Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.CON(C)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13]>C1COCC1>[F:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Br)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2)C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of 1-bromo-3-fluoro-benzene (57.7 g, 0.33 mol) in anhydrous THF (480 mL) was added dropwise to Mg (10.6 g, 0.44 mol) at rt under nitrogen. The mixture was stirred at 50-60° C. for 1 hr. The resulting Grignard reagent was used for the next step. The Grignard reagent was added dropwise to a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (60 g, 0.22 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen. After addition, the mixture was allowed to stir at rt for 1.5 hr. The mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-fluorobenzoyl)piperidine-1-carboxylate (67.5 g, 100%), which was used immediately in the next step without purification.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[N:32]=[C:31]([CH3:33])[C:30]([O:34][CH3:35])=[CH:29][CH:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:28]=[CH:29][C:30]([O:34][CH3:35])=[C:31]([CH3:33])[N:32]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: COc1ccc(I)nc1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)nc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 164 mg (0.66 mmol) of 6-iodo-3-methoxy-2-methyl-pyridine in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 60 mg of a white powder. LC-MSD, m/z for C23H18BrN3O3 [M+H]+=464.0, 466.0; HPLC retention time: 1.9 min.
Reaction SMILES: CP(Cl)(=O)OC.[C:7]([O:10][CH:11]([C:27]1[CH:31]([OH:32])[O:30][C:29](=[O:33])[CH:28]=1)[CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:11]([C:27]1[CH:31]([OH:32])[O:30][C:29](=[O:33])[CH:28]=1)[CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:9])[CH2:8][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)OCC(OC(C)=O)C1=CC(=O)OC1O
Agent: COP(C)(=O)Cl
Product: CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)C1=CC(=O)OC1O

Procedure:
Using methyl methylphosphonochloridate in place of dodecanoyl chloride in the above-described procedure for making 4-(1-acetoxy-2-dodecanoyloxyethyl)-5-hydroxy-2(5H)-furanone, the product obtained is 4-[1-acetoxy-2-OP(O)(OCH3)(CH3) ethyl]-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [S:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1](=[O:10])[C:5]=2[CH:6]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S1C=Nc2ccccc21
Reactant: O=C(O)c1ccccc1
Product: O=C(c1ccccc1)c1ccc2c(c1)S(=O)C=N2
Temperature: 130 °C

Procedure:
To a solution of 0.04 mol of benzothiazolinone in 150 g of polyphosphoric acid there is slowly added, with agitation, 0.05 mol of benzoic acid The reaction medium is heated to 130° C. for 4 hours. After cooling, the mixture is hydrolyzed in 10 volumes of ice-cold water
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:41]([O:43][C:44]([C:46]1[N:47]([CH3:52])[CH:48]=[C:49]([NH2:51])[N:50]=1)=[O:45])[CH3:42].C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:51][C:49]4[N:50]=[C:46]([C:44]([O:43][CH2:41][CH3:42])=[O:45])[N:47]([CH3:52])[CH:48]=4)=[O:17])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1nc(N)cn1C
Reactant: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)cn1C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
To a solution of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid (336 mg, 1.3 mmol, Intermediate E) in DMF (1 mL) are added N-hydroxybenzotriazole (351 mg, 2.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (498 mg, 2.6 mmol). After stifling for 10 min, 4-amino-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester (535 mg, 2.6 mmol), N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) and 4-dimethylaminopyridine (32 mg, 0.26 mmol) are added. The reaction mixture is heated at 60° C. for 16 h. DMF is removed under a stream of N2 at 40° C. and EtOAc (2 mL) and water (2 mL) are added. After stirring for 15 min, a white solid is formed and it is filtered and dried to afford the title compound (490 mg, 92%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]3[S:20][C:21]4[C:22]([N:27]=3)=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:12]=2[O:11][CH:10]=1)(C)(C)C.[ClH:29]>C(Cl)Cl.C(OCC)C>[ClH:29].[S:20]1[C:21]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:27]=[C:19]1[O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([CH2:8][NH2:7])=[CH:10][O:11][C:12]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 130 %

