Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:14]([OH:16])=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.[NH2:27][C:28]1[CH:29]=[C:30]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[CH:31]=[CH:32][C:33]=1[CH3:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:34][C:33]1[C:28]([NH:27][C:14]([C:1]2[C:13]3[NH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:16])=[CH:29][C:30]([C:35]2[CH:40]=[N:39][CH:38]=[N:37][CH:36]=2)=[CH:31][CH:32]=1
Reactant: Cc1ccc(-c2cncnc2)cc1N
Reactant: O=C(O)c1cccc2c1[nH]c1ccccc12
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ccc(-c2cncnc2)cc1NC(=O)c1cccc2c1[nH]c1ccccc12
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
To a suspension of 9H-carbazole-1-carboxylic acid (148 mg) and 1-hydroxybenzotriazole (114 mg) in dichloromethane (3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiinide hydrochloride (201 mg), and the m e was stirred for 15 minutes. After adding 5-(3-amino-4-methylphenyl)pyrimdine (136 mg) and 4dimethylaminopyridine (128 mg), the mixture was stirred for 24 hours. The mixture was evaporated under reduced pressure and the residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[6methyl-3-(pyrimidin-5-yl)-phenyl]-9H-carbazole-1-carboxamide (89 mg, 33.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([OH:12])=[N:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O>[CH2:23]([N:10]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:11]1=[O:12])[CH:22]=[CH2:21]
Reactant: CCOC(=O)c1ncc(-c2ccccc2)nc1O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccccc2)cnc(C(=O)OCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
2-Ethyloxycarbonyl-3-hydroxy-5-phenylpyrazine (214.4 mg, 0.88 mmol) was dissolved in dimethylformamide (2.1 ml), and sodium hydride (60% in oil, 42.1 g, 1.05 mmol) was added to it under cooling on ice and stirred for 30 minutes. After allyl bromide (0.11 ml, 1.32 mmol was added, the mixture was stirred at room temperature for 1 hour and then at 80° C. for 1 hour. The reaction solution was left to be cooled to room temperature, thereafter the reaction was terminated by adding distilled water, and the product was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) whereby the title compound was obtained (24 mg, 9.6% yield).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8]>O>[Cl:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7]1[O:8][C:7]([C:6]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:5]=2[Cl:4])=[N:2][N:3]=1
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Solvent: O
Product: Clc1ccc(-c2nnc(-c3ccc(Cl)cc3Cl)o2)c(Cl)c1
Temperature: 125 °C
Reaction time: 5 h
Yield: 75.1 %

