Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:13](Cl)[CH2:14][CH3:15]>C(O)C>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CCCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccc(C(C)(C)C)cc1

Procedure:
Into 70 ml. of ethanol (absolute), 0.92 g. of sodium metal was dissolved and 6.0 g. (0.04 M) of 4-tert-butylphenol was added and then, 3.5 g. (0.044 M) of n-propylchloride was added. The mixture was refluxed for 20 hours and ethanol was distilled off and water was added. The reaction product was extracted with benzene and benzene layer was washed with 3% NaOH aqueous solution and with water and dehydrated over sodium sulfate and then, benzene was distilled off and a residue was distilled under a reduced pressure to obtain 4-tert-butyl-1-n-propoxybenzene. The product was dissolved into 6 ml. of glacial acetic acid and then, 12 ml. of fuming nitric acid (d=1.5) was added at 0° to 5° C. to react them for 1 hour and then, the reaction was continued at the ambient temperature for 1 hour at 35° to 40° C. for 4 hours. The reaction mixture was poured into ice water and the product was extracted with chloroform and washed with water, with 3% Na2CO3 aqueous solution and with water and dehydrated over sodium sulfate and chloroform was distilled off and the residue was recrystallized from ethanol to obtain 4.5 g. (43%) of a pale yellow crystal. (melting point of 106° to 107° C.)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH3:22][CH:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NCCCC)CCC>>[CH3:22][CH:23]([NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccn2cc(-c3ccc(OCCCCl)cc3)nc12
Reactant: CC(N)c1ccccc1
Solvent: CCCCNCCCC
Product: Cc1cccn2cc(-c3ccc(OCCCNC(C)c4ccccc4)cc3)nc12

Procedure:
This compound was prepared according to the procedure described in Example 1 of U.S. Pat. No. 4,727,145. using 2-(4-chloropropoxyphenyl)-8-methylimidazo[1,2-a]pyridine and alpha-methylbenzylamine instead of 2-(4-chloropropoxyphenyl)-imidazo[1,2-a]pyridine and dibutylamine respectively. Analysis: Calc'd for C25H27N3O 3HCl; C, 6.11; H, 60.8; N, 8.49. Found: C, 6.51; H, 60.43; N, 8.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:11][C:10]([C:21](O)=[O:22])=[C:9]2[CH2:24][CH2:25][CH2:26][OH:27])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([C:41]([NH2:43])=[O:42])[CH2:36][CH2:37][N:38]([C:21]([C:10]3[CH:11]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=4[Cl:20])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:9]=3[CH2:24][CH2:25][CH2:26][OH:27])=[O:22])[CH2:39][CH2:40]2)=[CH:31][CH:30]=1
Reactant: NC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)n(-c3ccc(Cl)cc3)c2CCCO)CC1

Procedure:
Into a round-bottomed flask under nitrogen are introduced 300 mg of the acid obtained in step 3a) in 30 ml of DMF, 246 mg of 4-(4-chlorophenyl)piperidine-4-carboxamide (prepared according to the procedure described in patent application US 2005/0070549, in particular in Example 460, paragraphs 1394 to 1397), 0.62 ml of DIPEA and 250 mg of TBTU.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].OS(O)(=O)=O.OP(O)(O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22]>>[Cl:15][C:16]1[CH:21]=[C:20]([N+:1]([O-:4])=[O:2])[CH:19]=[CH:18][C:17]=1[Cl:22].[Cl:15][C:16]1[C:17]([Cl:22])=[CH:18][CH:19]=[CH:20][C:21]=1[N+:1]([O-:3])=[O:2]
Reactant: Clc1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Product: O=[N+]([O-])c1cccc(Cl)c1Cl

