Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=S)[CH3:9])=[CH:4][CH:3]=1.[C:25]([NH:28][NH2:29])(=O)[CH3:26]>C(#N)C.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[C:25]([CH3:26])=[N:28][N:29]=[C:11]2[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=S)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reactant: CC(=O)NN
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CC#N
Product: Cc1nnc([C@H]2CCCN2C(=O)OC(C)(C)C)n1[C@@H](C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the product of Step B (1.7 g, 4.6 mmol) and acetic hydrazide (0.76 g, 9.2 mmol) in 30 ml acetonitile was added mercury (II) acetate (2.2 g, 6.9 mmol) and the mixture was stirred at room temperature for overnight. The mixture was filtered over a Celite-fritted funnel and washed with more acetonitrile. The filtrate was concentrated in vacuo. Run wash column yield the desired product containing minor impurities (1.3 g, 72%), was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O.C(N(CC)CC)C>CCCCCC>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (0.20 g), prepared in a similar manner to that described in Example 11, and triethylamine (20 ml) was stirred at ambient temperature for 2.5 hours. Hexane (30 ml) was added to the mixture. The solid product collected by filtration of the mixture was washed with hexane (2×5 ml) and dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 233°-234.5° (0.16 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:45]=[C:44]2[C:40]([C:41]([CH3:53])([CH3:52])[C:42](=[O:51])[N:43]2[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:45]=[C:44]3[C:40]([C:41]([CH3:53])([CH3:52])[C:42](=[O:51])[N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)C(C)(C)c2ccc(CBr)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)C(C)(C)c2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.853 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.504 g of 6-bromomethyl-1-(3-methoxypropyl)-3,3-dimethyl-1,3-dihydroindol-2-one are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.14 (1:1 EtOAc-heptane); Rt=6.13.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CS(C)=O>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[O:15])[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2cccnc2)CC1
Yield: 33.6 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (15.0 g, 55.7 mmol), 1-(tert-butoxycarbonyl)piperazine (15.5 g, 83.5 mmol), diisopropylethylamine (9.70 ml, 55.7 mmol) and dimethylsulfoxide (300 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (5.74 g, 33.6%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:9][S:10][CH3:11])[CH:3]=1.[F:12][C:13]1[CH:26]=[CH:25][C:16]2[S:17][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:19]([CH3:20])[C:15]=2[CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:21]([C:18]2[S:17][C:16]3[CH:25]=[CH:26][C:13]([F:12])=[CH:14][C:15]=3[C:19]=2[CH3:20])(=[O:23])=[O:22])=[C:4]([CH2:9][S:10][CH3:11])[CH:3]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: CSCc1cc(Br)ccc1N
Product: CSCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 70.5 %

Procedure:
This compound was prepared in analogy to Example 1 starting from 4-bromo-2-methylsulfanylmethyl-phenylamine (Allen, David George; Eldred, Colin David; Judkins, Brian David; Mitchell, William Leonard, WO 9749699, 4.6 g) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (1.06 g) to obtain the desired compound (1.3 g) as a brownish solid. MS (ISN): 458.1, 460.0 (M−H)−
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[NH:19][CH2:20][CH:21](OC)OC)=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:21]=[CH:20][N:19]=[C:9]23)=[C:4]([F:26])[CH:3]=1
Reactant: COC(CNc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Br)cc1F)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(C(F)(F)F)n2ccnc2n1-c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(4-Bromo-2-fluorophenyl)-3,4-dihydro-2-((2,2-dimethoxyethyl)amino)-6-trifluoromethylpyrimidin-4-one synthesized in Example 14 was dissolved into concentrated sulfuric acid (100 ml) under ice-cooled condition and stirred for 4 hours at room temperature. The reaction solution was poured into ice water (500 ml), neutralized with an aqueous sodium hydroxide solution under ice-cooled condition, extracted with ethyl acetate and dried on anhydrous magnesium sulfate after washing with water. The solvent was distilled off under reduced pressure and then the thus obtained solid was washed with isopropyl ether to give the compound of interest (17.5 g) as a pale yellow solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]3[CH2:20][CH2:21][CH2:22][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]3[CH2:20][CH2:21][CH2:22][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)=[O:29]
Reactant: Fc1ccc(-c2nc(N3CCNCC3)nc3c2CCC3)cc1
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccco1)N1CCN(c2nc3c(c(-c4ccc(F)cc4)n2)CCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
A mixture of 2-(1-piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-cyclopentapyrimidine (1.0 g), 2-furoic acid (0.38 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.79 g) and chloroform (40 ml) is stirred at room temperature for 2 hours. The reaction mixture is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene, and the solution is subjected to silica gel column chromatography. The fractions eluted with toluene-ethyl acetate (9 : 1) are collected, and the product therefrom is recrystallized from ethanol to give the desired compound (0.62 g), m.p. 124°-125° C. (ethanol).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[C:9]([O-:12])(=[O:11])[CH3:10].[Pd+2:13].[C:14]([O-:17])(=[O:16])[CH3:15].[C:18]([O-:21])([OH:20])=[O:19].[Na+:22].C[N:24](C=O)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:24].[CH3:10][C:9]([O-:12])=[O:11].[CH3:15][C:14]([O-:17])=[O:16].[Pd+2:13].[C:18]([O-:21])([OH:20])=[O:19].[Na+:22]
Reactant: Brc1cccc(I)c1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Nc1cccc(I)c1
Temperature: 80 °C

