Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH3:58])[CH2:3][O:4][C:5](=[O:57])[C:6]([CH3:56])([CH3:55])[C:7]([O:9][CH2:10][O:11][C:12]1[N:13]([C:49]2[N:54]=[CH:53][CH:52]=[CH:51][N:50]=2)[N:14]=[C:15]([CH:17]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([NH2:48])=[N:39]C(=O)C3C=CC=CC=3)=[CH:34][CH:33]=2)[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH2:27][CH2:28][OH:29])[C:19]=2[F:30])[N:16]=1)=[O:8].CO>C(O)(=O)C>[C:5]([OH:57])(=[O:4])[CH3:6].[CH3:1][C:2]([CH3:59])([CH3:58])[CH2:3][O:4][C:5](=[O:57])[C:6]([CH3:56])([CH3:55])[C:7]([O:9][CH2:10][O:11][C:12]1[N:13]([C:49]2[N:50]=[CH:51][CH:52]=[CH:53][N:54]=2)[N:14]=[C:15]([CH:17]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:38](=[NH:39])[NH2:48])=[CH:36][CH:37]=2)[C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH2:27][CH2:28][OH:29])[C:19]=2[F:30])[N:16]=1)=[O:8]
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OCC(C)(C)C)n(-c3ncccn3)n2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 181.9 %

Procedure:
To a mixture of 2,2-dimethylmalonic acid 5-{(4-{amino[benzoylimino]methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester 2,2-dimethylpropyl ester (500 mg) and methanol (4 mL), acetic acid (1 mL) was added, and the resulting mixture was stirred at 40° C. for 4 hours. The mixture was concentrated under reduced pressure, and the residue obtained was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid) to obtain the captioned compound (430 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:27])[CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[CH3:3].CC(C1C=CC=C(C(C)C)C=1N[C:41](=[O:54])[CH2:42]NC(C)(C)CC1C=CC=CC=1)C>>[C:41]([N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:25])[CH3:26])=[CH:20][CH:19]=1)[CH2:15][C:14]([NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:2]([CH3:1])[CH3:3])=[O:27])(=[O:54])[CH3:42]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCc1ccc(N(C)C)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(C)(C)Cc1ccccc1
Product: CC(=O)N(CC(=O)Nc1c(C(C)C)cccc1C(C)C)Cc1ccc(N(C)C)cc1

Procedure:
When in the procedure of Example 79 an appropriate amount of the product from Example 73 was substituted for the product of Example 5 the title compound was obtained. Total yield, 0.41 g (73%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[C:4](Cl)[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=2)[C:18]([NH2:20])=[O:19])=[O:10])=[CH:11][CH:12]=1
Reactant: NC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1ccc(Br)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To solution of (4-bromo-2-chloro-phenoxy)-acetic acid (100 mg, 0.37 mmol), 2-amino isonicotinamide (77.89 mg, 0.56 mmol) and DMAP (92.58 mg, 0.75 mmol) in DMF 5 ml was added PyBOP (394.3 mg, 0.75 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1˜2:4:1) to afford 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.076 g, 52% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](NN)=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8]>CC(O)C.C(Cl)(Cl)Cl.C(O)C.[Ag]=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:15])[N:6]([CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)c(NN)nc(=O)n1Cc1cccs1
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CCO
Product: Cc1c(Cl)cnc(=O)n1Cc1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Silver oxide (238 mg) was added to a solution of 5-chloro-4-hydrazino-6-methyl-1-(2-thienylmethyl)pyrimidin-2-one (128 mg) in propan-2-ol (20 ml). The mixture was stirred at ambient temperature for 24 hours, when evaporation of solvent gave a gum. This was subjected to p.l.c. on silica, developing in chloroform-ethanol (25:1, two runs). The major band was eluted with ethyl acetate giving a gum (23 mg) containing the title pyrimidinone p.m.r. spectrum in CDCl3, signals relative to SiMe4 in p.p.m.: 2.6 (3H, s) 6-CH3 ; 5.4 (2H,s) 1-CH2 -.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:12][C:11]=1[N+:27]([O-:29])=[O:28])[CH3:2].[CH2:32]([I:34])[CH3:33].[CH2:35](O)[CH3:36]>>[I-:34].[I-:34].[CH2:30]([N+:3]([CH2:32][CH3:33])([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N+:22]([CH2:35][CH3:36])([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:12][C:11]=1[N+:27]([O-:29])=[O:28])[CH3:31]
Reactant: CCO
Reactant: CCI
Reactant: CCN(CC)CCCCCCc1ccc(CCCCCCN(CC)CC)c([N+](=O)[O-])c1
Product: CC[N+](CC)(CC)CCCCCCc1ccc(CCCCCC[N+](CC)(CC)CC)c([N+](=O)[O-])c1
Product: [I-]
Reaction time: 8 h

