Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([O:15]C)[CH:10]=2)=[O:7])=[C:4]([F:19])[CH:3]=1.[Si](I)(C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[O:7])=[C:4]([F:19])[CH:3]=1
Reactant: COc1cc(NC(=O)c2ccc(Cl)cc2F)ccn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(Cl)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 15.50 mmol) in acetonitrile (145.0 mL) was added TMSI (8.8 mL, 62.0 mmol). The reaction was stirred at 50° C. overnight. The acetonitrile was evaporated and the crude solid was triturated with ethyl acetate. The solid was isolated by filtration and washed with ethyl acetate to give 4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (3.8 g, 92%). ESI-MS m/z calc. 266.02. found 267.1 (M+1)+; Retention time: 1.23 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.68 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (d, J=7.1 Hz, 1H), 7.47 (dd, J=8.3, 2.0 Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 6.71 (dd, J=7.1, 2.1 Hz, 1H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C1C=CC=CC=1.O.[NH2:22][NH2:23]>O>[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:2]1[NH:23][N:22]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NN
Solvent: c1ccccc1
Solvent: O
Product: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Yield: 83 %

Procedure:
A mixture of 20.8 g (0.1 mole) of 4-chloro-3-nitroquinoline, 40 ml of benzene and 40 ml of hydrazine hydrate is refluxed for 2 hours, then cooled. The separated phase containing hydrazine hydrate is diluted with 150 ml of water. Yellow-white crystals separate. Thus, 16.8 g (83%) of 5-(o-aminophenyl)-4-nitropyrazole are obtained. M.p.: 175°-176° C. (ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([F:21])[CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([F:21])[CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)c(F)cc23)c1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3)c3cc(F)c(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: C([O:8][C:9]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:11]([CH3:19])[N:10]=1)C1C=CC=CC=1.O1CCCC1>[C].[Pd].C(O)C>[OH:8][C:9]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:11]([CH3:19])[N:10]=1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)Cc1cn(C)nc1O
Reaction time: 5 h
Yield: 79.4 %

Procedure:
A mixture of methyl 3-benzyloxy-1-methyl-1H-pyrazol-4-ylacetate (12.2 g), 5% palladium-carbon (25.0 g), tetrahydrofuran (100 ml) and ethanol (100 ml) was stirred under hydrogen atmosphere for 5 hrs. Palladium-carbon was filtered off and the filtrate was concentrated to give methyl 3-hydroxy-1-methyl-1H-pyrazol-4-ylacetate (6.33 g, yield 79%) as colorless crystals. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 118–119° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([NH:19][C:20](=O)C)=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1C1OCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[CH3:1][O:2][C:3]([C:4]1[N:19]=[CH:20][C:7]2[C:6]([CH:5]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])=[O:23]
Reactant: COC(=O)C(=Cc1cccc(F)c1C1OCCCO1)NC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc2cccc(F)c2cn1
Yield: 75.8 %