Procedure:
If nitration is carried out in the hitherto known manner in an HNO3 /H2SO4 mixture without addition of H3PO4, in the nitration of 1,2-dichlorobenzene the two isomers are typically formed in approximately 98.5% yield in a ratio of 3,4-dichloro- 1-nitrobenzene to 2,3-dichloro- 1-nitrobenzene of 8.2:1. If 1,2-dichlorobenzene is nitrated using phosphoric acid which is concentrated to 104%, simultaneously dispensing with sulphuric acid and with additional use of nearly anhydrous nitric acid, then a shift in favour of the 2,3-isomer is obtained. The ratio 3,4-: 2,3-dichloro-1-nitrobenzene accordingly falls to values of 5.95 or 5.45, depending slightly on the reaction temperature, as was found by our own experiments. The term 104% strength H3PO4 signifies a concentrated, i.e. dehydrated, phosphoric acid, which contains a proportion of pyrophosphoric acid and accordingly has a P2O5 content which corresponds to 104% H3PO4. The serious disadvantage of such a procedure is the great fall in the yield to 89% or even 86% as a specific function of the reaction temperature.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][S:6][C:5](=[S:8])[N:4]1[CH2:9][C:10]([OH:12])=O.[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:24][N:23]([C:10](=[O:12])[CH2:9][N:4]2[C:3](=[O:2])[CH2:7][S:6][C:5]2=[S:8])[C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CN1C(=O)CSC1=S
Yield: 39.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 99, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(4-oxo-2-thioxothiazolidin-3-yl)acetyl)pyrrolidine-2-carboxamide (13.5 mg, 39.9%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.92 (s, 1H), 7.51 (d, 2H), 7.30-7.16 (m, 9H), 6.93 (m, 2H), 4.76 (m, 1H), 4.60 (m, 1H), 4.43 (m, 1H), 4.35 (m, 2H), 2.87 (s, 2H), 2.68 (m, 3H), 1.95 (m, 2H). MS (EI) for C29H26FN3O4S2. found 564.7 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][NH2:14].C(O)(=O)C>O>[CH3:12][O:13][N:14]=[CH:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[N:5][C:6]=1[Cl:10]
Reactant: CON
Reactant: Nc1ncnc(Cl)c1C=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CON=Cc1c(N)ncnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1a (1.0 g), O-methyl-hydroxylamine hydrochloride (0.94 g) and a mixed solvent of acetic acid (25 mL) and H2O (4 mL) were added to a flask. The mixture was stirred at rt overnight, then concentrated. The residue was suspended in H2O and extracted with EtOAc. The organic layer was separated, dried with MgSO4, then concentrated to afford 4-amino-6-chloro-pyrimidine-5-carbaldehyde O-methyl-oxime Compound 9a (0.97 g, 92%). 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.70 (s, 1H), 3.98 (s, 3H). MS (ESI) m/z: 188 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:11]=[C:12](O)[C:13]2[S:19][CH2:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]=[C:12]([Cl:23])[C:13]2[S:19][CH2:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(COCc2ccccc2)nc2c1SCCC2
Product: Clc1nc(COCc2ccccc2)nc2c1SCCC2

