Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:7]([O:11][CH2:10][CH2:9][Br:30])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(C2OCCO2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCCBr)c1ccccc1

Procedure:
The preferred aldehyde for the second route is benzaldehyde, especially when the glycol is ethylene glycol and the N-halogenated imide is N-bromosuccinimide. More specifically, 2-phenyl-1,3-dioxolane can be prepared by mixing benzaldehyde and ethylene glycol in a 1.0 to 1.2 mol ratio in an organic solvent containing a catalytic amount of an organic acid, such as p-toluenesulfonic acid. The mixture is heated and allowed to reflux for about an hour and a half, then treated with potassium carbonate, filtered, and distilled to produce 2-phenyl-1,3-dioxolane. The dioxolane is subsequently dissolved in carbon tetrachloride with an equimolar amount of N-bromosuccinimide and a catalytic amount of benzoyl peroxide. After heating under reflux conditions for up to 16 hours, cooling, and filtering, the mixture produces a filtrate that can be further concentrated to yield an ester, 2-bromoethyl benzoate. The ester so produced is used as an alkylating agent when reacted with a tertiary amine yielding a quaternary ammonium salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:19]1[N:24]=[C:23]([O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[NH:16])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:21][N:20]=1
Reactant: N=C(N)Nc1ccc(-c2cccc(O)c2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N=C(N)Nc1ccc(-c2cccc(Oc3ccnc(Cl)n3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-(3′-hydroxy-biphenyl-4-yl)guanidine (550 mg), 2,4-dichloropyrimidine (146 mg) and potassium carbonate (196 mg) in DMF (8 ml) is stirred at rt for 20 h. This mixture is purified by preparative HPLC (gradient of water, 0.1% TFA/acetonitrile, 0.1% TFA from 80/20 to 0/100 on Nucleosil 100-10 C18 column). The fractions containing product are basified with 1 N NaOH to pH 8, evaporated and dried under reduced pressure. The residue is stirred in ethanol, the solvent is evaporated and dried under reduced pressure to afford crude N-[3′-(2-chloro-pyrimidin-4-yloxy)biphenyl-4-yl]-guanidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=1[NH2:34]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:32]=3[F:31])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: Nc1ccc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(F)cc1F)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 2,4-difluoroaniline (CAS Reg. No. 367-25-9) in the presence of DMAP to give [rac]-2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-N-(2,4-difluoro-phenyl)-acetamide as yellow oil. MS: m/e=484.3 [M+H+].
Reaction SMILES: [H-].[Na+].C[C:4]1(C)[C:13]2C(=CC=C(C#CC3C=CC(C([O-])=O)=CC=3)[CH:12]=2)N[C:6](=O)[CH2:5]1.ICCCCCCC.[CH3:35][C:36]1([CH3:63])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:46]#[C:47][C:48]3[CH:58]=[CH:57][C:51]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][CH:49]=3)[CH:44]=2)[N:39]([CH:59](C)[CH3:60])[C:38](=[O:62])[CH2:37]1>CN(C=O)C>[CH3:63][C:36]1([CH3:35])[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:46]#[C:47][C:48]3[CH:58]=[CH:57][C:51]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][CH:49]=3)[CH:44]=2)[N:39]([CH2:59][CH2:60][CH2:6][CH2:5][CH2:4][CH2:13][CH3:12])[C:38](=[O:62])[CH2:37]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(=O)N3C(C)C)cc1
Reactant: CC1(C)CC(=O)Nc2ccc(C#Cc3ccc(C(=O)[O-])cc3)cc21
Agent: CCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCN1C(=O)CC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21

Procedure:
NaH (98.4 mg, 2.7 mmol), ethyl 4-[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-quinolinyl )ethynyl]benzoate (Compound 4, 635 mg, 1.8 mmol) and iodo heptane (2.73 mL, 18 mmol) in 3 mL of DMF were reacted substantially in accordance with the procedure used for the preparation of ethyl 4-[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-iso-propyl-6-quinolinyl)ethynyl]benzoate (Compound 5), to give the title compound as white solids.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[CH3:22][O:21][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:35]3[CH2:34][CH2:33][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][CH3:24])[CH2:37][CH2:36]3)[C:9](=[O:23])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc(OC)c2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Solvent: CCO
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2c1
Yield: 71 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 35) and 1-(2-methoxyphenyl)piperazine; yield 71%; m.p. 140°-142° C. (from ethanol).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:17]([CH3:33])[C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=2[Cl:30])[CH:21]=1)=[O:19].C(N(CC)CC)C>C1C=CC=CC=1>[ClH:30].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH:17]([C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=3[Cl:30])[CH:21]=2)=[O:19])[CH3:33])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccccc4)CC3)ccc2c1Cl
Yield: 101.5 %

