Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:26])=[CH:4][C:3]=1[CH3:28].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:28][C:3]1[CH:4]=[C:5]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:26])[CH:6]=[CH:7][C:2]=1[O:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 55 °C

Procedure:
A solution of 1-(4-hydroxy-3-methylphenyl)-3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}propan-1-one (intermediate 10, 0.28 g) in dry acetonitrile (15 ml) was treated with ethyl bromoacetate (0.076 ml) and cesium carbonate (0.449 g) and heated at 55° C. for 18 hours. The reaction was filtered, and the filtrate evaporated to give material which was further purified by flash column chromatography using cyclohexane:ethyl acetate (3:1) as eluent to give the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].C(N(C(C)C)CC)(C)C.[C:32]1([CH2:38][NH2:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH2:38]([NH:39][C:20](=[O:21])[CH2:19][N:3]1[CH2:4][CH2:5][C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]1=[O:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ccccc1
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.031 g, 0.105 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.044 g, 0.115 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.027 mL, 0.157 mmol) followed by phenylmethanamine (0.014 mL, 0.126 mmol). After stirring overnight, the reaction was loaded onto a silica gel column (Analogix® SF15-12, Burlington, Wis.), and the product was eluted with a gradient of 0.4% to 5.25% methanol/dichloromethane over 20 minutes with a flow rate of 30 mL/minute. The product residue was dissolved in dichloromethane/diethyl ether followed by the addition of hexanes which upon concentration gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.34 (m, 15H), 6.23 (t, J=5.8 Hz, 1H), 4.32 (d, J=5.8 Hz, 2H), 4.06 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 2.80 (t, J=6.5 Hz, 2H); MS (ESI−) m/z 383 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12](C(O)=O)=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.SC1C=C(C=CC=1)[C:25]([OH:27])=[O:26]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:16][CH:17]=2)[C:25]([OH:27])=[O:26])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(O)c1cccc(S)c1
Reactant: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Product: Cc1ccc(Sc2cccc(C(=O)O)c2)c([N+](=O)[O-])c1
Yield: 80.9 %

Procedure:
The product from Example 84a (0.94 g, 3.29 mmol) was reacted with 3-mercapto-benzoic acid (0.51 g, 3.31 mmol) as described in Example 84b to give the title compound (0.77 g, 80%).
Reaction SMILES: [OH-].[K+].CO.[Cl:5][C:6]1[C:7]([O:17][CH3:18])=[C:8]([C:13]([Cl:16])=[CH:14][CH:15]=1)[C:9]([NH:11][OH:12])=[O:10].[CH3:19][O:20][C:21](=[O:24])[CH2:22]Br>C(Cl)Cl>[Cl:5][C:6]1[C:7]([O:17][CH3:18])=[C:8]([C:13]([Cl:16])=[CH:14][CH:15]=1)[C:9]([NH:11][O:12][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[O:10]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)NO
Reactant: COC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CONC(=O)c1c(Cl)ccc(Cl)c1OC

Procedure:
To a solution of 2.15 g. of potassium hydroxide in 50 ml. of methanol was added 7.55 g. of 3,6-dichloro-2-methoxy benzohydroxamic acid followed by stirring until dissolution was obtained. To this solution was added dropwise 3.03 ml. methylbromoacetate in 25 ml. of methanol. The reaction mixture was refluxed for 2 hours and allowed to stir overnight at ambient temperature. To the reaction mixture was added 0.36 g. of additional potassium hydroxide and the mixture heated to reflux for 4 hours, then cooled, filtered, and the filtrate concentrated in vacuo to give a crude semi-solid product. This crude product was taken up in methylene chloride and washed with water, 5% aqueous NaHCO3, brine, then dried over MgSO4, filtered and evaporated in vacuo to give a viscuous oil. The oil crystallized from an ethyl acetate-hexane mixture to the title product as a white solid, m.p. 102°-105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12](NC1C=CC(C(O)=O)=CC=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Product: Cc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C