Procedure:
To a solution of 2 [6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-ylmethyl]-carbamic acid tert-butyl ester (0.10 g, 0.25 mmol) in DCM (1.2 mL) was added 2 M HCl in diethyl ether (0.38 mL). The reaction was stirred (rt, 16 h) before additional HCl (0.38 mL) was added. The reaction was stirred (rt, 24 h) and concentrated to provide the title compound as a white solid (98 mg, 130%). Additional mass is likely due to retained HCl and/or solvent. MS (ESI): mass calcd. for C15H11N3O2S, 297.06; m/z found, 298.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11]=O.[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)[CH3:15]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: C=O
Reactant: CNC
Solvent: CCO
Product: CN(C)Cc1ccc(O)c([N+](=O)[O-])c1
Yield: 21.3 %

Procedure:
A mixture of o-nitrophenol (1.0g, 7.19 mmoles), 37% aqueous formalin solution (0.81 ml, 10.78 mmoles) and 25% aqueous dimethylamine solution (1.9 ml, 10.78 mmoles) in 25 ml absolute ethanol was refluxed overnight and the volatile components then removed on a rotary evaporator. The resulting residue was chromatographed on silica gel (silica Woelm® 32-63 μ from Universal Scientific Inc.) using 5% methanol in methylene chloride as the eluent. The first major yellow band to elute contained 0.3g (23% yield) of 4-dimethylaminomethyl-2-nitrophenol. The next yellow band to elute contained 0.3g (23% yield) of the isomeric product, 2-dimethylaminomethyl-5-nitrophenol. The bismannich product remained on the column. The same results were obtained by using N,N,N',N'-tetramethyldiaminomethane instead of the dimethylamine and formalin.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH2:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C@@H:33]([NH:36][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)ccc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: COc1ccc(F)cc1C(=O)c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc1N
Yield: 87.8 %

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-phenyl)-methanone (400 mg, 1.18 mmol, Example 48) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (233 mg,1.25 mmol, Astatech), to give (R)-3-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (447 mg). MS (M+H)+, 432.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH:40]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:24]=[CH:23][CH:22]=[C:11]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19](=[O:21])[NH:46][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:17][CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN2CCC(C(=O)O)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A suspension of crude 1-(3-tert-butoxycarbonylamino-benzyl)-piperidine-4-carboxylic acid (6.7 g, 20 mmol) in DCM (250 mL) and DMF (0.2 mL) is treated with oxalyl chloride (25 mmol, 2.21 mL) dropwise at 0° C. during 20 min. under nitrogen. The reaction mixture is stirred at RT for 2 h. Then the solvent is evaporated under reduced pressure and dried under high vacuum. The crude acid chloride is dissolved in DCM (250 mL) and treated with DIPEA (20 mmol, 3.42 mL) and cooled down to 0° C. A solution of cyclohexylamine (2.18 g, 22 mmol) in DCM (20 mL) is added dropwise over 15 min. and the resulting mixture is stirred for 2 h. at RT. The reaction mixture is washed twice with aq. sat. NaHCO3 (100 mL) and dried over MgSO4. After evaporation of the solvent, the crude residue is purified by flash chromatography on silica gel using a mixture of DCM/MeOH 9:1. After concentration of the product containing fractions, the title compound (2.44 g, 29%) is obtained as a beige powder: LC-MS A: tR=0.66 min; [M+H]+=416.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C.[Ag]=O>[CH3:24][N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Yield: 84.3 %