Procedure:
First, 600 mg of 1,4-bis(6-diethylaminohexyl)-2-nitrobenzene was dissolved in 7 ml of absolute ethanol, and after adding 2.18 g of ethyl iodide at a room temperature with stirring, the mixture was refluxed for 3 hours and then cooled. The reaction mixture was evaporated under a reduced pressure, diluted with 3 ml of acetone, and after adding 1 ml of ethyl acetate allowed to stand in a freezer overnight. Resulting crystal was collected by filtration, washed with acetone/ethyl acetate (1:1), and dried under a reduced pressure to obtain 555 mg of the title compound as a pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9](O)=[C:8]([Cl:14])[CH:7]=1.[O:16]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]O)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:15])[Cl:1])[CH:11]=[C:10]([Cl:12])[C:9]=1[CH2:27][C:26]1[CH:29]=[CH:30][C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:24][CH:25]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCc1ccc(Oc2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(Cc2ccc(Oc3ccccc3)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of 0.46 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.32 g of p-phenoxybenzyl alcohol and 0.46 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.35 g of diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, and then mixed with 20 ml of diethyl ether. The precipitate was filtered, and the filtrate was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.51 g of 3,5-dichloro-4-(4-phenoxybenzyl)-1-(3,3-dichloro-2-propenyloxy)benzene (68% yield), nD25.5 1.6084.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=1.[Cl:37]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (110 mg, 0.202 mmol) [prepared in Example 25] and N-chlorosuccinimide (35 mg, 0.263 mmol) in THF (2 mL) was stirred in a sealed tube at 70° C. After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification: LCMS (ES) m/z=578 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:20][O:17][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: COc1cccc(C(O)CC2CCCN2C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(CC2CCCN2C)OC)c1
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
1.0 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol dissolved in 15 ml of dimethyl formamide is added dropwise within 5 minutes, with stirring and exclusion of moisture, to a suspenion of 0.25 g of 80 p.c. sodium hydride. Stirring is effected for 30 minutes and a solution of 0.85 g methyl iodide in 10 ml of dimethyl formamide is added drop by drop. The mixture is kept at 60° for 2 hours, treated with water and extracted with diethyl ether. The etheral phase is concentrated. There are obtained 0.7 g of the title compound as oily mixture of diastereoisomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:23]([CH:19]1[CH2:20][C:21](=[O:22])[N:17]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[CH:7][C:2]=2[F:1])[CH2:18]1)=[O:25]
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2F)C1
Reactant: CN
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2F)C1

Procedure:
The title compound is prepared in analogy to Example 20d) from (RS)-1-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid and methylamine.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:9]([NH:12][S:13]([CH2:16][CH2:17][S:18][CH3:19])(=[O:15])=[O:14])([CH3:11])[CH3:10])#[N:8]>O.CO>[C:7]([C:9]([NH:12][S:13]([CH2:16][CH2:17][S:18]([CH3:19])=[O:2])(=[O:14])=[O:15])([CH3:11])[CH3:10])#[N:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCCS(=O)(=O)NC(C)(C)C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)CCS(=O)(=O)NC(C)(C)C#N
Yield: 36.5 %

Procedure:
To a stirred solution of 4.27 g (0.020 moles) sodium metaperiodate in 40 ml water which had been cooled to about 0° C. in an ice bath, 4.10 g (0.0184 mole) N-(2-cyano-2-propyl)-2-methylthioethylsulfonamide (the product of Example 27) in about 10 ml methanol was added slowly. Initially, the mixture was homogeneous, but after the addition was complete (after about three minutes), a thick precipitate formed. Additional methanol (15 ml) and water (60 ml) was added, thinning the precipitate to allow stirring. The mixture was stirred overnight in a slowly melting ice bath and then filtered. The solid was washed with methylene chloride. The filtrate was washed three times with 50 ml methylene chloride. The methylene chloride fractions were combined and evaporated to dryness to give 2.2 g of crude product, as a white solid. Recrystallization from ethanol gave 1.6 g of the above-identified product as a solid, melting point 142°-144° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5]>C(Cl)Cl.O>[Br:1][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)c1ccc(Br)cc1
Yield: 86 %