Procedure:
4-Amino-3-methylbenzoic acid (5 g, 33.1 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting orange-brown solid was recrystallized from ethyl acetate and hexanes to provide the desired product (4.99 g) as tan prismatic crystals: m.p. 180-182° C.; 1H NMR (CD3OD) δ 1.51 (9h, s), 2.27 (3H, s), 7.66 (1H, d, J=8.1 Hz), 7.79-7.82 (2H, m), 8.32 (1H, s); 13C NMR (CD3OD) δ 17.98, 28.62, 81.47, 123.12, 127.05, 129.14, 130.65, 132.99, 142.45, 155.33, 168.70; Anal. Calc. for C13H17NO4, C: 62.15, H: 6.82, N: 5.58; Found C: 62.07, H: 6.86, N: 5.46; m/z (EI) 251; HRMS Calc. for C13H17NO4, 251.1158; Found, 251.1153.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCOCC1.CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([O:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: OCCN1CCOCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCCN4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and N-(2-hydroxyethyl)morpholine in dioxane and DMF. ES-MS m/e (%): 500 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N+:16]([C:4]1[CH:3]=[C:2]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Yield: 53.4 %

Procedure:
A solution of tert-butyl 4-bromo-2-nitrophenylcarbamate 175 (3.97 g, 12.5 mmol), 2-thiophene boronic acid 176 (1.68 g, 13.4 mmol), sodium carbonate (3.98 g, 37.56 mmol) and Pd(PPh3)4 (0.94 g, 0.814 mmol) were stirred at 110° C. in a mixture of DME and water (2:1, 70 mL overnight. The solution was evaporated to dryness, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to provide the crude product which was purified by flash chromatography (10% ethyl acetate in hexane) to provide the title compound 177 (2.14 g, 53% yield). 1H NMR: (DMSO) δ (ppm): 400 MHz, (DMSO) d (ppm): 9.63 (s, 1H), 8.12 (d, J=2.3 Hz, 1H), 7.92 (dd, J=8.4, 2.2 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.61 (q, J=2.2 Hz, 2H), 7.15 (dd, J=5.1, 3.7 Hz, 1H), 1.46 (s, 9H). MS: (calc.) 320.08; (obt.) 343.1 (M+Na).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[K+].[CH3:7][N:8]1[C:12](Cl)=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1>C1OCCOCCOCCOCCOCCOC1.CS(C)=O.O>[CH3:7][N:8]1[C:12]([S:1][CH2:2][CH2:3][OH:4])=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1
Reactant: OCCS
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1nc(Cl)c(Cl)c1SCCO
Temperature: 140 °C
Yield: 38.1 %

Procedure:
To a mixture of 26.5 g (0.34 moles) 2-mercaptoethanol, 19 g of 85% potassium hydroxide, and a few drops of 18-Crown-6 in 250 ml of DMSO, 60 g (0.32 moles) 1-methyl-3,4,5-trichloro pyrazole (product of Example 1 or 1A) were added in portions. When the addition was complete, the reaction mixture was heated to 140° C. for 1 day. The cooled reaction mixture was diluted with water and extracted with ether. The organic phase was washed four times with 200 ml water per time, dried and stripped. The crude product was chromatographed on a silica gel column. The product, 1-methyl-3,4-dichloro-5-(2-hydroxyethyl)thio pyrazole, was eluted from the column with ethyl acetate, yielding 27.7 g (37.7% yield) of a yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:31]4[S:32][C:28]([CH3:27])=[CH:29][N:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1cncs1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ncc(C)s3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 5-methylthiazole
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccccc3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.89 g of 4,5-bis(4-methoxyphenyl)-2-phenylthioimidazole in 100 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is crystallized from ether/hexane. Recrystallization from ether/hexane yields 3.36 g of 4,5-bis(4-methoxyphenyl)-2-phenylsulfinylimidazole, mp 188°-190°.
Reaction SMILES: [NH2:1][NH2:2].[CH:3]1([C:6](=O)[CH2:7][CH:8]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[C:9](OCC)=[O:10])[CH2:5][CH2:4]1>C(O)(=O)C>[CH:3]1([C:6]2[CH2:7][CH:8]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[CH2:16][CH2:15]3)[C:9](=[O:10])[NH:1][N:2]=2)[CH2:5][CH2:4]1
Reactant: NN
Reactant: CCOC(=O)C(CC(=O)C1CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(=O)O
Product: O=C1NN=C(C2CC2)CC1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hydrazine (0.3 mL, 9.6 mmol) was added to a solution of benzyl 4-[3-cyclopropyl-1-(ethoxycarbonyl)-3-oxopropyl]piperidine-1-carboxylate (186 mg, 0.48 mmol) in acetic acid (7 mL). The reaction mixture was heated at 50° C. After 1 h, the reaction mixture was concentrated. The residue was diluted with dichloromethane and neutralized by saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound. MS 356.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17](O)=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[C:41](N(C)C)=[N+:42](C)[CH3:43])C2C=CC=CC=2N=N1.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:41][N:42]([CH3:43])[C:17]([C:16]1[N:15]=[C:14]([C:20]([F:21])([F:22])[F:23])[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=12)=[O:18]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Reaction time: 12 h
Yield: 99.9 %