Procedure:
9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of dimethylformamide, and 14.0 g of silver oxide are added thereto. 42.6 g of methyl iodide are added to the mixture at room temperature under stirring, and the mixture is further stirred for 2 days in the dark. The reaction mixture is filtered to remove insoluble materials, and the filtrate is condensed under reduced pressure. The residue obtained is dissolved in ethyl acetate. Then, the ethyl acetate solution is washed with water, dried and condensed under reduced pressure. The residue thus obtained is washed with n-hexane. 8.45 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are thereby obtained as colorless crystals. Yield: 84.3% M.p. 102°-103° C.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:28]=[CH:29][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.03 min, MH+ 521. NMR: δH [2H6]-DMSO 10.12,(1H, s), 9.33,(1H, t), 9.15,(1H, s), 8.78,(1H b), 8.36–8.32,(2H, m), 7.86,(1H, s), 7.78,(1H, d), 7.69–7.65,(3H, m), 7.31,(2H, m), 7.21,(1H, s), 7.11,(2H, m), 4.51,(2H, d), 2.99,(3H, s), 2.32,(3H, s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:20])[CH2:12][CH2:11][CH2:10][NH:9][C:8]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:7]1=2.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[CH3:5][C:6]1([CH3:20])[CH2:12][CH2:11][CH2:10][N:9]([C:1](=[O:3])[CH3:2])[C:8]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:7]1=2
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCCC(C)(C)c2ccc([N+](=O)[O-])cc21
Yield: 73.4 %

Procedure:
Acetyl chloride (0.77 mL, 11 mmol) was added to a suspension of crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.2 g, 5.45 mmol) and NaHCO3 (1.37 g, 16.3 mmol) in CH2Cl2 (20 mL). The mixture was heated at reflux for 1 h. After cooling, the mixture was poured into water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to afford 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone (1.05 g, 64% over two steps).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCc2ccccc21

Procedure:
A stirred solution of 38.4 g (0.20 mole) of 1,4-dichloro-2-nitrobenzene and 59.6 g (0.50 mole) of indoline in 400 ml of dimethylformamide (DMF) was heated under nitrogen at 140°-145° C. overnight (23 hours). The DMF solvent was then removed in vacuo and the residue was dissolved in 500 ml of dichloromethane. This solution was extracted with H2O, with dilute hydrochloric acid, with brine, then dried over Na2SO4 and concentrated to an oil. This was adsorbed on a tall chromatography column containing 1.5 kg of silica gel packed in toluene. Elution with toluene brought forth 22.1 g (40% overall yield) of product, which crystallized. A small portion was recrystallized from hexane to afford 1-(4-chloro-2-nitrophenyl)indoline, m.p. 97°-99° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[C:3]([OH:5])=O.[C:12](OC(=O)C)(=[O:14])[CH3:13].[CH2:19](N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:12]([N:1]1[CH:2]([C:3](=[O:5])[CH3:19])[CH2:6][CH2:7][CH2:8][C:9]1=[O:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: NC(CCCC(=O)O)C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Product: CC(=O)C1CCCC(=O)N1C(C)=O
Temperature: 60 °C

Procedure:
A 50-mL round bottom flask is charged with racemic 2-aminoadipic acid (2.3 g, 1.43×10−3 mol) and triethylamine (7.5 mL), acetic anhydride (7.5 mL), and a catalytic amount of DMAP (15 mg). The mixture is heated to 60° C. for 24 h; the progress of the reaction is followed by TLC (eluent: ethyl acetate/petroleum ether, 8/2). Once the reaction is complete, the crude reaction product is concentrated as much as possible (rotary evaporator and vane pump) and then washed with water (5×20 mL). The water washings are extracted with CH2Cl2 (2×20 mL). The organic layers are combined and concentrated. Purification of 8 is carried out on a silica gel column (eluent: ethyl acetate/petroleum ether, 8/2). The fractions are dried, concentrated and the product crystallized in the form of pale yellow flakes.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: Cc1ccccc1-c1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E.MS (ESI): predicted mass calcd. for C21H18ClN5O2, 407.9
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1C
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1C

Procedure:
A solution of 24 g (0.22 mol) of 2,3-dimethylpyridine in 100 ml of methylene chloride is treated while cooling with ice with a solution of 46.6 g (0.27 mol) of m-chloroperbenzoic acid in 100 ml of methylene chloride. The reaction mixture is heated under reflux for 2 hours and concentrated in a rotary evaporator. The residue is chromatographed on silica gel with ethyl acetate/methylene chloride (3:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. By recrystallization from ether there is obtained 2,3-dimethylpyridine 1-oxide of melting point 56°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([S:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:14]#[N:15].Cl.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][NH:42][CH2:41][CH2:40]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:13]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:42]2[CH2:41][CH2:40][C:39]3[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=3)[CH2:43]2)[C:14]#[N:15])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(C#N)(CCCCCCCCCCCBr)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Product: COc1ccc(C(C#N)(CCCCCCCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 57.9 %