Procedure:
2-Acetylamino-3-(2-[1,3]dioxan-2-yl-3-fluoro-phenyl)-acrylic acid methyl ester (10.6 g, 32.8 mmol) and pyridinium para-toluene sulfonate (2.06 g, 8.2 mmol) are heated to reflux for 20 hours in an acetone/water (120 ml/15 ml) mixture. The solvents are removed by evaporation and the aqueous residue is extracted with ethylacetate. The organic layer is washed with brine and dried over MgSO4 and evaporated. The crude product is recrystallised from ethylacetate/ether to afford 5.1 g of the desired compound. MS (ES+): m/e=206.2 (MH+)
Reaction SMILES: [C:1]([CH:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O:3][CH2:4][CH3:5])=[O:2].C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([CH:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][Br:29])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCC(Oc1ccccc1C)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CCC(Oc1ccccc1CBr)C(=O)OCC
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-carbethoxy-4-(2-methylphenoxy)butyrate (0.05 mol) and NBS (0.055 mol) and 150 mg of benzoyl peroxide in 150 mL of CCl4 is refluxed and shined with a sun lamp for 2 hours. Filtration and evaporation of solvent gives 2-(1,3-dicarbethoxypropoxy) benzyl bromide which is used without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[C:9]([F:15])[C:8]=1[F:16])([CH3:4])([CH3:3])[CH3:2].C[N+]([O-:22])(C)C>CS(C)=O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:22])=[C:9]([F:15])[C:8]=1[F:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c(F)c1F
Reactant: C[N+](C)(C)[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C=O)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
To a solution of 4-bromomethyl-2,3-difluoro-benzoic acid tert-butyl ester (12.9 g, 42.1 mmol) in DMSO (80 mL) and DCM (40 mL) at 0° C. was added trimethylamine N-oxide (3.4 g, 45.3 mmol). The reaction mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The resultant residue was partitioned between iced water and ethyl acetate. The organic layer was separated and washed with brine twice, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue which was subjected to flash chromatography (Si—PPC, gradient 0% to 10%, TBME in cyclohexane) to afford the title compound as a white solid (4.34 g, 43%). 1H NMR (CDCl3, 400 MHz) 10.38 (1 H, d, J=0.8 Hz), 7.71 (1 H, dddd, J=7.4, 5.6, 1.7, 0.8 Hz), 7.63 (1 H, ddd, J=7.4, 5.6, 1.5 Hz), 1.61 (9 H, s).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[N:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[N:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][CH:12]=3)=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)nc3)CC2)c(C)c1
Yield: 39.6 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 4 and (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 127 and by the reaction and treatment in the same manner as in Example 1, the title compound (170 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].C(N(CC)CC)C.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method E using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.150 g, 0.626 mmol), methylene chloride (6 mL), triethylamine (0.348 mL, 2.50 mmol), catalytic 4-dimethylaminopyridine, phenacetyl chloride (0.106 g, 0.626 mmol). m.p. dec. 213° C.; 1H NMR (250 MHz, DMSO-d6) δ 3.69 (s, 2 H), 6.85 (s, 1 H), 7.29 (m, 4 H), 7.53 (m, 3 H), 7.83 (m, 2 H), 9.40 (bs, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N>C(O)C.O1CCCC1.[Ni]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C#N)cc2)CC1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
[Step 2] To a mixture of 1-(4-cyanobenzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (1.36 g) in ethanol (84 ml) and tetrahydrofuran (14 ml) was added 28% aqueous ammonia (3 ml) and then Raney nickel (500 mg) was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room temperature for 2 hrs., and undesired substances were removed by filtration. The filtrate was concentrated under reduced pressure to give 1-(4-aminomethylbenzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (1.05 g, 77%).
Reaction SMILES: [C:1]1([C:7]([Cl:10])([Cl:9])[Cl:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:11][S:12]([C:3]1[CH:2]=[C:1]([C:7]([Cl:10])([Cl:9])[Cl:8])[CH:6]=[CH:5][CH:4]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: ClC(Cl)(Cl)c1ccccc1
Product: O=S(=O)(Cl)c1cccc(C(Cl)(Cl)Cl)c1