Procedure:
A mixture was prepared by slowly adding 10 grams (g) of hydrazine hydrate to 400 g of vigorously stirring polyphosphoric acid at ~50° C. To this mixture was added 76 g (0.4 mole) of 2,4-dichlorobenzoic acid. A slurry developed and it was stirred at 125° C (+5°) for 5 hours. The reaction products were cooled slightly and poured into ~1.5 liter (1) of cold water. The solid which precipitated was recovered by filtration, washed with water, dried and recrystallized from chlorobenzene to give 54 g (75% of theoretical) of the desired 2,5-bis(2,4-dichlorophenyl)-1,3,4-oxadiazole.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([OH:27])[CH3:26].[O-]CC.[Na+]>O>[CH2:1]([N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[O:27][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CS(=O)(=O)c1nc2cnc3cccnc3c2n1Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1nc2cnc3cccnc3c2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
To 1-benzyl-2-methanesulfonyl-1H-imidazo[4,5-c][1,5]naphthyridine (6.8 g, 20.1 mmol) was added ethanol (200 mL) and the suspension was stirred at room temperature. To this suspension was added sodium ethoxide (2.0 g) and the reaction was heated at reflux for 1 hour. After 1 hour additional sodium ethoxide was added, and the reaction was heated at reflux for 2 hours and then cooled to ambient. To this reaction was added water (500 mL), and the suspension was stirred for 30 minutes. The gray precipitate was isolated by filtration and washed with water and ether. The solid was dried under reduced pressure to afford 1-benzyl-2-ethoxy-1H-imidazo[4,5-c][1,5]naphthyridine (4.5 g) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:23][O:22][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20])[O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCN1CCCCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: COc1cc(OCCN2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
1-Piperidineethanol (1.8 g, 14 mmol) was added to a mixture of powdered KOH (0.78 g, 14 mmol) and Aliquat 336 (0.56 g, 1.4 mmol), and the resulting mixture was stirred for 5 minutes at 80° C. Then 4-fluoro-2-methoxy-1-nitrobenzene (2.0 g, 12 mmol) was added, and stirring proceeded at this temperature for 30 minutes. The mixture was cooled and partitioned between methylene chloride (75 mL) and water (75 mL), and the organic phase was washed with water (75 mL) and extracted with dilute aqueous HCl (3×60 mL). The combined aqueous phases were washed with methylene chloride (3×75 mL), basified (3N NaOH), and extracted with methylene chloride (3×75 mL). The combined organic extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 1.6 g, in 49% yield; 1H NMR (DMSO-d6) δ 1.48-1.53 (m, 6H), 2.40-2.44 (m, 4H), 2.67 (t, J=5.8 Hz, 2H), 3.93 (s, 3H), 4.21 (t, J=5.8 Hz, 2H), 6.67 (dd, J=9.3 Hz, J=1.5 Hz, 1H), 6.81 (d, J=1.5 Hz, 1H), 7.95 (d, J=9.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1>>[C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]3)=[N:21][CH:22]=1)=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 64 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (260 mg, 1.1 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (470 mg, 1.6 mmol) to afford the desired product (350 mg, 65%) as an orange-red solid: 1H NMR (300 MHz, CDCl3) δ 11.48 (s, 1H), 9.04 (s, 1H), 8.10 (d, J=8.7 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.31 (dd, J=9.0, 2.8 Hz, 1H), 6.73 (d, J=9.0 Hz, 1H), 4.80 (br s, 1H), 3.85-3.62 (m, 3H), 3.55-3.25 (m, 3H), 2.71 (s, 3H), 1.96-1.84 (m, 1H), 1.82-1.70 (m, 1H), 1.72-1.55 (m, 1H), 1.45 (s, 9H); ESI MS m/z 497 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(O)(=O)=O)C=CC=CC=1.[C:40]1([C:46]2([NH:52][C:53]([N:55]3[CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:54])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:11].[ClH:27].[CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15][N:49]2[CH2:50][CH2:51][C:46]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([NH:52][C:53]([N:55]3[CH2:56][CH2:57][CH2:58][CH2:59]3)=[O:54])[CH2:47][CH2:48]2)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C(=O)CO1
Reactant: O=C(NC1(c2ccccc2)CCNCC1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COC(CCN2CCC(NC(=O)N3CCCC3)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Temperature: 90 °C
Yield: 65.2 %

Procedure:
A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.2 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonylamino)piperidine benzenesulfonate and 0.95 g of K2CO3 in 3 ml of DMF is heated at 80-100° C. for 3 hours. After cooling to RT, the reaction mixture is poured into water and the precipitate formed is wrung, washed with water and dried under vacuum. The precipitate is chromatographed on silica H using a DCM/MeOH mixture (from 100/2; v/v to 100/3; v/v) as the eluent. The product obtained is dissolved in the minimum amount of DCM and acidified to pH 1 by the addition of a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.54 g of the expected product. M.p.=158-160° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](O)=[O:5].CC[N:15]=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.N>O1CCCC1.CN(C)C(=O)C>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Nc1cc(F)cc(F)c1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: NC(=O)c1c(N)cc(F)cc1F
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of 2-amino-4,6-difluoro benzoic acid (4.0 g, 23.12 mmol, Butt Park Ltd.) in tetrahydrofuran (1.0 L) and N,N-dimethylacetamide (150 mL) was added EDCl.HCl (13.44 g, 70 mmol, Aldrich), HOBT (9.5 g, 70 mmol, Aldrich) and ammonia as a 0.5M solution in dioxanes (460 mL, 230 mmol, Aldrich). The resultant slurry was stirred for 24 hours, and then solids removed by filtration through celite. The filtrate was taken to a residue under reduced pressure and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by chromatography on SiO2 (Ethyl acetate/Hexanes) to afford analytically pure 2-amino-4,6-difluorobenzamide as a white crystalline solid (3.11 g, 78% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 6.21-6.27 (m, 1 H), 6.27-6.32 (m, 1 H), 6.52 (s, 2 H), 7.48 (s, 1 H), 7.53 (s, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:11][C:12]1[N:16]=[CH:15][N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[N:13]=1
Reactant: Cc1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 70 °C