Procedure:
7-Tert-butoxycarbonyl-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 20a (330 mg, 1 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), dimethylamine hydrochloride (156 mg, 2 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 50 mL of ethyl acetate, and washed successively with saturated ammonium chloride solution (30 mL) and saturated sodium chloride solution (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude tert-butyl 1-(dimethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 22a (362 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C#C[Si](C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
8-Chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (6.62 g) was dissolved in 146 mL of DMF at room temperature under argon. The solution was treated with trimethylsilyl acetylene (8.94 g, 12.9 mL) followed by triethylamine (3.68 g, 5.07 mL). The mixture was then treated with bis-chloro-bis-(triphenyl-phosphine) palladium (II) (0.64 g) followed by cuprous iodide (0.51 g). The solution was stirred at room temperature for 3 hours. The mixture was concentrated to a solid. It was treated with cold water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered, and concentrated to a dark solid (5.73 g). It was dissolved in chloroform and ethyl acetate and chromatographed on silica gel with 17% ethyl acetate in hexane to give a yellow solid (2.61 g). A portion (0.24 g) of the solid was recrystallized from toluene (5 mL). The crystals were cooled in an ice bath and filtered off to give light-yellow crystals (0.162 g); mp 218.8°-219.4° C. (dec); MS: m/z=334 (M+1). Analysis for C16H16ClNO3Si: Calculated: C, 57.56; H, 4.83; N, 4.20; Found: C, 57.49; H, 5.01; N, 4.27.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[F:11][C:12]([F:18])([F:17])[CH2:13][C:14](O)=O>Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH2:13][C:12]([F:18])([F:17])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 100 °C

Procedure:
To 4,5-dichloro-1,2-phenylenediamine (25 g) was added 3,3,3-trifluoropropionic acid (25 mls) and 4N HCl (90 mL). The resulting mixture was heated to 100° C. overnight. The reaction mixture was quenched with water, basicified with concentrated NH4OH, extracted with EtOAc, and dried over Na2SO4. The crude product was filtered through a plug of silica gel, eluting with 30% EtOAc/hexanes, and collecting the red band. The fractions were concentrated to yield a mixture of the desired title compound and 4,5-dichloro-1,2-phenylenediamine. The crude material was dissolved in small amount of CH2Cl2 and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19](C)(=O)=O)[N:14]=1)=[O:4].S.[K].O.Cl>C(O)C>[SH:19][C:15]1[N:14]=[C:13]([C:7]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=2[NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:23])[CH:18]=[CH:17][N:16]=1
Reactant: Cc1ccc(NC(=O)C(C)C)c(-c2ccnc(S(C)(=O)=O)n2)c1
Agent: Cl
Agent: S
Agent: [K]
Solvent: CCO
Solvent: O
Product: Cc1ccc(NC(=O)C(C)C)c(-c2ccnc(S)n2)c1
Yield: 75.9 %

Procedure:
3.3 g (0.01 mol) 2-methyl-N-[4-methyl-2-[2-(methylsulfonyl)-4-pyrimidinyl]phenyl]propanamide was dissolved in 35 mL absolute ethanol and 3 g potassium hydrogen sulfide was added to this solution with stirring. The reaction mixture was stirred overnight at room temperature. 50 mL water was added and the volume reduced under vacuum to 40 mL. An additional 40 mL water was added and the solution thus obtained was made acidic with concentrated hydrochloric acid. The yellow precipitate was collected by filtration, washed with a little water, then dissolved in 50 mL 1N sodium hydroxide and treated with charcoal. The charcoal was filtered off and the filtrate was made acidic with concentrated hydrochloric acid. The bright yellow precipitate was collected by filtration, washed with water, then dried in a vacuum oven to yield 2.18 g of N-[2-(2-mercapto-4-pyrimidyl)-4-methylphenyl]-2-methylpropanamide. 1H NMR (CDCl3): δ 1.21 (d,6H), 2.40 (s,3H), 2.75 (m,1H), 7.40-8.60 (5H), 11.4(s,1H,NH), 11.9(s,1H,SH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](=[O:12])[NH:13][CH3:14])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:25][P:26](=[O:33])([O:27][CH2:28][CH3:29])[O:30][CH2:31][CH3:32])=[CH:34][CH:35]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(Cl)c(Nc3ccccc3C(=O)NC)n2)cc1)OCC
Yield: 23.8 %

