Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.[BH3-]C#N.[Na+].Cl>CO.C(O)(=O)C>[C:1]1([CH2:7][CH2:8][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CCN2CCCc3ccccc32)cc1
Reaction time: 1 h

Procedure:
To phenylacetaldehyde (6.0 g, 0.050 mol), 1,2,3,4-tetrahydroquinoline (13 g, 0.1 mol) and acetic acid (0.5 ml) in methanol (50 ml) was added NaBH3CN (1.18 g). After stirring for 1 hour, the mixture was poured into 800 ml 1N HCl and extracted 3×100 ml ether. The combined organic layers were washed 1×100 ml 1N HCl and 2×100 ml H2O, dried (K2CO3) and concentrated to 100 ml. The concentrate was perfused with excess HCl gas to form an oily hydrochloride salt of title product. The solvent was decanted and the residual washed 2×50 ml ether. The washed salt was distributed between excess 5% K2CO3 and ether, and the organic layer separated, dried (K2CO3) and stripped to yield title product as an oil, 6.5 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O.[BH4-].[Na+]>C1COCC1>[CH:24]1([CH2:23][O:22][C:14]2[CH:15]=[C:16]([CH2:17][OH:18])[CH:20]=[CH:21][C:13]=2[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(c1ccc(CO)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoic acid (for reference procedure see Example 18, WO 2010/089107, which is incorporated herein by reference in its entirety) (200 mg, 0.519 mmol) was dissolved in THF (10.5 ml), then CDI was added (154 mg, 0.95 mmol). The mixture was stirred at RT for 2 days, then H2O (1.75 ml) and NaBH4 (36 mg, 0.95 mmols) were added. The solvent was removed by evaporation under vacuum. The crude was dissolved in EtOAc (80 ml) and washed with water. The organic phase was dried over Na2SO4 and evaporated under vacuum to yield 200 mg of the desired product.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:24]([C:32]1[CH:58]=[CH:57][C:35]2[N:36]=[C:37]([C:39]3[C:40]([CH3:56])=[C:41]([C:45]([N:47]4[CH2:52][CH2:51][CH:50]([C:53]([OH:55])=O)[CH2:49][CH2:48]4)=[O:46])[NH:42][C:43]=3[CH3:44])[NH:38][C:34]=2[CH:33]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH3:59][N:60]([CH3:64])[CH2:61][CH2:62][NH2:63]>N1C=CC=CC=1>[CH3:59][N:60]([CH2:61][CH2:62][NH:63][C:53]([CH:50]1[CH2:51][CH2:52][N:47]([C:45]([C:41]2[NH:42][C:43]([CH3:44])=[C:39]([C:37]3[NH:38][C:34]4[CH:33]=[C:32]([C:24](=[O:31])[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:58]=[CH:57][C:35]=4[N:36]=3)[C:40]=2[CH3:56])=[O:46])[CH2:48][CH2:49]1)=[O:55])[CH3:64]
Reactant: Cc1[nH]c(C(=O)N2CCC(C(=O)O)CC2)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cc1[nH]c(C(=O)N2CCC(C(=O)NCCN(C)C)CC2)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 60 °C
Reaction time: 10 h
Yield: 54.3 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole monohydrate (25 mg, 0.16 mmol) were added to a pyridine (4 ml) solution of the ((4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrol-2-yl)-carbonyl)piperidine-4-carboxylic acid (70 mg, 0.15 mmol) obtained in Example 45. N,N-Dimethylethylenediamine (13 mg, 0.15 mmol) was added to the reaction mixture and heated. The reaction mixture was stirred at 60° C. (internal temperature) for 10 hours, and then allowed to cool to room temperature with stirring. The solvent was evaporated, and the residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2) to afford N-dimethylaminoethyl-1-((4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrol-2-yl)-carbonyl)piperidine-4-carboxamide (44 mg, 55%) as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[N:35]=[C:34]([N:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([N:36]([CH3:37])[CH3:38])[N:35]=2)[CH2:26][CH3:27])=[O:25])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCc1cccc(N(C)C)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1cccc(N(C)C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with (6-ethylaminomethyl-pyridin-2-yl)-dimethyl-amine
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: C1COCCN1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1N1CCOCC1