Procedure:
Into 12 mL of dry DMF in an oven dried, nitrogen filled tube was placed M (3.0 g, 15 mmol), 1-iodo-3-bromobenzene (1.6 mL, 13 mmol), palladium(II)acetate (0.42 g, 1.9 mmol), tetrabutylammoniumchloride (3.5 g, 13 mmol), and solid NaHCO3 (2.6 g, 31 mmol). The tube was sealed and heated to 80° C. for 16 hours. The cooled reaction mixture was diluted with EtOAc, passed through a small plug of silica gel to remove the catalyst, and extracted 2× with brine. The solution was then dried over Na2SO4, concentrated, and purified by flash chromatography eluting with 2:1 and 1:1 heptane: EtOAc to afford N (1.8 g, 5 mmol, 40%) (MS;M+H: 356.1, 358.1). Likewise N′ was formed (0.92 g, 3.1 mmol, 77%) (MS;M+H: 293.2) from M (1.0 g, 5 mmol), 3-iodoaniline (0.5 mL, 4.2 mmol), Pd(OAc)2 (0.14 g, 0.62 mmol), Bu4NCl (1.16 g, 4.2 mmol), and NaHCO3 (0.87 g, 10 mmol) in 4 mL of dry DMF.
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14]C(O)(CC3C=CC=CC=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)CCN2CC[C:49]([OH:59])([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)CC2)C=CC=CC=1>>[C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:52]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[Cl:36])([CH2:49][OH:59])[CH2:12][CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cl
Reactant: OC1(Cc2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Product: OCC1(c2ccccc2Cl)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
1-(3,3,3-triphenylpropyl)-4-hydroxy-4-benzylpiperidine and 1-(3,3,3-triphenylpropyl)-4-hydroxy-4-benzylpiperidine hydrochloride;
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:26]1([N:23]2[CH2:24][CH2:25][N:20]([C:16]3[N:15]=[C:14]([C:12]4[S:4][C:3]5[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=5[C:1](=[O:10])[N:13]=4)[CH:19]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1cccc(N2CCN(c3ccccc3)CC2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(N3CCN(c4ccccc4)CC3)n2)sc2ccccc12
Yield: 33.3 %

Procedure:
A mixture of methyl thiosalicylate (0.25 g, 1.5 mmol), 2-cyano-6-(4-phenyl-1-piperazinyl)pyridine (0.40 g, 1.5 mmol), triethylamine (0.32 ml, 2.3 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure and the crude crystals were recrystallized from ethanol to give the titled compound (0.20 g, 33%) as crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][S:6]([CH:9]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)(=[O:8])=[O:7]>CO.[Pd]>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][S:6]([CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)(=[O:8])=[O:7]
Reactant: CN(C)CCNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCNS(=O)(=O)C1CCNC1
Reaction time: 29 h
Yield: 88.3 %