Procedure:
Bromine (1.29 mL, 25.1 mmol) was added dropwise at 15-20° C. to a solution of 4-bromoacetophenone (5 g, 25.1 mmol) in DCM (40 mL) and the mixture was stirred at this temperature until the bromine colour was discharged. The mixture was diluted with water and the organic phase was separated. This was dried over sodium sulfate and concentrated to afford 2-bromo-1-(4-bromo-phenyl)-ethanone (6 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[N:12])[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=1.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>ClCCl.N1C=CC=CC=1>[Cl:20][C:21]1[S:25][C:24]([S:26]([N:1]([S:26]([C:24]2[S:25][C:21]([Cl:20])=[CH:22][CH:23]=2)(=[O:28])=[O:27])[C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[C:11]#[N:12])[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=2)(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2c(C#N)cccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(N(S(=O)(=O)c2ccc(Cl)s2)S(=O)(=O)c2ccc(Cl)s2)c2c(C#N)cccc21
Temperature: 45 °C
Reaction time: 60 h
Yield: 56 %

Procedure:
1,1-Dimethylethyl 3-amino-4-cyano-1H-indazole-1-carboxylate (for a preparation see Intermediate 63) (4.3 g, 16.65 mmol) was dissolved in a mixture of dichloromethane (40 mL) and pyridine (40 mL). 5-Chloro-2-thiophenesulfonyl chloride (7.23 g, 33.3 mmol) was added to the solution and it was stirred at 45° C. under nitrogen for 60 h. LCMS showed approx 30% starting material remaining, so further quantity of 5-chloro-2-thiophenesulfonyl chloride (3.5 g, 16.12 mmol) was added to the reaction, and the mixture was stirred for 2 h. LCMS showed no change in product so the reaction was concentrated under vacuo. The residue was dissolved in DCM (200 mL) and washed 3 times with water (200 mL). The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue (10 g) was dissolved in DCM and loaded onto a 750 g silica column and purified by chromatography on the Companion system using a 0-25% ethyl acetate-DCM gradient. Appropriate fractions were evaporated in vacuo to give the title compound (5.8 g, 56%) as an orange solid. LCMS (System A) RT=1.45 min, ES+ve m/z 636/638 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)[N:13]=[C:12]([N:22]3[CH:27]4[CH2:28][CH2:29][CH:23]3[CH2:24][O:25][CH2:26]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>N1C=CC=CC=1.CN(C=O)C>[CH:23]12[N:22]([C:12]3[N:13]=[C:14]([N:16]4[CH2:17][CH2:18][S:19][CH2:20][CH2:21]4)[N:15]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)[N:11]=3)[CH:27]([CH2:28][CH2:29]1)[CH2:26][O:25][CH2:24]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3CCSCC3)nc(N3C4CCC3COC4)n2)cc1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Nc1ccc(-c2nc(N3CCSCC3)nc(N3C4CCC3COC4)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
A suspension of 8-(4-(4-nitrophenyl)-6-thiomorpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.418 g, 1.01 mmol) in pyridine (3 ml) and DMF (6 ml) was prepared. Tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was then added and the off-white suspension was allowed to stir at room temperature for 16 hours, at which time the suspension was light yellow. The suspension was filtered, washing with methanol, and concentrated. LCMS indicated reaction had not gone to completion. The crude product was dissolved in DMF (6 ml) and pyridine (3 ml) and additional tin(II) chloride dihydrate (0.569 g, 2.52 mmol) was added. The solution was allowed to stir at room temperature for 18 hours, then filtered. The precipitate was washed with methanol and the filtrate was concentrated to provide 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-thiomorpholino-1,3,5-triazin-2-yl)aniline (0.195 g, 50%) as a yellow solid. (M+H) 385.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[S:15]1[C:19]([C:20](=O)[CH3:21])=[CH:18][C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2>>[S:15]1[C:19]([CH:20]([NH:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:21])=[CH:18][C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)c1cc2ccccc2s1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc2ccccc2s1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-benzo[b]thiophen-2-yl-ethanone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([C@H:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[OH:8])[OH:6])[CH3:2].BrN1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>C(O)(=O)C>[O:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:7](=[O:8])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(=O)C(=O)OCC
Temperature: 55 °C
Reaction time: 3 h

Procedure:
L-Tartaric acid diethyl ester (300 g), acetic acid (3 l), 1,3-dibromo-5,5-dimethylhydantoin (894 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (4.5 g) were mixed, and the reaction solution was stirred at 55° C. for 3 hours. The reaction solution was concentrated under reduced pressure until its volume became 1.5 l to afford a solution of the title compound in acetic acid as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[C:12]([O-:15])([O-])=[O:13].[K+].[K+]>CO>[Cl:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:13][CH3:12])[N:3]=1.[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:15][CH3:12])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [K+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(Cl)n1
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Yield: 200.8 %