Procedure:
5-Morpholin-4-y1-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and morpholine. Mass spectrum (ES) MH+=407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=[C:10]([CH:23]3[CH2:28][CH2:27][N:26](C(=O)C)[CH2:25][CH2:24]3)[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)=[C:10]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[NH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCC(c2nn(S(=O)(=O)c3ccc(C)cc3)c(-c3ccc(Cl)cc3)c2-c2ccncn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncn2)cc1
Reaction time: 2.5 h
Yield: 74.7 %

Procedure:
This reaction was conducted in a 250 ml round bottom flask. To 4-{3-(1-acetylpiperidin-4-yl)-5-(4-chlorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-yl}pyrimidine (9) (6.86 g) was added 6 M HCl (40 ml). The mixture was stirred and heated to reflux. The reaction was monitored by HPLC, and determined to be complete after 2.5 hr. The mixture was then cooled in an ice/water bath, and 6 M NaOH was slowly added until the pH was between 13–14. The resulting product was isolated via vacuum filtration to yield 3.25 g of 4-[3-(4-chlorophenyl)-5-piperidine-4-yl-1H-pyrazol-4-yl]pyrimidine (79.8% yield) as a white solid.
Reaction SMILES: Cl.[C:2]1([NH:8][S:9]([C:12]2[CH:19]=[CH:18][C:15]([NH:16][CH3:17])=[C:14]([NH2:20])[CH:13]=2)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=O)=[CH:25][CH:24]=1)#[N:22]>P(Cl)(Cl)(Cl)=O>[C:2]1([NH:8][S:9]([C:12]2[CH:19]=[CH:18][C:15]3[N:16]([CH3:17])[C:30]([CH2:29][C:26]4[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)=[N:20][C:14]=3[CH:13]=2)(=[O:10])=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CNc1ccc(S(=O)(=O)Nc2ccccc2)cc1N
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(Cc2ccc(C#N)cc2)nc2cc(S(=O)(=O)Nc3ccccc3)ccc21

Procedure:
Prepared analogously to Example 1a from 4-phenylaminosulphonyl-2-amino-N-methyl-aniline-hydrochloride and 4-cyano-phenylacetic acid in phosphorus oxychloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:33]C)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]3[C:15]=1[CH:16]=[N:17][C:18]([CH3:25])=[N:19]3)[C:7]([C:27]([F:30])([F:29])[F:28])([OH:26])[CH2:6][C:5]2([CH3:32])[CH3:31].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[CH:8]([NH:13][C:14]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]4[C:15]=3[CH:16]=[N:17][C:18]([CH3:25])=[N:19]4)[C:7]([C:27]([F:28])([F:29])[F:30])([OH:26])[CH2:6][C:5]([CH3:31])([CH3:32])[C:4]=2[C:3]=1[OH:33]
Reactant: COc1c(Cl)c(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(C)ncc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ncc2c(NC3c4cc(C)c(Cl)c(O)c4C(C)(C)CC3(O)C(F)(F)F)ccc(F)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
40 mg (0.08 mmol) of (rac.) 6-chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 0.8 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for four hours at room temperature. Since no reaction was carried out, another 0.8 ml of the boron tribromide solution was added. After 16 hours of stirring at room temperature, the reaction was complete. At −30° C., saturated sodium bicarbonate solution is now carefully added in drops, and the batch is diluted with ethyl acetate. After the cold bath is removed, it is stirred vigorously at room temperature for 10 minutes. The batch is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and the residue is chromatographed on silica gel (mobile solvent:methanol/dichloromethane) after the solvent is spun off. 38.2 mg (98.4%) of the desired compound is isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[S:12][C:13]([NH2:16])=[N:14][N:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([O:8][C:9]([C:11]1[S:12][C:13]([NH:16][C:25]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[N:14][N:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1nnc(C(=O)OCc2ccccc2)s1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1nnc(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of the product of Step (d) (0.1 g, 0.000425 mol) in THF (6.07 mL) was added benzyl isocyanate (0.0525 mL, 0.000425 mol), and the mixture was stirred overnight at room temperature. After 24 hours, the mixture was rotary evaporated and the concentrate was diluted with ethyl ether and dichloromethane. A solid was filtered and washed with ethyl ether. The mother filtrate was rotary evaporated and the residue triturated with ethyl ether and dichloromethane to give additional solids. The solids were combined to give 0.12 g of 5-(3-benzyl-ureido)-1,3,4-thiadiazole-2-carboxylic acid benzyl ester; mp 188-192° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[C:20]([CH3:25])=[N:21][CH:22]=[N:23][CH:24]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[C:20]([CH3:25])=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Cc1ncncc1N
Product: Cc1ccc(Nc2cncnc2C)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 5-Amino-4-methylpyrimidine instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a light yellow solid, MS (ISP): m/e=324.3 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)O1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:30]([C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37](I)=[CH:38][N:39]=4)[CH:36]=3)=[CH:29][N:28]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:27]=2)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C)C=O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:30]([C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([C:9]5[CH:10]=[CH:11][C:12]([C:13]([NH2:15])=[O:14])=[CH:16][CH:17]=5)=[CH:38][N:39]=4)[CH:36]=3)=[CH:29][N:28]([C:41]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[N:27]=2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(I)n3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Yield: 43.2 %