Procedure:
A mixture of 4-fluoro-1-nitrobenzene (0.28 g, 2.0 mmol), 3-methyl-1H-1,2,4-triazole (0.18 g, 2.2 mmol), K2CO3 (0.55 g, 4.0 mmol) and DMF (2 mL) was heated at 70° C. overnight. The reaction mixture was cooled down to room temperature, diluted with water, extracted with EtOAc (3×). The organic solution was dried over anhydrous MgSO4 and concentrated in vacuo to provide a solid. Purification of this material by column chromatography on silica gel (40% EtOAc/hexane) provided 3-methyl-1-(4 nitrophenyl)-1H-1,2,4-triazole as the major product. 1H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H), 8.39 (d, 2H), 7.88 (d, 2H), 2.53 (s, 3H). Further elution with 65% EtOAc/hexane provided 5-methyl-1-(4-nitrophenyl)-1H-1,2,4-triazole as the minor product. 1H NMR (CDCl3, 400 MHz) δ 8.34 (d, 2H), 7.93 (s, 1H), 7.66 (d, 2H), 2.59 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[N:17]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[C:26](=[O:29])(O)[O-:27].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:16]1[C:21]([NH:22][C:26]([O:27][CH2:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[O:29])=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[N:17]=1)[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(c1nc(OC)ccc1N)S(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(c1nc(OC)ccc1NC(=O)OCc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 9.45 g (0.026 m) of [3-amino-6-methoxy-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethyl ester dissolved in 150 mL of methylene chloride is added 150 mL of saturated sodium bicarbonate followed by 5.56 mL (0.038 m) of carbo-benzyloxy chloride. The reaction mixture is stirred for 20 hours at room temperature. The water layer is separated from the organic layer and the organic layer is dried (Na2SO4) and evaporated to yield 15.73 grams of [3-benzyloxycarbonylamino-6-methoxy-pyridin-2-yl]-[toluene-4-sulfonyl]-acetic acid ethyl ester as a yellow solid. 1H NMR (CDCl3) δ 7.8 (m, 1H), 7.6 (m, 1H), 7.3 (m, 10H), 6.7 (m, 1H), 5.2 (m, 3H), 4.0 (m, 2H), 3.3 (s, 3H), 3.1 (m, 2H), 1.1 (m, 3H). TLC (7/3 hexanes/ethyl acetate) Rf=0.6. Step 5:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(Cl)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(Cl)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-chlorobenzoxazole (100 mg, 0.33 mmol) and 1,2,4-benzenetricarboxylic anhydride (69 mg, 0.36 mmol) the title compound was obtained (92 mg, 58%). 1H NMR (DMSO) δ 8.41(dd, 1H), 8.37(t, 1H), 8.09–8.05(m, 2H), 7.92(d, 1H), 7.79(d, 1H), 7.47(m, 2H), 7.03(d, 1H), 3.34(m, 2H), 1.74(m, 2H), 1.05(t, 3H). MS m/z 474.0 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[N:5][C:6]([CH:18]2[CH2:20][CH2:19]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)#[N:2].O.O.[Sn](Cl)Cl>CCO>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[CH:7]=[C:6]([CH:18]3[CH2:19][CH2:20]3)[N:5]=[C:4]([O:21][S:22]([C:25]([F:27])([F:28])[F:26])(=[O:24])=[O:23])[C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1c(-c2ccc(N)cc2)cc(C2CC2)nc1OS(=O)(=O)C(F)(F)F
Yield: 86.1 %