Procedure:
The procedure of Example 3 is repeated using 3.14 g of α-(11-bromoundecyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.03 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 2.2 g of the desired product as a light yellow oil.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](Cl)=[O:4].ClC(Cl)(Cl)C(=O)CC(Cl)=O.[NH2:18][C:19]([NH2:21])=[O:20].[C:22]([OH:25])(=[O:24])[CH3:23]>>[C:22]([OH:25])(=[O:24])[C:23]1[NH:21][C:19](=[O:20])[NH:18][C:3](=[O:4])[CH:2]=1
Reactant: NC(N)=O
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(=O)O
Agent: O=C(Cl)CC(=O)C(Cl)(Cl)Cl
Product: O=C(O)c1cc(=O)[nH]c(=O)[nH]1

Procedure:
To recap, this invention involves: converting trichloroacetyl chloride with ketone to γ,γ ,γ -trichloroacetoacetyl chloride, adding the reaction mixture to urea dissolved in a polar organic solvent, e.g., acetic acid; evaporating out the resulting 6-trichloromethyluracil; and hydrolyzing the 6-trichloromethyluracil to form orotic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[CH2:44]([O:51][NH:52][C:14](=[O:16])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Yield: 59 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propanoic acid (2.84 g, 6.85 mmol), carbonyldiimidazole (1.22 g, 7.52 mmol) and O-benzylhydroxylamine hydrochloride (1.32 g, 8.27 mmol) in tetrahydrofuran (15 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)-propionamide as a yellow solid (2.1 g, 59% yield): mp, 159.0-161.0° C.; 1H NMR (DMSO-d6) δ1.30 (t, J=6.9 Hz, 3H, CH3), 3.03 (dd, J=7.7, 14.8 Hz, 1H, CHH), 3.15 (dd, J=8.0, 14.9 Hz, 1H, CHH), 3.72 (s, 3H, CH3), 3.96 (q, J=6.9 Hz, 2H, CH2), 4.64 (s, 2H, PhCH2), 5.66 (t, J=7.8 Hz, 1H, NCH), 6.87-6.95 (m, 2H, Ar), 6.99 (br s, 1H, Ar), 7.23-7.41 (m, 5H, Ar), 8.06 (t, J=7.7 Hz, 1H, Ar), 8.14-8.18 (m, 1H, Ar), 8.26-8.31 (m, 1H, Ar), 11.24 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.66, 34.09, 50.62, 55.46, 63.72, 76.69, 111.86, 112.46, 119.83, 122.47, 126.94, 128.18, 128.67, 130.28, 133.08, 135.79, 136.38, 144.36, 147.69, 148.68, 162.99, 165.69, 166.18. Anal. Calcd for C27H25N3O8: C, 62.42; H, 4.85; N, 8.09. Found: C, 62.12; H, 4.92; N, 7.82.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13](=O)[NH:14][N:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[ClH:19].[Cl:19][C:13]1[N:14]=[N:15][C:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1
Reactant: CC(C)N1CCC(c2ccc(=O)[nH]n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)N1CCC(c2ccc(Cl)nn2)CC1
Product: Cl
Temperature: 60 °C
Yield: 88 %

Procedure:
6-(1-Isopropylpiperidin-4-yl)pyridazin-3-on (5.76 g, 26 mmol) was added to POCl3 (50 mL) and the reaction mixture was heated for 2 hours at 60° C. The excess of POCl3 was evaporated in vacuo and ethanol (96%) was added under an exothermic reaction. The reaction mixture was cooled and a precipitate was obtained. The product was filtered off after drying in vacuo and 6.34 g (88%) white crystals were isolated.