Procedure:
222 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide prepared according to T. Ishiyama et al., J. Org. Chem., 60, 7508 (1995), 323 mg of 6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazolyl]-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 39), 200 mg tripotassium phosphate, 30 mg tetrakis(triphenylphosphine)palladium and 30 mL N,N-dimethylformamide were heated at 75° C. for 3 hours under nitrogen atmosphere. The solvent was removed, and the residue was purified by NH silica gel chromatography (hexane/ethyl acetate) to give 138 mg of the title compound (film).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16])(C)(C)C.[CH2:18](N(CC)CC)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6](=[O:5])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CN
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl[2-(aminomethyl)benzyl]carbamate (0.2 g, 0.93 mmol) and triethylamine (260 μL, 1.9 mmol) in DCM (10 mL) was added AC2O (0.285 g, 0.00279 mol) dropwise and the reaction stirred for 2 h at r.t. The reaction was concentrated, the residue dissolved in EtOAc (20 mL) then washed with saturated aq NaHCO3 (2×10 mL). The organic layer was dried (Na2SO4) and concentrated to give the crude product (0.25 g, 90%). To a solution of this in DCM (5 mL) was added 2 mL of 4M HCl/dioxane and the solution was stirred for 1 h. The reaction was concentrated to give the title compound (0.16 g, 95%) which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[CH2:28]([O:8][C:7]([CH:5]1[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]1)=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CC(C(=O)O)C(C(=O)O)O1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Product: O=C1CC(C(=O)O)C(C(=O)OCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5.3 g of (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylic acid was dissolved in 90 ml of acetone, and 6.6 g of N,N'-dicyclohexylcarbodiimide was added thereto, followed by stirring at room temperature for 2.5 hours. 3.3 ml of benzyl alcohol was added to the reaction solution, followed by stirring at the same temperature for 2 days. Insoluble matters were filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1+chloroform/methanol=50/1) to obtain 6.55 g of the above-identified compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9](=[O:12])[CH2:10]Cl)=[O:5])[CH3:2].C(N(CC)CC)C.Cl>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[C:9](=[O:12])[CH2:10][C:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCN(C(=O)CCl)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN1C(=O)CC1(C(=O)OCC)C(=O)OCC
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 19.7 g. (0.056 moles) of diethyl N-(2-ethoxycarbonylethyl)-N-(chloroacetyl)-amino-malonate prepared according to Example 2 in 200 ml. of dry benzene 13 ml. (9.5 g., 0.095 moles) of triethyl amine are added and the reaction mixture is boiled for 3 hours. The solution is shaken with two 50-ml. portions of a 5% aqueous hydrochloric acid solution and subsequently with 50 ml. of water, the benzene phase is dried with magnesium sulfate, filtered and the filtrate is evaporated in vacuo. 16.5 g. (93%) of the named compound are obtained. The product is practically uniform and can be used for further conversions without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([C:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=O)[NH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>[C:6]1([C:12]2[CH:13]=[N:14][C:15]([Cl:3])=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(-c2ccccc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ncc(-c2ccccc2)c2ncccc12
Temperature: 0 °C