Procedure:
The title compound was prepared following substantially the same procedure described in Example 1, Step B using the title compound from Step A hereof and phosphorus oxychloride. The procedure gave 0.8 gm of product as a brown solid which was used in Step C without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:26])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:29](=[O:31])[CH3:30])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-nitrophenyl}methanamine (0.3 g) and acetic anhydride (0.1 g) in dichloromethane (50 mL), a solution of triethylamine (0.1 g) in dichloromethane (5 mL) was added dropwise under ice cooling, and the mixture was then stirred for one hour at room temperature. The reaction solution was diluted with water, and the organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatogaphy to yield N-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-nitrobenzyl}acetamide (0.2 g).
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19].[CH3:21][N:22]([CH3:37])[CH2:23][CH2:24][NH:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:37][N:22]([CH3:21])[CH2:23][CH2:24][N:25]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=1)[C:2]([O:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:20])[CH3:14])=[O:3]
Reactant: CN(C)CCCO
Reactant: COC(=O)c1ccc(CNCCN(C)C)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(CCN(C)C)C(=O)OCCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of p-nitrophenyl chloroformate (18.1 g) in methylene chloride (300 mL) is added dropwise 3-(dimethylamino)propanol (14.2 mL) and the mixture is stirred at room temperature for 4 hours. To the mixture is added successively methyl 4-[[[2-(dimethylamino)ethyl]amino]methyl]benzoate (13.7 g) and triethylamine (25 mL) and the mixture is stirred at room temperature for one day. The reaction mixture is washed with a saturated potassium carbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant crude product is purified by flash column chromatography on NH-silica gel (Chromatorex NH silica gel, Solvent; ethyl acetate:n-hexane=1:1) to give methyl 4-[[N-[2-(dimethylamino)ethyl]-N-[[3-(dimethylamino)propoxy]carbonyl]amino]methyl]benzoate (7.97 g, yield; 38%) as a colorless oil. MS (APCI) m/z: 366 [M+H]+
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C(C1C=C(C)C(=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)(C)(C)C.Cl>C(OCC)C>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[C:6]=1[CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 2.53 g of 2,7-di-tert-butyl-fluorene (9.10 mmol) was dissolved in 70 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 6.4 ml of a n-butyl lithium/hexane solution (1.56M: 9.98 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, a solution prepared by dissolving 3.01 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (10.0 mmol) in 40 ml of dehydrated diethyl ether was added and stirred with refluxing for 7 days. The reaction mixture was added to 100 ml of a hydrochloric acid aqueous solution (1N) and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-brown liquid. The liquid was purified by a column chromatography using 180 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. The remainder was re-crystallized using methanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.65 g (2.85 mmol) as a pale yellow solid (yield: 31%).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:13]1[C:17]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:16][CH2:15][NH:14]1.[NH2:30][C:31]1[CH:32]=[C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:34]=[CH:35][C:36]=1[NH:37]C(=O)OC(C)(C)C.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-]>ClCCl>[NH2:37][C:36]1[CH:35]=[CH:34][C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:32][C:31]=1[NH:30][C:8]([C:7]1[CH:11]=[CH:12][C:4]([NH:1][C:2]([N:14]2[CH2:15][CH2:16][C:17]3([CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH2:13]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=C=Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(NC(=O)N2CCC3(CCNCC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL dichloromethane was added tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (60 mg, 0.275 mmol) slowly over a period of 10 minutes. The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl (3-aminobiphenyl-4-yl)carbamate (78.2 mg, 0.275 mmol) was then added, followed by the addition of diisopropylethylamine (48 μL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Argonaut MP-Carbonate scavenging resin (285 mg, 0.825 mmol) was then added and stirred overnight at room temperature. The mixture was then filtered from scavenging resin and concentrated. Added dichloromethane (1 mL) and stirred, then treated with trifluoroacetic acid (1 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [M+H]+ 470.2, obs'd 470.1
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)([Cl:16])=[O:15].[CH2:18]([N:20](CC)CC)[CH3:19]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5].[NH2:20][CH2:18][C:19]([O:6][CH2:4][C:3]1[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN(CC)CC
Product: NCC(=O)OCc1ccccc1
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
As shown in scheme E, reaction of 2-chloro-5-nitrobenzoic acid with thionyl chloride gave 2-chloro-5-nitrobenzoyl chloride, which on further treatment with benzyl glycinate in the presence of triethylamine gave benzyl 2-(2-chloro-5-nitrobenzamido)acetate (intermediate 6). Treatment of intermediate 6 either with K18F or K19F in the presence of kryptofix [2.2.2] or 18-crown-6 to yield benzyl 2-(2-fluoro-5-nitrobenzamido)acetate, which on further reduction with hydrogen gas or hydrogen source in the presence of Pd/C gave 2-(5-amino-2-fluorobenzamido)acetic acid (compound 5).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:9].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12]>[OH-].[Na+]>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:11]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:9])=[O:12])=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O
Reactant: O=C1CCCCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
5 g (44.2 mmole) of ε-caprolactam was dissolved in 19.48 g of 20 wt % NaOH and heated to reflux for 3-5 hours. After ε-caprolactam was hydrolyzed completely, the mixture was cooled down to 5˜10° C. and then 25 g of water and 10 g of 4-nitrobenzyl chloroformate were added. The mixture was stirred 1 hour at 5-10° C. and then washed with 25 g of ethyl acetate twice. The pH of the aqueous layer was adjusted to 1-2 by adding 16% HCl and extracted with ethyl acetate twice. Combined ethyl acetate layer was washed with water. The organic layer was dried by sodium sulfate and concentrated to obtain 6-(4-nitro-benzyloxycarbonylamino)-hexanoic acid. Purity was 93.9%.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:24]=1[C:25](Cl)=[O:26].C(OCC)(=O)C.C(O)C>C(OCC)(=O)C.O.C(OCC)(=O)C>[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:24]=1[C:25]([N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:26]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1cc(OC)c(C(=O)Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc1OC
Reaction time: 18 h