Procedure:
A mixture of the above benzyl carbamate (171 mg, 0.481 mmol) and 10% Pd on carbon in MeOH (15 mL) was hydrogenated for 29 hrs. The reaction mixture was filtered through celite, the celite pad was washed with MeOH, and the solvent was removed under vacuum to give N-[2-(dimethylamino)ethyl]-3-pyrrolidinesulfonamide (94 mg, 89%), which was used in the next step without further purification: 1H NMR (DMSO-d6) δ 6.93 (br s, 1H), 3.62 (m, 1H), 3.04-2.99 (m 4H), 2.83 (m, 1H), 2.72 (m, 1H), 2.31 (t, J=6.8 Hz, 2H), 2.14 (s, 6H), 1.92 (m, 2H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].Cl.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15]([OH:17])=[O:16]>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCOc1ccc(C(=O)O)cc1Cl
Yield: 77.7 %

Procedure:
In accordance with step (2) of the reaction system 1.73 g of material A was dissolved in 50 ml of ethanol. 3.3 g of hexylbromide and potassium hydroxide (1.2 g KOH+5 ml H2O) was added and the mixture heated under reflux conditions for 10 hours. Following reflux, a 10% potassium hydroxide solution was added and the mixture refluxed for 2 hours. The mixture was hydrolyzed and then added to dilute hydrochloric acid to promote crystalization. The crystals were washed with water to yield 2 g of 3-chloro-4-n-hexyloxybenzoic acid (hereinafter referred to as material B'). The benzoic acid B' had a melting point of 140° C. and the absorption spectrum is illustrated in FIG. 5.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[CH2:15]([N:17]([CH2:41][CH3:42])[CH:18]1[CH:23]([CH3:24])[CH2:22][CH:21]([C:25]2[C:30]3[C:31](S)=[N:32][C:33]4=[CH:34][CH:35]=[CH:36][C:28]([C:29]=34)=[CH:27][CH:26]=2)[CH:20]([CH:38]([CH3:40])[CH3:39])[CH2:19]1)[CH3:16].[N:43]1([CH2:48][CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][N:45]=[CH:44]1>C(O)C>[CH2:15]([N:17]([CH2:41][CH3:42])[CH:18]1[CH:23]([CH3:24])[CH2:22][CH:21]([C:25]2[C:30]3[C:31]([NH:51][CH2:50][CH2:49][CH2:48][N:43]4[CH:47]=[CH:46][N:45]=[CH:44]4)=[N:32][C:33]4=[CH:34][CH:35]=[CH:36][C:28]([C:29]=34)=[CH:27][CH:26]=2)[CH:20]([CH:38]([CH3:40])[CH3:39])[CH2:19]1)[CH3:16]
Reactant: CCN(CC)C1CC(C(C)C)C(c2ccc3cccc4c3c2C(S)=N4)CC1C
Reactant: NCCCn1ccnc1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Product: CCN(CC)C1CC(C(C)C)C(c2ccc3cccc4c3c2C(NCCCn2ccnc2)=N4)CC1C

Procedure:
6-Bromobenz(cd)indol-2-(1H)-one is treated with ethyl chloroformate in alkaline solution to yield the N-carbethoxy derivative. Successive reactions with magnesium, formaldehyde, and 48% hydrobromic acid leads to 6-bromomethylbenz(cd)indol-2(1H)-one, which on treatment with diethylamine yields the 6-diethylaminomethyl derivative. Treatment with P2S5 in refluxing pyridine leads to 6-diethylaminomenthylbenz(cd)indol-2-thiol, which on reaction with molar equivalents of 3-(1H-imidazol-1yl)propanamine and mercuric acetate in refluxing ethanol, under the conditions of Example 55, leads to the preparation of the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][NH2:37]>>[CH2:24]([N:23]([CH2:26][CH3:27])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[N:37]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21])[CH3:25]
Reactant: NNc1ccccc1F
Reactant: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-diethyl-benzenesulfonamide (A-21) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=468.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[O:19][CH:20]([F:22])[F:21])=[N:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[O:19][CH:20]([F:21])[F:22])=[N:6][CH:7]=1
Reactant: CNc1nc(Nc2ccc(C(=O)OC)cc2OC(F)F)ncc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(Nc2ccc(C(=O)O)cc2OC(F)F)ncc1Cl
Temperature: 25 °C
Yield: 52 %

