Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:27]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[N:27]=1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a mixture of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine, hydrochloride (37.1 g, 0.10 mol, see Example 1b, step 5) and phenyl pyridazin-3-ylcarbamate (21.5 g, 0.10 mol, see Example 39, steps 1 and 2) in acetonitrile (400 mL) was added dropwise diisopropylethyl amine (25.8 g, 0.20 mol). A solution formed after 2 h of stirring. The slightly turbid solution was stirred at ambient temperature for 17 h. It was poured into 2.5 L of stirred ice-water. The resulting mixture was stirred for 1 h. The solid was filtered off, rinsed with 300 mL of water and pressed dry under suction. This was dissolved in 400 mL of dichloromethane. Water was removed using a sep funnel and then the solution was dried over magnesium sulfate and concentrated in vacuo to ˜50 mL. The viscous solution was diluted with 65 mL of ethyl acetate and then with 85 mL of methyl t-butyl ether. A solution formed, and then a solid began separating. The crystallizing mixture was kept at −10° C. for 2 h and filtered. The solid was rinsed with EtOAc:MTBE (40 mL) and pressed dry under suction. Further drying in vacuo at 40° C. for 7 h provided 30.3 g (66%) of product. The mother liquor was concentrated in vacuo to 19 g of a viscous oil. This was dissolved in 15 mL of ethyl acetate. The solution was diluted with 60 mL of methyl t-butyl ether, seeded and kept at 5° C. for 18 h. The solid which crystallized was filtered off, rinsed with 10 mL of methyl t-butyl ether, and pressed dry under suction. 9.0 g (20%) of additional product was obtained. Total yield=39.3 g (86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH2:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:13][N:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=1)[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])(=[O:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(N(N)C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(N(NC(C)=O)C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl 1-[4-(ethoxycarbonyl)phenyl]hydrazinecarboxylate (5.60 g) and acetic anhydride (10 ml) were mixed, and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution, and washed with water and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 (volume ratio)→1:1 (volume ratio)), and further recrystallized from ethyl acetate-hexane to give the title compound (4.42 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CN(C=O)C>[O:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][N:11]2[CH:12]=[C:13]([N:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:10]2)[CH2:32][CH2:33]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c[nH]nc2-c2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cn(CCN3CCOCC3)nc2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.1 g) was taken in dry DMF (2 ml) and a solution of tert-butyl 4-(3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate (0.5 g in 2 ml of DMF) was added slowly at 0° C. The reaction mixture was stirred for 30 min at 0° C. and a solution of 2-chloroethylmorpholine hydrochloride (0.3 g) in DMF (1 ml) was added very slowly. The reaction mixture was allowed to stir over night at room temperature. The reaction mixture was quenched with cold water (5 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of solvent under reduced pressure gave crude product, which, was purified by column chromatography using ethyl acetate/hexane (2:8) as eluent to afford compound tert-butyl 4-(1-(2-morpholinoethyl)-3-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate as pure solid product.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.BrC1C=C(C)C(C(N2CCC(N3CCC[C@H]3CO)CC2)=O)=C(C)C=1.[F:47][C:48]([F:81])([F:80])[C:49]1[CH:50]=[C:51]([C:59]2[N:64]=[C:63]([CH3:65])[C:62]([C:66](N3CCC(N4CCCC4)CC3)=[O:67])=[C:61]([CH3:79])[N:60]=2)[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1.[N:82]1([CH:97]2[CH2:102][CH2:101][NH:100][CH2:99][CH2:98]2)[CH2:87][CH2:86][CH:85]([O:88]C(=O)C2C=CC=CC=2)[CH2:84][CH2:83]1>>[F:81][C:48]([F:47])([F:80])[C:49]1[CH:50]=[C:51]([C:59]2[N:60]=[C:61]([CH3:79])[C:62]([C:66]([N:100]3[CH2:99][CH2:98][CH:97]([N:82]4[CH2:83][CH2:84][CH:85]([OH:88])[CH2:86][CH2:87]4)[CH2:102][CH2:101]3)=[O:67])=[C:63]([CH3:65])[N:64]=2)[CH:52]=[C:53]([C:55]([F:56])([F:58])[F:57])[CH:54]=1
Reactant: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: O=C(OC1CCN(C2CCNCC2)CC1)c1ccccc1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4 B, 2-(3,5-bis-trifluoromethyl-phenyl)-4,6-dimethyl-pyrimidine-5-carboxylic acid (example 15) was converted into its acid chloride, reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester (example 22) and subsequently saponified to give the title compound as colorless solid. MS: 531.1 (MH+).
Reaction SMILES: Br[CH:2]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH3:7][CH2:6][O:5][C:3]([CH:2]([P:9]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:16])[F:8])=[O:4]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)C(F)Br
Product: CCOC(=O)C(F)P(=O)(OCC)OCC
Yield: 67.2 %