Procedure:
Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (1.8 mmol) and sodium carbonate (0.76 g, 7.2 mmol) in ethyl acetate/water (10 mL/10 mL). With stirring, add a solution of 2,4,5-trimethoxybenzoyl chloride (1.1 g, 1.8 mmol) in ethyl acetate (1 mL). After 18 hours, separate the layers and extract the aqueous layer twice with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 9/1 ethyl acetate/ethanol to give the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[CH2:11][C:12]#[N:13].[NH2:14][C:15]1[N:20]=[C:19]([NH2:21])[C:18]([CH:22]=O)=[CH:17][N:16]=1>C(OCCO)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[C:11]1[C:12]([NH2:13])=[N:21][C:19]2[N:20]=[C:15]([NH2:14])[N:16]=[CH:17][C:18]=2[CH:22]=1
Reactant: N#CCc1c(Br)cccc1Br
Reactant: Nc1ncc(C=O)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCCO
Product: Nc1ncc2cc(-c3c(Br)cccc3Br)c(N)nc2n1
Temperature: 0 °C
Yield: 63.3 %

Procedure:
To a solution of 0.23 g 60% sodium hydride suspension in 11.0 mL of 2-ethoxyethanol was added 4.18 g of 2,6-dibromophenylacetonitrile and 2.00 g of 2,4-diaminopyrimidine-5-carboxaldehyde. The reaction was refluxed for 4 hours, cooled, and poured into ice water. The residue was washed well with acetonitrile then diethyl ether to give 3.62 g of 6-(2,6-dibromophenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 422=M+ +C2H5, 396 (Base), 394=M+ +H, 393=M+ ; mp 284-289° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23](=[O:25])[CH3:24])=[CH:17][C:16]=1[O:26][CH2:27][CH3:28]>CC(C)=O>[CH3:1][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23](=[O:25])[CH3:24])=[CH:17][C:16]=1[O:26][CH2:27][CH3:28]
Reactant: CCOc1cc(C=CC(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOc1cc(C=CC(C)=O)ccc1OC
Yield: 65.1 %

Procedure:
Anhydrous sodium carbonate (3.98 g) and dimethyl sulfate (3.78 g, 30 mmol) were added to a solution of 4-(4-hydroxy-3-ethoxyphenyl)-3-buten-2-one (6.2 g, 30 mmol) in acetone (40 ml). The reaction mixture was stirred under refluxing for 8 hr. The precipitated yellow solid was filtered, washed with acetone, and then recrystallized from anhydrous ethanol to give 4.3 g of a yellow crystal, mp 95-96° C., yield 65.3%.
Reaction SMILES: [ClH:1].[CH2:2]([O:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH2:11])[CH2:3][CH2:4][CH2:5][CH3:6].[NH4+].[OH-].Cl.N([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]3[N:43]=[CH:42][NH:41][C:39]3=2)[N:34]=[C:33]([CH3:44])[CH:32]=1)C1C=CC=CC=1>C(O)C>[ClH:1].[CH2:2]([O:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[NH:11][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]3[N:43]=[CH:42][NH:41][C:39]3=2)[N:34]=[C:33]([CH3:44])[CH:32]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: CCCCCOc1ccc(N)cc1OCCCCC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCOc1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1OCCCCC
Reaction time: 8 h

Procedure:
Ten grams (0.033 m.) of 3,4-dipentoxyaniline hydrochloride was dissolved in 500 ml. of ethanol, then neutralized with 28% NH4OH. After adding 7.2 g. (0.033 m.) of the compound of Example I, C., the mixture was refluxed with stirring overnight. Concentration in vacuo gave 17 g. The crude product was recrystallized from 300 ml. of MeOH to yield 16 g. m.p. 236°-238°C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].F[C:38](F)(F)[C:39](O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCCC1CCN(C(OCC2C=CC=CC=2)=O)CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:24][CH:23]1[CH2:39][CH2:38][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCC(CCCCCBr)CC1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(5-bromopentyl)-1-piperidinecarboxylate. LCMS (System B): tRET=3.31 min; MH+ 525