH 1 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate and separated into liquids. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to give 181 mg of 3,4,6-trifluoro-2-methylbenzoic acid (yield: 92%).
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH:14]1[C:29](=[O:30])[N:16]2[C:17]([C:25]([O:27][CH3:28])=[O:26])=[C:18]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][S:20][C@H:15]12>>[C:1]1([S:7]([CH2:9][C:10]([NH:13][CH:14]2[C:29](=[O:30])[N:16]3[C:17]([C:25]([O:27][CH3:28])=[O:26])=[C:18]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][S:20][C@H:15]23)=[O:12])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1=C(CN=[N+]=[N-])CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(O)CS(=O)c1ccccc1
Product: COC(=O)C1=C(CN=[N+]=[N-])CS[C@@H]2C(NC(=O)CS(=O)c3ccccc3)C(=O)N12

Procedure:
368 mg. of phenylsulfinylacetic acid and methyl 7-amino-3-azidomethyl-3-cephem-4-carboxylate were reacted in the same manner as described in Example 4 and 503 mg. of methyl 7-(phenylsulfinylacetamido)-3-azidomethyl-3-cephem-4-carboxylate were obtained.
Reaction SMILES: Cl.COC[C:5]([O:7][CH2:8][CH:9]=[NH:10])=O.[OH:11][CH2:12][C:13]([CH2:15]O)=O.[NH3:17]>C(Cl)Cl>[OH:11][CH2:12][C:13]1[N:17]=[C:9]([CH2:8][O:7][CH3:5])[NH:10][CH:15]=1
Reactant: O=C(CO)CO
Reactant: N
Reactant: COCC(=O)OCC=N
Agent: Cl
Solvent: ClCCl
Product: COCc1nc(CO)c[nH]1
Temperature: 68 °C

Procedure:
A mixture of 30.6 g (0.20 mol) of iminoethyl methoxyacetate-hydrochloride, 18 g (0.20 mol) of 1.3-dihydroxyacetone and 200 ml of liquid ammonia was heated to 68° C. for 3 hours in a stirred autoclave at a pressure of 27 bar (analogously to: P. Dziuron et al. Arch. Pharm. 307, 1974, p.470). Then the ammonia was eliminated and 200 ml of methylene chloride were added. The white precipitate formed was filtered off and washed with methylene chloride. The filtrate was evaporated down and the residue obtained was purified by chromatography (aluminium oxide; methylene chloride/ethanol=90:10 to 85:15). Yield: 26.7 g (94% of theory), Rf value: 0.43 (silica gel; methylene chloride/ethanol=9:1) C6H10N2O2 (142.20) Mass spectrum: (M)+ =142
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([N:26]4[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:36][C:37]1[C:42](B(O)O)=[CH:41][CH:40]=[CH:39][N:38]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:28]1([CH3:33])[CH2:27][N:26]([C:15]2[CH:14]=[CH:13][C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:42]5[C:37]([F:36])=[N:38][CH:39]=[CH:40][CH:41]=5)=[CH:8][CH:9]=4)[C@@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:31][CH2:30][O:29]1
Reactant: OB(O)c1cccnc1F
Reactant: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)CCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)CCO1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A 25 mL RB flask was charged with (R)-2-amino-2′-(2,2-dimethylmorpholino)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (270 mg, 0.526 mmol), tetrakis(triphenylphosphine)palladium(0) (60.8 mg, 0.053 mmol), 2-fluoropyridin-3-ylboronic acid (119 mg, 0.841 mmol), DMF (2629 μL) and sodium carbonate (2M solution) (789 μL, 1.577 mmol). The mixture was stirred under argon for 2 hrs at 85° C. The mixture was diluted with water (2 ml) and extracted with 10 ml of EtOAc. The organic layer was washed with water, brine, passed through plug of Celite and concentrated. Dark residue was purified by silica gel chromatography on a 12 g RediSep column using 5-70% DCM/MeOH/NH4OH in DCM to afford (S)-2′-(2,2-dimethylmorpholino)-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine. Found MS: MH+=461.