Procedure:
Ethyl bromofluoroacetate (ex Fluorochem) (25 g) and triethyl phosphite (ex Aldrich) (29 g) were heated together at 140-5° for 6 hours in a vessel equipped with a fractionating column. When all the ethyl bromide had distilled off the residue was distilled to give triethyl 2-fluoro-2-phosphonoacetate (22 g) (bp 98°-108° at 0.8 mm). The latter (20 g) was added dropwise to hexane washed sodium hydride (3.3 g) of 60% dispersion) in dry ether (85 ml). After 3 hours at room temperature and 30 mins under reflux, acetone (6.1 ml) was added and the mixture stirred for 4 days at room temperature under nitrogen. After conventional work up the crude product was distilled to give ethyl 2-fluoro-3-methyl-but-2-enoate (4 g) (bp. 60°-2° at 15 mm). (Ref. Machleidt & Wessendorf, Ann. 674, 1, (1964)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[CH3:12][O:13][CH2:14]Cl.Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][O:13][CH3:14]
Reactant: Oc1ccc(Br)cc1F
Reactant: COCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A reaction vessel was charged with 111 g of 2-fluoro-4-bromophenol and 700 ml of DMF, and 20 g of 70% sodium hydride was added with stirring at room temperature. The mixture was stirred at room temperature for 1 hour and 56 g of methoxymethyl chloride was then added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction liquid was poured into dilute hydrochloric acid and the organic layer was extracted with benzene. The benzene layer was washed with water and dried over Glauber's salt. The benzene was distilled off and the residue was distilled under reduced pressure to obtain 110 g (yield 88%) of 3-fluoro-4-methoxymethoxybromobenzene.
Reaction SMILES: I[C:2]1[CH:30]=[CH:29][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:28]=[CH:27][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:31]1([B-](F)(F)F)[CH2:33][CH2:32]1.[K+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.O>[CH:31]1([C:2]2[CH:30]=[CH:29][C:5]([O:6][CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][C:12]([CH2:13][N:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]4)=[CH:27][CH:28]=3)=[CH:4][CH:3]=2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCOc3ccc(I)cc3)cc2)CC1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCOc3ccc(C4CC4)cc3)cc2)CC1
Temperature: 130 °C
Yield: 22.9 %

Procedure:
tert-Butyl 4-{4-[2-(4-iodophenoxy)ethyl]benzyl}piperazine-1-carboxylate (209 mg), potassium cyclopropyltrifluoroborate (86 mg), Pd(OAc)2 (6 mg), di(1-adamantyl)-n-butyl-phosphine (13 mg), Cs2CO3 (391 mg), and toluene/water (10:1) (3.3 mL) were mixed in a 5 mL process vial. The vial was sealed, and the reaction mixture was heated with microwaves to 130° C. for 1 hour. After filtration through a Celite pad, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/0 to 0/1) to give tert-butyl 4-{4-[2-(4-cyclopropylphenoxy)ethyl]benzyl}piperazine-1-carboxylate as a pale yellow solid (40 mg).
Reaction SMILES: O[N:2]=[C:3]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].C(O)(=O)C.[OH-].[NH4+].C(Cl)Cl>[Zn].CCOC(C)=O>[NH2:2][CH:3]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[CH:4]([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1ccc(C(=NO)C(C)C)cc1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C(N)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To the crude ethyl 4-(1-(hydroxyimino)-2-methylpropyl)benzoate in a 100-mL round-bottom flask was added acetic acid (8 mL) and zinc dust (1.33 g, 20.3 mmol). The mixture was stirred at rt for 1 h, then filtered through a pad of Celite. The pad was rinsed with ethanol (50 mL). Combined filtrate was concentrated to give a solid. To the solid residue was added ammonium hydroxide (20 mL) and DCM (50 mL). The solution was stirred at rt for 10 min. After separation, the aqueous layer was extracted with DCM (2×50 mL). Combined organic phases were washed with brine, dried (MgSO4), and concentrated to give an oil. Flash column chromatography (EtOAc:hexanes:TEA, 20:80:2 to 100:0:2) afforded ethyl 4-(1-amino-2-methylpropyl)benzoate (0.563 g, 55%) as a clear oil. LC-MS: (FA) ES+ 222; 1H NMR (CDCl3, 300 MHz) δ7.99 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 4.37 (q, J=7.2 Hz, 2 μl), 3.68 (d, J=7.0 Hz, 1H), 1.86 (m, 1H), 1.39 (t, J=7.0 Hz, 3H), 0.96 (d, J=7.0 Hz, 3H), 0.77 (d, J=7.0 Hz, 3H).
Reaction SMILES: [S:1]([N:5]=[C:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)OC1C=CC=CC=1)(=[O:4])(=[O:3])[NH2:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(#N)C>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[N:5][S:1](=[O:3])(=[O:4])[NH2:2])[O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Br)c1
Reactant: NS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: NS(=O)(=O)N=C(Nc1cccc(Br)c1)Oc1ccccc1
Temperature: 70 °C