Procedure:
Benzotrichloride is chlorosulfonated with chlorosulfonic acid to yield m-chlorosulfonylbenzotrichloride, and the product is heated to obtain m-chlorosulfonylbenzoylchloride. (U.S. Pat. No. 3,290,370)
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH2:28][OH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:29][CH2:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C[C@]12CCCCC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
The title compound II-an was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6α-hydroxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.50 (m, 3H), 2.52-0.74 (m, 21H), 1.11 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: C(Cl)(=O)CCCCCCCCCCCCC.[C:17]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N)CCCCCCCCCCCCC.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:33]([NH:32][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCNC(=O)CCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCCN
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
N-myristyl myristamide Myristoyl chloride (2.5 g; 10 mmole) was added to a room temperature methylene chloride solution of n-tetradecylamine (2.1 g; 10 mmole, TCI chemicals) and DBU (2.3 g; 15 mmole). The resulting mixture was stirred at room temperature for 4 hours, diluted with CH2Cl2, washed with brine solution, dried, and purified by column chromatography on silica gel, to give 3.40 g, 80.9% of product. 1H NMR (CDCl3): δ 5.38 (6s, 1H), 3.24 (q, 2H), 2.16 (t, 2H, J=7.8 Hz), 1.58-1.66 m, 2H), 1.40-1.57 (m, 2H), 1.20-1.40 (m, 42H), 0.89 (t, 6H).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]([O:8][CH:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:10]#[C:11][CH2:12]O)(=[O:7])[CH3:6]>CCOCC>[C:5]([O:8][CH:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:10]#[C:11][CH2:12][Br:2])(=[O:7])[CH3:6]
Reactant: BrP(Br)Br
Reactant: CC(=O)OC(C#CCO)COc1ccc(F)cc1
Solvent: CCOCC
Product: CC(=O)OC(C#CCBr)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus tribromide (10.6 g., 0.039 mole) is added dropwise during 15 minutes to a solution of 4-acetoxy- 5-(4-fluorophenoxy)-2-pentyn-1-ol (25.1 g., 0.1 mole) in ether (80 ml.). The resulting solution is stirred at room temperature for 1 hour and then heated at reflux for 30 minutes. The solution is poured into ice water (100 ml.). The organic layer is separated, washed with water, and dried over sodium sulfate. The solvent is evaporated under reduced pressure to leave the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([S:11][CH2:12][CH3:13])[N:3]=1.F[P-](F)(F)(F)(F)F.[N:21]1([O:30][C:31](N(C)C)=[N+](C)C)[C:25]2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH3:31][O:30][N:21]([CH3:25])[C:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([S:11][CH2:12][CH3:13])=[N:5][CH:6]=1)=[O:10]
Reactant: CCSc1ncc(C(=O)O)c(N)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Yield: 90.9 %

Procedure:
To a solution of 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid (1.00 g, 5.40 mmol, Sigma) in dimethylformamide were added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.06 g, 8.1 mmol, Aldrich), 1-hydroxy-benzotriazole hydrate (1.09 g, 8.1 mmol, Aldrich) followed by diisopropylethylamine (3.94 g, 29.7 mmol) at 0° C. After stirring for 10–15 minutes, N,O-dimethyl-hydroxylamine. HCl (790 mg, 8.1 mmol, Aldrich) was added. The reaction was stirred at 0° C. to room temperature for 2 hours and then diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated. The crude product was purified on silica gel with 1:1 hexane/ethyl acetate to give 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide as a white solid (1.189 g, 98% yield). HRMS, observed: 242.0836; Calcd for M+: 242.0837
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH3:43])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH3:43])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34]
Reactant: O=C(O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
To a stirred solution of 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (7-01) (3 g, 7.28 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8-a) (1.51 g, 8.01 mmol) in pyridine (40 mL) was added POCl3 (2 ml, 21.84 mol) at −10° C. The mixture was stirred at 0° C. for 2 h. After completion of the reaction, ice cooled-water (30 mL) was added to the reaction mixture at 0° C. The mixture was extracted with ethyl acetate (4×200 mL). The separated organic part was washed with saturated aqueous solution of NaHCO3, dried and concentrated to get a crude product which was purified by normal silica column using 40% ethyl acetate in hexane to get 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]methyl-amide (9-01) (2.1 g, 49.4%) as a yellow sticky mass.
Reaction SMILES: Cl[P:2]1([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[N:7]=[P:6](Cl)([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[N:5]=[P:4](Cl)([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[N:3]=1.ClP1(Cl)N=P(Cl)(Cl)N=P(Cl)(Cl)N=1.[C:46]1([OH:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[H-].[Na+]>C1COCC1>[O:52]([P:2]1([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[N:7]=[P:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[N:5]=[P:4]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[N:3]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Oc1ccccc1
Reactant: Nc1ccccc1OP1(Cl)=NP(Cl)(Oc2ccccc2N)=NP(Cl)(Oc2ccccc2N)=N1
Agent: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccccc1OP1(Oc2ccccc2)=NP(Oc2ccccc2)(Oc2ccccc2N)=NP(Oc2ccccc2)(Oc2ccccc2N)=N1