Procedure:
In analogy to GP 3, reaction of 1.49 g trifluoromethanesulphonic acid 3-cyano-6-cyclopropyl-4-(4-nitro-phenyl)-pyridin-2-yl ester (3.6 mmol, 1 eq.) with 4.1 g tin(II) chloride dihydrate (18.19 mmol, 5 eq.) in 20 mL EtOH yielded 1.2 g of the desired aniline (3.1 mmol, 86% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:23])[CH:21]=[CH2:22].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CO>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:23])[CH:21]=[CH2:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
To an ice-cold solution of 0.158 g (0.5 mM) of 7-amino-4-(3-bromoanilino)-quinazoline [J Med Chem, 1995:3482] and 0.108 g of acrylic acid in 5.0 mL of dry dimethylformamide (DMF) was added 0.288 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDAC). After stirring for 5 minutes, the mixture became a solution, and the ice bath was removed. The reaction continued to stir at room temperature for 3 hours. The reaction was then poured into a mixture of ice and water and made basic with the addition of a saturated solution of sodium bicarbonate. This aqueous mixture was extracted three times with ethyl acetate, and the pooled extracts were dried over magnesium sulfate. The solution was filtered and concentrated in vacuo to afford a light yellow solid. The solid was dissolved in 100 mL of methanol, filtered, and concentrated in vacuo to approximately 10 mL. The solid which precipitated from solution was collected and dried in vacuo at 80° C. to give 50 mg of N-[4-(3-bromophenylamino)-quinazolin-7-yl]acrylamide, mp >265° C. Chemical ionization mass spectra: m/e 369.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12.C[Si](C)(C)NC(=O)C.CS([O:41][C:42](=O)[C:43]([C:52]1[N:56]=[C:55]([NH2:57])[S:54][N:53]=1)=[N:44][O:45][C:46]([C:49]([OH:51])=[O:50])([CH3:48])[CH3:47])(=O)=O.C(OCC)(=O)C>O1CCCC1>[NH2:57][C:55]1[S:54][N:53]=[C:52]([C:43](=[N:44][O:45][C:46]([C:49]([OH:51])=[O:50])([CH3:48])[CH3:47])[C:42]([NH:3][C@@H:4]2[C:27](=[O:28])[N:6]3[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]4[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=4)[CH2:9][S:10][C@H:5]23)=[O:41])[N:56]=1
Reactant: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Reactant: CC(C)(ON=C(C(=O)OS(C)(=O)=O)c1nsc(N)n1)C(=O)O
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+](C)(C)Cc3cc(=O)c(O)c[nH]3)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
7β-Amino-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate dihydrochloride (181 mg) was suspended in tetrahydrofuran (9.1 ml). To the suspension was added N-(trimethylsilyl)acetamide (788 mg), and the mixture was stirred at 35° C. for 30 minutes and cooled to 5° C. To the resulting solution was added a solution of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetic methanesulfonic anhydride (syn isomer) (169 mg) in tetrahydrofuran (0.5 ml). The mixture was warmed to 20° C. and stirred for 1.2 hours. The mixture was poured into ethyl acetate (200 ml) and the resulting precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried in vacuo. The powder was suspended in water (40 ml) and adjusted to pH 1 with 1N hydrochloric acid. After the insoluble materials were removed by filtration, the filtrate was chromatographed on Diaion HP-20 (15 ml) and the elution was carried out with 15% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (120 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10](I)[CH2:9]1)[CH3:2]>N.O.[Pd]>[CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](I)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Pd]
Agent: N
Solvent: O
Product: CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 71.3 %

Procedure:
A solution of 2.50 g of 2',3'-dideoxy-5-ethyl-3'-iodouridine in a mixture of 90 ml of ethanolic ammonia and 17 ml of water was hydrogenated over 5% palladium on barium sulfate catalyst at room temperature and under atmospheric pressure for 3 hours. The mixture was filtered and the filtrate was evaporated. The residue was extracted twice with 250 ml of hot ethyl acetate each time and the combined ethyl acetate extracts were evaporated. The residue was chromatographed on a short column of silica gel using ethyl acetate for the elution and the product was crystallized from a mixture of ethyl acetate and hexane to give 1.17 g of 2',3'-dideoxy-5-ethyluridine in the form of a white solid of melting point 109°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=466.1, tR (minutes, Method F)=2.97
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8]C=CC=2)[C:6](=O)[C:5]1=O)CC.[CH3:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCC(C)C>>[CH2:5]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([CH3:15])=[CH:24][CH:23]=2)[C:19](=[O:26])[C:20]1=[O:25])[CH2:6][CH:7]([CH3:12])[CH3:8]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CC(C)CCBr
Product: Cc1ccc2c(c1)C(=O)C(=O)N2CCC(C)C

Procedure:
Made in an analogous fashion to 1-propylindoline-2,3-dione using commercially available 5-methyl isatin (purchased from Fisher Scientific) and 1-bromo-3-methylbutane (purchased from Fisher Scientific). 1H NMR δ 7.41 (m, 2H), 6.78 (d, 1H), 3.71 (t, 2H), 2.33 (s, 3H), 1.57 (m, 3H), 0.99 (d, 6H).
Reaction SMILES: Cl.[CH2:2]([NH:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:18]C)[C:12]=2[O:16]C)[CH2:7]1)[CH2:3][CH3:4].[BrH:20]>>[BrH:20].[CH2:2]([NH:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:18])[C:12]=2[OH:16])[CH2:7]1)[CH2:3][CH3:4]
Reactant: CCCN[C@H]1CCc2c(ccc(OC)c2OC)C1
Agent: Br
Agent: Cl
Product: CCCN[C@H]1CCc2c(ccc(O)c2O)C1
Temperature: 130 °C

Procedure:
A solution of (S)-N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (22 g; 76.9 mmoles), prepared as described in example 2, in 48% hydrobromic acid (220 ml) was heated under reflux (about 130° C.) for 3 hours. The solvent was evaporated to dryness under vacuum and the residue was taken twice with toluene, by evaporating to dryness each time. The resultant crude was collected with ethyl acetate and filtered obtaining (S)-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine hydrobromide (23 g).