Procedure:
Diphenyl sulfamoylcarbonimidate, from step A, (0.05 g, 0.17 mmol) and 3-bromoaniline (18 μl, 0.17 mmol) were dissolved in acetonitrile (0.5 ml) and heated to 70° C. for 12 hours. The reaction was concentrated under vacuum to afford phenyl N-3-bromophenyl-N′-sulfamoylcarbamimidate, which was carried on crude to the next reaction.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][N:24]2[C:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[O:37])[CH:16]=1>CO>[ClH:1].[ClH:1].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2[C:36]([O:38][C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[O:37])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc(F)cc2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Oc1ccc(F)cc1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 97 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 4-tert-butyl 1-(4-fluorophenyl) 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate TFA salt (88.9 mg, 0.163 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 63.7 mg (97%) of the desired product as a yellow solid. LC-MS: RT=4.07 min, [M+H]+=332.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:2][CH2:3][CH2:4][C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(CCN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
A suspension of 11.5 g. (50 mMol) ethyl 4-(2-aminoethyl)-benzoate hydrochloride (J.A.C.S., 65, 2281, 2284/1943) and 12.65 g. (125 mMol) triethylamine in 150 ml. methylene chloride is stirred for 30 minutes at ambient temperature, cooled to 0° C. and a solution of 11.55 g. (50 mMol) 4-chlorobenzenesulphonic acid chloride in 50 ml. methylene chloride slowly added dropwise thereto. After ending of the reaction, the reaction mixture is extracted twice with dilute hydrochloric acid, washed with water and the organic phase then dried over anhydrous sodium sulphate. After evaporation of the solvent, there are obtained 11.4 g. (62% of theory) of colourless crystals; m.p. 88° C., after recrystallisation from ethanol.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][C:11]=1[C:20]([O:22]C)=[O:21].FC(F)(F)C(O)=O>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:20]([C:11]1[CH:12]=[C:13]([N+:16]([CH3:19])([CH3:18])[CH3:17])[CH:14]=[CH:15][C:10]=1[Cl:9])([OH:22])=[O:21]
Reactant: COC(=O)c1cc([N+](C)(C)C)ccc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[N+](C)(C)c1ccc(Cl)c(C(=O)O)c1

Procedure:
A solution of 0.5 g (1.32 mmol) 18b, 12 ml dest. water and 12 ml trifluoroacetic acid was refluxed for 2 days. The reaction mixture was evaporated, dried by use of oil pump vacuum over night and treated with diethyl ether. The resulting solid was filtered, washed extensively with diethyl ether and dried by oil pump vacuum. The solid crude product 18c was obtained in 98% yield (471 mg, 1.3 mmol) and crude compound 18c was used for the next step without purification.
Reaction SMILES: [Na+].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([CH3:37])[CH:8]=[CH:9][C:10]=1[S:11]([NH:14][C:15]1[C:24]2[C:23]([S:25]([O-:28])(=[O:27])=[O:26])=[CH:22][C:21]([S:29]([O-:32])(=[O:31])=[O:30])=[CH:20][C:19]=2[C:18]([S:33]([O-:36])(=[O:35])=[O:34])=[CH:17][CH:16]=1)(=[O:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].[N+:44]([C:47]1[CH:48]=[C:49]([S:53](Cl)(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=1)([O-:46])=[O:45]>O>[N+:44]([C:47]1[CH:48]=[C:49]([S:53]([NH:4][C:5]2[CH:6]=[C:7]([CH3:37])[CH:8]=[CH:9][C:10]=2[S:11]([NH:14][C:15]2[C:24]3[C:23]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:22][C:21]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:20][C:19]=3[C:18]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:17][CH:16]=2)(=[O:13])=[O:12])(=[O:55])=[O:54])[CH:50]=[CH:51][CH:52]=1)([O-:46])=[O:45]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(S(=O)(=O)O)c3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Reaction time: 16 h
Yield: 29.3 %