Procedure:
The procedure of Example 6 was used, with a sample of trichloro-tris(aminophenoxy)cyclotriphosphazene, prepared as in Example 4, as the starting phosphazene reagent. The reagent amounts were: hexachlorocyclotriphosphazene, 0.05 mole; phenol, 0.21 mole; sodium hydride, 0.22 mole. The product was isolated as an amber oil, which contained traces of THF.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH3:30][NH:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=1)[C:35](O)=[O:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C:17]3([NH:22][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][N:40]=[C:32]([NH:31][CH3:30])[CH:33]=4)[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OCC3(N)CCCC3)c21
Reactant: CNc1cc(C(=O)O)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1cc(C(=O)NC2(COc3cccc4c3C(N)=NS(=O)(=O)N4)CCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
To a stirred suspension of 4-amino-5-((1-aminocyclopentyl)methoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (200 mg, 0.577 mmol) in DMF (5 mL) was added triethylamine (0.32 mL, 2.31 mmol). After being stirred at room temperature for 10 min., a mixture of 2-(methylamino)isonicotinic acid (88 mg, 0.577 mmol), EDCI (122 mg, 0.635 mmol) and HOBt (86 mg, 0.635 mmol) in 10 ml of DMF were added, and the reaction mixture was then stirred at room temperature overnight and at 55° C. for 2 hrs. The resulting solution was purified by preparative HPLC (10-90% CH3CN in water). The clean fractions were collected and re-crystallized from ethanol/water, dried at 60° C. under vacuum to provide the title compound (87 mg) in 34% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.84 (m, 6H), 2.15-2.21 (m, 2H), 2.76 (J=4.8 Hz, 3H), 4.40 (s, 2H), 6.59-6.64 (m, 3H), 6.70-6.72 (m, 1H), 6.77 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.8 Hz, 1H), 7.88 (s, 1H), 8.00 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 8.38 (s, 1H), 10.97 (s, 1H). MS 445 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([Cl:14])[N:3]=1.[Cl:15]N1C(=O)CCC1=O>C(O)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH:11]([CH3:12])[CH3:13])[C:5]([Cl:15])=[C:4]([Cl:14])[N:3]=1
Reactant: CC(C)CNc1cc(Cl)nc(N)[n+]1[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCO
Product: CC(C)CNc1c(Cl)c(Cl)nc(N)[n+]1[O-]
Yield: 58.9 %

Procedure:
6.30 g of 2-amino-4-isobutylamino-6-chloropyrimidine 3-oxide are suspended in 110 ml of ethanol. 4.85 g of N-chlorosuccinimide are added. The reaction mixture is heated under reflux for 2 hours and then evaporated to dryness. The residue is taken up in 50 ml of water. The pH is adjusted to 8 by addition of concentrated sodium hydroxide solution. The precipitate formed is filtered on sintered glass, washed with water until neutral and dried under vacuum over phosphorus pentoxide. It is recrystallized from 150 ml of ethanol. 4.30 g of 2-amino-4-isobutylamino-5,6-dichloropyrimidine 3-oxide are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][OH:16]>>[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][O:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCCC(F)(F)F
Product: COC(=O)c1ccc(OCCC(F)(F)F)nc1
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (1.37 g, colorless oil) from methyl 6-chloronicotinate (2.0 g, 11.7 mmol) and 3,3,3-trifluoropropan-1-ol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:2]=1.[N:16]1([CH2:22][CH2:23][O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:35])=[CH:27][CH:26]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([CH2:22][CH2:23][O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH:35][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)=[CH:27][CH:26]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2cccnc2)c1

Procedure:
Compound is prepared from 3-pyridin-3-yl-benzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. (0.218 g) (63%). Mp: 77-78° C. 1H NMR (300 MHz, DMSOd6) 10.42 (s, 1H), 9.06 (s, 1H), 8.63 (d, J=3.9 Hz, 1H), 8.48 (s, 1H), 8.22 (d, J=8.1 Hz, 2H), 8.10 (d, J=7.5 Hz, 1H), 7.98 (m, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.56-7.47 (m, 4H), 7.04 (d, J=8.4 Hz, 1H), 4.33 (brt, 2H), 3.60 (brs, 4H), 2.88 (brs, 2H), 2.57 (brs, 4H). MS: 454 (M+1).