Procedure:
A mixture of N-benzyl piperazine dihydrochloride (1.5 g, 7.05 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl) propan-1-one (2.8 g, 8.5 mmol) and triethyl-amine (2.38 g, 23.5 mmol) in benzene (150 ml) was treated according to the general preparation 2 to obtain 2.14 g of N1-benzyl-N4-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl] piperazine dihydrochloride, yield 60%, mp 252-253° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])([O-])=O.[K+].[K+].N#N>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.COCCOC>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])=[CH:41][CH:40]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3cnc(C4CCCN4C(=O)OCc4ccccc4)[nH]3)cc2)cc1
Temperature: 85 °C
Yield: 41.1 %

Procedure:
2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid benzyl ester (2.31 g, 5.42 mmol), (4-tert-Butoxycarbonylaminophenyl)-boronic acid (1.28 g, 5.42 mmol), Pd(PPh3)4 (313 mg, 0.271 mmol) and K2CO3 (6 mL of 2 M aqueous solution, 11.92 mmol) were combined with 1,2-dimethoxyethane (20 mL). The suspension was stirred while N2 was bubbled through the solution for 14 min. A reflux condenser was attached and the suspension was heated to 85° C. for 15 hours. It was then cooled, diluted with ethyl acetate (150 mL), washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by silica column chromatography (25% to 50% EtOAc/hexanes) to provide 2-[5-(4′-tert-Butoxycarbonylamino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid benzyl ester (1.20 g, 41%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.[I-].[Na+]>[CH2:12]([O:1][N:2]1[C:6](=[O:7])[C:5]2[C:4](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:3]1=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: O=C1CCC(=O)N1O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 261.5 %

Procedure:
3.0 g (18 mmol) of N-hydroxysuccinimide was dissolved in 30 mL of N,N-dimethylformamide, mixed with 0.81 g (20 mmol) of 60 wt % sodium hydride (dispersed in mineral oil) under cooling with ice and stirred at room temperature for 30 minutes. After the stirring, 2.8 mL (20 mmol) of bromohexane and 35 mg (0.23 mmol) of sodium iodide were added dropwise successively under cooling with ice, and the reaction mixture was stirred at 70° C. for 20 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water, and the solid precipitated in the reaction mixture was collected by filtration and dried to give 5.82 g of the desired product as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)=[O:4].[C:38](O)(=[O:41])[CH:39]=[CH2:40].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([NH:5][C:3]([CH2:2][NH:1][C:38](=[O:41])[CH:39]=[CH2:40])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: C=CC(=O)O
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)NCC(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Yield: 27 %

Procedure:
320 mg of 2-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-acetamide as a starting material was dissolved in 10 ml of THF, and cooled to 0° C. The solution was reacted with 0.06 ml of acrylic acid, 0.1 ml of pyridine and 234 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 1 hour and at room temperature for 5 hours. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (96 mg, 27%).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.C[Si](C)(C)[O-:41].[K+]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([OH:41])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[Si](C)(C)[O-]
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: [K+]
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and potassium trimethylsilanolate.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].OO.C([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=3[CH:30]=2)=[CH:15][CH:14]=1)(=O)C>C(O)(=O)C>[C:3]([O:5][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=3[CH:30]=2)=[CH:15][CH:14]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc3oc(C(=O)O)cc3c2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: OO
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(-c2ccc3oc(C(=O)O)cc3c2)cc1

Procedure:
2 ml of trifluoroacetic acid and 92 ml of 30% hydrogen peroxide solution were added to a mixture of 13 g of 10 in 300 ml of acetic acid. The mixture was heated at 70°-75° C. for 10 hours, then was cooled in a refrigerator. The solid that formed was collected and dried. The acetic acid solution was poured into 3.6 liters of ice water. The solid that formed was collected and dried (P2O5). The two solids were combined and dissolved in 150 ml of tetrahydrofuran. The solution was filtered, concentrated to 20 ml and chilled. The solid that formed was collected, dried under reduced pressure, and recrystallized from tetrahydrofuran to give 11, mp: 251°-254° C.
Reaction SMILES: [P:1]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C@@H:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[CH2:28][N:27]2[C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH:21]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].C1CCC=CC=1>CO.[Pd]>[P:1]([OH:11])([OH:3])([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C@@H:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[CH2:28][N:27]2[C:39]([N:41]([CH3:42])[CH3:43])=[O:40])[CH:21]=1)=[O:2]
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1cccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1=CCCC=C1
Solvent: CO
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1cccc(OP(=O)(O)O)c1
Reaction time: 0.25 h