Procedure:
A slurry of 2,6-dichloro-3-nitropyridine (92%, 9.9 g, 47 mmol) and K2CO3 powder (6.5 g, 47 mmol) in methanol (100 mL) was stirred for a week at RT. The reaction was filtered and concentrated. The residue was partitioned in ethyl acetate and 60% sat. aq. NaHCO3. The organic solution was washed with 60% sat. aq. NaHCO3 (2×), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2-chloro-6-methoxy-5-nitropyridine and 2-chloro-6-methoxy-3-nitropyridine (8.9 g, 100%) as a light yellow solid: 1H NMR (CDCl3, 300 MHz, ppm) 8.31 (d, 8.3 Hz, 1H), 8.28 (d, 8.9 Hz, 1H), 7.10 (d, 8.3 Hz, 1H), 6.82 (d, 8.9 Hz, 1H), 4.15 (s, 3H), 4.06 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].II>>[CH3:1][N:2]([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CNc1cccc(F)c1
Agent: CC(=O)[O-]
Agent: II
Agent: [Na+]
Product: CN(Cc1ccc(F)cc1)c1cccc(F)c1

Procedure:
N-methyl-N-p-fluorobenzyl-m-fluoroaniline was prepared from 26.3 grams (0.21 mole) of N-methyl-m-fluoroaniline, 30.6 grams (0.21 mole) p-fluorobenzyl chloride (Aldrich), 17.8 grams anhydrous sodium acetate and 0.18 grams iodine according to the procedure described in Example III. Yield 35.4 grams (72 percent), boiling point 131°-137° C. at 0.2 mmHg.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][N:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10](=[O:17])[N:9]([C:18]2[CH:23]=[C:22]([O:24]C(C)C)[C:21]([Cl:28])=[CH:20][C:19]=2[F:29])[C:8]1=[O:30]>C(Cl)Cl.O>[NH2:6][N:7]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10](=[O:17])[N:9]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:28])=[CH:20][C:19]=2[F:29])[C:8]1=[O:30]
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 0 °C

Procedure:
Conc. sulfuric acid (3 ml) was added to a solution of 1-amino-3-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (4.5 g) in methylene chloride (50 ml) stirred at 0° C. . After 1 hour the mixture was diluted with water and processed. The oily product was chromatographed on silica gel eluting with ethyl acetate:hexane, 2:3, to give 1-amino-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione as a pale yellow amorphous solid (3.6 g,). 1H NMR (CDCl3, TMS): 7.27(1H, d, J=8.8 Hz), 6.88(1H, d, J=6.5 Hz), 6.28(1H, s), 5.86(1H, br. s), 4.61(2H, s)
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(O)(=O)CCCCCCCCCCCCCC.[CH:43]1([N:49]=[C:50]=[N:51][CH:52]2[CH2:57][CH2:56][CH2:55]CC2)CCCCC1>O1CCCC1>[CH3:1][N:49]([C:50]1[CH:55]=[CH:56][CH:57]=[CH:52][N:51]=1)[CH3:43]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: CCCCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 500 mg of radicicol, 830 mg of pentadecanoic acid, 15 ml of dry tetrahydrofuran, 707 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 782 mg of the title compound were obtained.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[Cl:33][C:34]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[NH2:52][C:53]1[CH:54]=[C:55]([C:60]([N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[O:61])[CH:56]=[CH:57][C:58]=1[NH2:59]>>[Cl:33][C:34]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44]2[NH:59][C:58]3[CH:57]=[CH:56][C:55]([C:60]([N:62]4[CH2:63][CH2:64][O:65][CH2:66][CH2:67]4)=[O:61])=[CH:54][C:53]=3[N:52]=2)=[N:41][NH:42][CH:43]=1)=[O:37]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1N
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1Cl
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(C(=O)N3CCOCC3)ccc2[nH]1)c1c(F)cccc1Cl

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2-chloro-6-fluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 95A) and (3,4-diamino-phenyl)-morpholin-4-yl-methanone (Example 94B) to give 2-chloro-6-fluoro-N-{3-[5-(morpholine-4-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (18 mg) as a beige solid. (LC/MS: Rt 2.89, [M+H]+ 469.15).
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:21].[H][H]>C1(C)C=CC=CC=1.[Ni]>[NH2:21][CH:17]([CH3:18])[CH2:16][C:15]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)=[O:20]
Reactant: N
Reactant: [H][H]
Reactant: CC(=O)CC(=O)Nc1ccc(Nc2ccccc2)cc1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CC(N)CC(=O)Nc1ccc(Nc2ccccc2)cc1

Procedure:
Thirty grams (0.11 mol) of N-(4-anilinophenyl)-3-oxo butanamide was dissolved in 300 ml of toluene. This was mixed with 30 g. (1.8 mol) of anhydrous ammonia, Raney nickel catalyst, and 800 psi of hydrogen gas at a temperature of 70° C. for 2 hours. The catalyst was removed and the solvent stripped off under vacuum. Purification was done by flash chromatography and recrystallization from hot toluene. The product was obtained in a yield of 16 g. with a melting point of 130-132° C.