Procedure:
To a stirred solution of 2.0 g of 8-(3-amino-p-toluenesulfonamido)-1,3,5-naphthalenetrisulfonic acid trisodium salt and 342 mg of anhydrous sodium carbonate in 10 ml of water is added 1.5 g of m-nitrobenzenesulfonyl chloride. The mixture is stirred for 16 hours. An additional 170 mg of anhydrous sodium carbonate is added followed by 750 mg of m-nitrobenzenesulfonyl chloride and the mixture is stirred for an additional 16 hours. The reaction mixture is evaporated and the residue dissolved in hot water. A product is precipitated on the addition of absolute ethanol. The product is collected, washed with ethanol and ether and dried. Additional product is collected from the filtrate and is washed and dried as above. The above fractions of product are combined and dissolved in water, then 2.5 ml of 5 N sodium hydroxide is added and the mixture is stirred for 30 minutes. The mixture is acidified with glacial acetic acid and evaporated. The residue is dissolved in hot water and precipitated with ethanol. The product is collected and washed twice with ethanol and ether and dried to yield 700 mg of 8-(3-m-nitrobenzenesulfonamido-p-toluenesulfonamido)-1,3,5-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:7])[CH3:6].N1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCC(O)CC>CCOCC>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH:22]([CH2:23][CH3:24])[CH2:21][CH3:20])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: c1ccncc1
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Solvent: CCC(O)CC
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCC(CC)OC(=O)c1ccc(OC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
Thionyl chloride in an amount of 60 ml was added to 11.9 g (0.06 mol) of 4-acetoxy-2-fluorobenzoic acid, and the mixture was allowed to react under reflux for 7 hours. Then, excessive thionyl chloride was distilled off, and then 10 ml of pyridine and 3.5 g (0.0420 mol) of 3-pentanol were dropwise added. After the dropwise addition, the mixture was stirred at room temperature over 1 day and night, and then diluted with 200 ml of ether. An organic layer was consecutively washed with diluted hydrochloric acid, with a 1N sodium hydroxide aqueous solution and with water, and dried over magnesium sulfate. The solvent was distilled off, and the resultant crude end product was purified by silica gel column chromatography using hexane/ethyl acetate as a solvent to give 10.7 g (yield 90%) of the end product.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3][CH:4]([OH:8])[CH:5]=[CH:6][CH3:7]>O=[Mn]=O.C(Cl)Cl>[CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])=[CH:3][C:4](=[O:8])[CH:5]=[CH:6][CH3:7]
Reactant: CC=CC(O)C=C(C)CCC=C(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC=CC(=O)C=C(C)CCC=C(C)C

Procedure:
60 g. of the alcohol prepared according to paragraph (b) above, 700 g. of MnO2 and 1800 ml. of CH2Cl2 were stirred for 2 days at 20°-25°. After filtration and evaporation, the distillation of the residue gave 49 g. of crude ketone, b.p. 70°-75°/0.1 Torr, which was purified by vapour phase chromatography using a "20 M Carbowax" column and helium carrier at 140°. nD20 =1.5041; d420 =0.8958.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([CH3:17])[CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:3]=1[F:18].O.[NH2:20][NH2:21]>CS(C)=O>[F:18][C:3]1[C:4]([N:10]([CH3:17])[CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[NH:20][NH2:21]
Reactant: NN
Reactant: CSc1nc(Cl)c(F)c(N(C)Cc2nccs2)n1
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(NN)c(F)c(N(C)Cc2nccs2)n1
Temperature: 80 °C
Yield: 43.4 %

Procedure:
6-Chloro-5-fluoro-N-methyl-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (0.4928 g, 1.621 mmol) was dissolved in 5 mL of DMSO and hydrazine monohydrate (0.63 mL, 12.96 mmol). The reaction vessel was pressure sealed and heated to 80° C. for 2 hours. The reaction mixture was purified by RP-HPLC to provide 5-fluoro-6-hydrazino-N-methyl-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine as a beige solid (0.2112 g, 43%). LCMS: (M+H)+=301.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:29]5[CH:30]=[CH:31][CH:32]=[C:33]6[C:28]=5[CH:27]=[CH:26][NH:25]6)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3cccc4[nH]ccc34)cc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A solution of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.256 mmol) in dioxane (2 mL) was treated with 1H-indol-4-ylboronic acid (0.386 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10.4 mg), and 2M aq potassium carbonate (0.511 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH ˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The brown residue was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The combined product fractions were neutralized with the addition of saturated aq sodium bicarbonate, concentrated under reduced pressure, and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Further purification of the resulting solid by flash chromatography (0-7% methanol/dichloromethane) gave the title compound as a white amorphous solid (55 mg, 48% yield). MS(ES)+ m/e 428.0 [M+H]+.