Procedure:
A solution of 2-[(2,5-dichloropyrimidin-4-yl)amino]-N-methylbenzamide (29.7 mg, 0.100 mmol), diethyl (4-aminobenzyl)phosphonate (29.2 mg, 0.120 mmol), TFA (23 uL, 0.30 mmol) and TFE (1.0 mL) was heated at 100° C. for 30 minutes in a microwave reactor. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (15 mL), dried over anhydrous NaSO4, filtered, and concentrated in vacuo to yield a yellow solid. This material was purified by preparative HPLC (MDP) to afford 12 mg of diethyl {4-[(5-chloro-4-{[2-(methylcarbamoyl)phenyl]amino}pyrimidin-2-yl)amino]benzyl}phosphonate (yield: 24%). 1H NMR (CD3OD, 400 MHz): δ=1.26 (t, J=7.07 Hz, 6 H), 2.92 (s, 3 H), 3.15-3.24 (m, 2 H), 3.99-4.08 (m, 4 H), 7.12 (td, J=7.64, 1.14 Hz, 1 H), 7.21 (dd, J=8.59, 2.53 Hz, 2 H), 7.48 (ddd, J=8.53, 7.26, 1.64 Hz, 1 H), 7.55 (d, J=8.08 Hz, 2 H), 7.65 (dd, J=7.83, 1.52 Hz, 1 H), 8.06 (s, 1 H), 8.70 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 506.15 [MH+] (TOF, polar).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:8](I)[CH3:9]>C(O)C>[CH2:8]([N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: C1CNCCNC1
Reactant: CCI
Solvent: CCO
Product: CCN1CCCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Homopiperazine (100 g) is dissolved in ethanol (500 ml), and thereto is added dropwise gradually ethyl iodide (19.8 ml). The mixture is stirred at room temperature overnight, and the insoluble materials are removed by filtration. The filtrate is evaporated to remove the solvent. Purification is perfomed by distillation to give 1-ethylhomopiperazine (50 g) as colorless oil.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:13][NH2:14]>C(O)(=O)C>[CH2:10]([C:9]1[NH:14][N:13]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1)[CH3:11]
Reactant: CCOC(=O)C(=O)CC(=O)CC
Reactant: NN
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A solution of ethyl 2,4-dioxohexanoate (˜0.464 mol), prepared as described in Part A of Example 10, in glacial acetic acid (300 mL) was cooled to 0° C. Hydrazine (8.91 g, 0.278 mol) was added dropwise. The reaction was allowed to warm to ambient temperature, stirred overnight, and concentrated under reduced pressure. The residue was adjusted to pH 10 with the addition of 2 M aqueous sodium carbonate. The mixture was extracted with chloroform (3×250 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 27.0 g of ethyl 5-ethyl-1H-pyrazole-3-carboxylate, which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:15][CH2:16][CH3:17])[CH2:7]/[C:8]/2=[CH:11]\[C:12](O)=[O:13])=[CH:4][CH:3]=1.[Cl:18]CCl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH2:15][CH2:16][CH3:17])[CH2:7]/[C:8]/2=[CH:11]\[C:12]([Cl:18])=[O:13])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CCCC1C/C(=C\C(=O)O)c2cc(F)ccc21
Product: CCCC1C/C(=C\C(=O)Cl)c2cc(F)ccc21

Procedure:
This compound was prepared in an analogous manner to Example 18h with replacement of (E)-2-(6-fluoro-3-methyl-1-indanylidnene)acetic acid with (E)-2-(6-fluoro-3-propyl-1-indanylidene)acetic acid (15.01 g, 64.07 mmol). The product residue was dissolved in dichloromethane and used without purification in Example 27j.