Procedure:
Dibenzyl 3-{(2S)-4-(2,5-difluorophenyl)-1-[(dimethylamino)carbonyl]-2,5-dihydro-1H-pyrrol-2-yl)phenyl phosphate (8-1, 108 mg, 0.18 mmol) was dissolved in 4:1 MeOH:cyclohexadiene (2 mL) and treated with 10% Palladium on carbon (100 mg). The reaction was stirred vigorously for 15 min, and then filtered over celite using MeOH to wash the compound throughly from the celite. The washings were concentrated and purified by reverse phase column chromatography (C-8, 10-90% CH3CN/H2O with 0.1% TFA gradient) to provide 3-{(2S)-4-(2,5-difluorophenyl)-1-[(dimethylamino)carbonyl]-2,5-dihydro-1H-pyrrol-2-yl}phenyl dihydrogen phosphate (8-2) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.20 (m. 7H), 6.42 (br s, 1H), 6.08 (m, 1H), 5.00 (dd, J=14.0, 3.6 Hz, 1H), 4.55 (d, J=14.0 Hz, 1H), 2.92 (s, 6H). LRMS m/z (M+H) 425.4 found, 425.3 required.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C@@H:10]1[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][C@@H:11]1[C:17]1[CH:22]=[CH:21][C:20](N)=[CH:19][CH:18]=1)=[O:9])[CH3:6].[I-:24].[K+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>S(=O)(=O)(O)O.C(O)(=O)C.O>[CH2:5]([O:7][C:8]([C@@H:10]1[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][C@@H:11]1[C:17]1[CH:22]=[CH:21][C:20]([I:24])=[CH:19][CH:18]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccc(N)cc2)CC(=O)N1C
Reactant: [I-]
Agent: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)[C@H]1[C@@H](c2ccc(I)cc2)CC(=O)N1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44 %

Procedure:
To a 0° C. solution of sodium nitrite (80 mg, 1.15 mmol) in sulfuric acid (2 mL) was added dropwise a solution of (±)-(4R*,5R)-5-ethoxycarbonyl-1-methyl-4-(4-aminophenyl)pyrrolidin-2-one (prepared according to the procedure for Intermediate U, 200 mg, 0.763 mmol) in glacial acetic acid (2 mL). The mixture was allowed to warm to room temperature and stirred for 40 min. The reaction was then cooled to 0° C. and a solution of potassium iodide (300 mg) and iodine (233 mg) in water (2 mL) was added in one portion. The dark mixture was stirred for 10 min at 0° C., followed by addition of enough aqueous solution of saturated sodium thiosulfate to lighten the reaction color. The mixture was then diluted with water (10 mL) and extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The oily residue was purified by flash chromatography (gradient from 75% EtOAc/hex to 100% EtOAc) to give (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-iodophenyl)pyrrolidin-2-one (125 mg, 44%) as a white powder: mp 120-121° C.; TLC (EtOAc) Rf0.59; HPLC ES-MS m/z (rel abundance) 374 (MH+, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](CC2(C3C=CN=CC=3)CC2)[CH2:10][CH:9]1[CH2:24][CH2:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:24][CH2:25][OH:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCC1CN(CC2(c3ccncc3)CC2)CCN1Cc1ccccc1
Solvent: CC#N
Product: OCCC1CNCCN1Cc1ccccc1

Procedure:
2-[1-Benzyl-4-(1-pyridin-4-yl-cyclopropylmethyl)-piperazin-2-yl]-ethanol. A 250 mL flask was charged with the product obtained above (1.34 mmol, 1.0 equiv.), 2-(1-benzyl-piperazin-2-yl)-ethanol (1.18 g, 5.36 mmol, 4.0 equiv.), and 10 mL acetonitrile. The flask was equipped with a reflux condenser, and then placed into a preheated 100° C. bath. After stirring for 24 h, the solution was diluted with CH2Cl2 and saturated NaHCO3, extracted (2×10% MeOH/CH2Cl2), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 3% MeOH/CH2Cl2) provided 310 mg of the product as a yellow oil (0.88 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([CH3:15])[C:13]#[N:14].[C:20](OC)(=[O:23])[CH2:21][SH:22].C(N(CC)CC)C>C(O)C>[CH3:15][N:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[CH3:1])[C:13]1[S:22][CH2:21][C:20](=[O:23])[N:14]=1
Reactant: COC(=O)CS
Reactant: Cc1ccccc1OCc1ccccc1N(C)C#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccccc1OCc1ccccc1N(C)C1=NC(=O)CS1
Yield: 42.9 %