Procedure:
12.1 ml (130 mmol) of phosphoryl chloride are added dropwise at room temperature to a suspension of 22.2 g (100 mmol) of 8-phenyl-1,6-naphthyridin-5(6H)-one [173773-04-1] in 100 ml of toluene. After addition of 5 drops of N,N-dimethylaniline, the reaction mixture is heated under reflux for 5 h. After cooling, the reaction mixture is diluted with 300 ml of toluene, poured onto 1000 g of ice and rendered alkaline (pH about 9) by addition of 5 N NaOH. The organic phase is separated off, washed once with 300 ml of sat. sodium chloride solution, dried over magnesium sulfate, and the toluene is removed in vacuo. Yield: 22.9 g (95 mmol), 95%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]([C@H:17]2[O:19][C@@H:18]2[C:20]([O:22]CC)=[O:21])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:8]1([CH:7]([NH:14][C:15]([C@H:17]2[O:19][C@@H:18]2[C:20]([OH:22])=[O:21])=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In ethanol (300 mL) was dissolved ethyl (2S,3S)-3-diphenylmethylcarbamoyloxirane-2-carboxylate (5.50 g, 16.9 mmol.) obtained in Example 1. To the resulting solution was added a solution of 0.5N sodium hydroxide in ethanol (40.4 mL, 20.2 mmol.), and the mixture was stirred for 3 hours at room temperature. The solvent was distilled off under reduced pressure, and washed with two 100 mL portions of ethyl ether after addition of water (300 mL). The aqueous portion was made to show pH 1-2 by addition of 2N hydrochloric acid, and extracted with three 100 mL portions of ethyl acetate. The organic portion was washed with an aqueous sodium chloride saturated solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the desired compound as a white crystalline powdery product (4.76 g, yield: 95%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)(C)C>[C:10]([C:9]1[C:8]([NH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:16]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:14][CH:13]=1)([OH:12])=[O:11]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COC(=O)CNc1c(C(=O)O)cccc1[N+](=O)[O-]

Procedure:
A mixture of methyl glycinate (15.9 g, 127 mmol), 2-chloro-3-nitrobenzoic acid (6.07 g, 30.1 mmol) and Na2CO3 (22.9 g, 216 mmol) in tert-BuOH (40 mL) was heated at reflux for 18 h. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between H2O (200 mL) and EtOAc (200 mL). The aqueous layer was acidified to pH 2 and the organic layer was extracted. The aqueous layer was extracted further with EtOAc (2×200 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=255 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:17]([Cl:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=3[Cl:23])[CH:8]=2)[N:3]=1.[NH2:24][C@@H:25]1[CH2:29][O:28][CH2:27][C@@H:26]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[Cl:18][C:17]1[C:16]([O:19][CH3:20])=[CH:15][C:14]([O:21][CH3:22])=[C:13]([Cl:23])[C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:24][C@@H:25]1[CH2:29][O:28][CH2:27][C@@H:26]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:11]=[CH:10]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Cl)ncc3c2)c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1COC[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4COC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
A mixture of 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (1.02 g, 2.76 mmol), tert-butyl ((3R,4S)-4-aminotetrahydrofuran-3-yl)carbamate (0.85 g, 4.20 mmol), and sodium bicarbonate (0.58 g, 6.90 mmol) was stirred in NMP (5.5 mL, 0.5M) at 95° C. for 12 hours. The reaction was removed from the oil bath and while cooling to room temperature was treated with about 90 mL of water and then sonicated and stirred for 20 minutes. A yellow-orange solid was isolated by filtration, rinsed several times with small amounts of water, and dried under vacuum for nearly 1 hour to yield 3.35 g of crude, which was purified by silica gel chromatography to yield 1.10 g (74.5% yield) of tert-butyl ((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydrofuran-3-yl)carbamate as a light yellow foam. MS (ES+) C25H28Cl2N4O5 requires: 534, found: 535 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].I[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1>>[CH3:14][C:9]1[CH:8]=[C:7]([N:1]2[CH2:4][CH2:3][C:2]2=[O:5])[CH:12]=[C:11]([CH3:13])[CH:10]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: O=C1CCN1
Product: Cc1cc(C)cc(N2CCC2=O)c1
Yield: 94.9 %

Procedure:
Using general procedure A, 2-azetidinone (88 mg, 1.24 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 1:1; 15 mL fractions). Fractions 5-10 provided 173 mg (95% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.01 (s, 2H), 6.76 (s, 1H), 3.61 (t, J=4.5 Hz, 2H), 3.10 (t, J=4.5 Hz, 2H), 2.32 (s, 6H).