Procedure:
Methyl 4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoate (500 mg) was dissolved in 5 mL of THF and 5 mL of water. After dissolution, 234 mg of lithium hydroxide was added and the reaction was stirred at room temperature over night. The mixture was checked by LCMS and then carefully acidified with 1N HCl and partitioned with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography to give 250 mg of 4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-3-(difluoromethoxy)benzoic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:10])=[N:2]1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:2]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1noc2ccccc12
Product: CN(C(=O)Oc1noc2ccccc12)c1ccccc1

Procedure:
The title product was prepared from benzo[d]isoxazol-3-ol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (53%, colorless oil). HPLC-MS: m/z=291.1 (M+23); Rt: 4.05 min.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[O:20])[CH:14]=3)[C:9]2=[O:34])[CH2:6][CH2:5][C:4](=[O:35])[NH:3]1.Cl>C(Cl)Cl.C(OCC)C>[O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])[CH:14]=3)[C:9]2=[O:34])[CH2:6][CH2:5][C:4](=[O:35])[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC(N2Cc3cc(CNC(=O)C4CCNCC4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methylcarbamoyl)piperidine-1-carboxylate (0.48 g, 1.0 mmol) in methylene chloride (100 mL) is treated with HCl (5 mL of a 2N solution in diethyl ether), and stirred at ambient temperature for 48 hours. The mixture is evaporated under vacuum, and triturated in ethyl acetate (10 mL), filtered, and dried under vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][C:13]=2[S:25]([NH2:28])(=[O:27])=[O:26])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:18]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][C:30]([F:29])([F:41])[F:42])[CH:33]=3)[CH:3]=2)(=[O:10])=[O:9])=[C:13]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NS(=O)(=O)c1cc(Oc2ccccc2)ccc1NS(=O)(=O)c1cccc(Br)c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(Oc2ccccc2)ccc1NS(=O)(=O)c1cccc(-c2cccc(OC(F)(F)F)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of 2-(3-bromophenylsulfonamido)-5-phenoxybenzenesulfonamide (Example 155a) (150.0 mg, 0.31 mmol), 3-(trifluoromethoxy)benzeneboronic acid (192 mg, 0.93 mmol), tricyclohexyl phosphine (25 mg, 0.09 mmol) and potassium phosphate (131 mg, 0.62 mmol) in DMF (10 mL), was added Pd(OAc)2 (14 mg, 0.06 mmol). The reaction mixture was stirred at 80° C. overnight, diluted with 1N HCl and the product was extracted with ethyl acetate. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using methanol/DCM (1:99) to afford the title compound (92 mg, 53%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>O1CCCC1>[S:14]([O:12][CH:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])(=[O:16])(=[O:15])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CCCc1ccccc1
Solvent: C1CCOC1
Product: CC(CCCc1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 5-phenyl-2-pentanol (482 g.; 2.94 moles) in tetrahydrofuran (2250 ml.) at 0° C. was added methanesulfonyl chloride (300 ml). at such a rate that the internal temperature does not rise above 10° C. (total addition time 4.5 hours). After addition is complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for an additional hour. The reaction mixture was filtered and the supernate concentrated to a light yellow oil (2800 g.) which was dissolved in chloroform (2 liters) and washed with water (4x 1 liter), brine (1x 1 liter), charcoal treated (50 g.), dried (MgSO4), filtered through diatomaceous earth and concentrated to a light orange oil (687 g., 95% yield). This material was suitable for use without further purification.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][C:23]([CH2:28]O)([CH2:26][OH:27])[CH2:24][OH:25]>>[C:1]([O:20][CH2:28][C:23]([CH2:26][OH:27])([CH2:24][OH:25])[CH2:22][OH:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCC(CO)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(CO)(CO)CO
Temperature: 130 °C

Procedure:
A four-necked round-bottom flask equipped with a stirrer, a thermocouple, and a nitrogen inlet tube was charged with 4 moles of stearic acid per 1 mole of pentaerythritol. The ingredients in the flask were heated at 130° C. for 5 hours under a nitrogen atmosphere, to carry out an esterification reaction. The reaction product was purified with methyl ether, to give pentaerythritol stearate. Here, the resulting compound had an acid value of 0.3 mgKOH/g, and a hydroxyl value of 1.8 mgKOH/g.