Procedure:
A solution of 6.3 g (0.01 mol) of 40% pure N-[2-(2-methylphenoxymethyl)-phenyl]-N-methyl-cyanamide, 1.1 g (0.01 mol) of methyl thioglycolate and 0.15 g of triethylamine in 100 ml of ethanol is heated under reflux for 18 hours. The mixture is concentrated and the residue is chromatographed over silica gel using cyclohexane/ethyl acetate (1:3). 1.4 g (43% of theory) of 2-{methyl-[2-(2-methylphenoxymethyl)-phenyl]-amino}-thiazol-4-one are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][CH2:30][C@@H:31]([OH:35])[C@H:32]([OH:34])[CH3:33]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:29][CH2:30][CH:31]([OH:35])[CH:32]([OH:34])[CH3:33])=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28]
Reactant: C[C@@H](O)[C@H](O)CN
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NCC(O)C(C)O)nc21
Yield: 90.9 %

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-(2,3-dihydroxy-butylamino)-1-ethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 7 using 0.40 g (0.97 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.245 g (2.33 mmol) of (2R,3R)-1-amino-butane-2,3-diol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.40 g (91%) of title compound: mp 171° C.–173° C. MS (APCI) (m+1)/z 454.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]=[CH:12][C:11]([C:14]([NH:16][C@@H:17]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[NH:34])[NH2:33])[CH:27]=2)[CH2:18][C:19]([O:21]CC)=[O:20])=[O:15])=[CH:10][CH:9]=1>Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:9]=[CH:10][C:11]([C:14]([NH:16][C@@H:17]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[NH:33])[NH2:34])[CH:27]=2)[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C[C@H](COc1cccc(C(=N)N)c1)NC(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1cccc(OC[C@@H](CC(=O)O)NC(=O)c2ccc(-c3ccccc3)cc2)c1
Temperature: 60 °C
Reaction time: 19 h

Procedure:
120 mg (0.18 mmol) of ethyl (3R)-3-[(biphenyl-4-carbonyl)amino]-4-(3-amidinophenoxy)butyrate trifluoroacetate was dissolved in 5 ml of concentrated hydrochloric acid, and the solution was stirred at 60° C. for 19 hours. The solvent was evaporated, and the residue was treated by the reversed-phase high-performance liquid chromatography with silica gel, containing octadodecyl group chemically bonded thereto, as the filler. After the elution with a mixed solvent of water and acetonitrile containing 0.1% (v/v) of trifluoroacetic acid, the fraction of the intended product was freeze-dried to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([I:8])=[CH:6][N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH3:46][NH:47][O:48][CH3:49]>CN(C=O)C.C(N(CC)C(C)C)(C)C>[CH3:49][O:48][N:47]([CH3:46])[C:9]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([I:8])[N:4]=1)=[O:11]
Reactant: Nc1ncc(I)nc1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1nc(I)cnc1N
Temperature: 80 °C
Yield: 57.4 %

Procedure:
27.50 g (0.104 mol) of 3-amino-6-iodo-pyrazine-2-carboxylic acid, 63.0 g (0.125 mol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) and 18.70 g (0.193 mol) of N,O-dimethylhydroxylamine hydrochloride were placed in a nitrogen flushed flask and then dissolved in a mixture of 100 ml of anhydrous DMF and 27 ml of N,N-di-iso-propylethylamine. The mixture was heated to 80° C. for 16 hours. The solvent was evaporated at 50-60° C. under reduced pressure to afford a dark oil. The oil was extracted three to four times with 300 ml of toluene. The toluene phases were combined and evaporated. The resulting oil was purified via chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 18.40 g (59.72 mmol; 58%) of 3-amino-6-iodo-pyrazine-2-carboxylic acid methoxy-methyl-amide as a yellow solid. 1H-NMR (d6-DMSO) δ: 8.28 [1H] s, 6.78 [2H] s, 3.66 [3H] s, 3.25 [3H] s. MS: m/z 309 [MH+].