Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:33]=[N:32][CH:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COc1cncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)c1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-methoxypyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 243. NMR (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.00 (3H, s), 4.05-4.10 (4H, m), 7.35 (1H, s), 8.23 (1H, s), 8.38 (1H, s), 9.26 (1H, s). MS (ESI+): MH+505.19 (100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:20]=[C:21]4[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]4[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1
Reactant: OCc1ccc(Oc2cncc(Cl)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cncc(Cl)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:14][C:15]1[N:20]=[C:19](S(C)(=O)=O)[N:18]=[C:17]([NH:25][C:26]2[NH:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[CH:16]=1>CC(O)(C)C>[Cl:14][C:15]1[N:20]=[C:19]([S:13][C:4]2[CH:5]=[C:6]3[C:11](=[C:2]([F:1])[CH:3]=2)[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[N:18]=[C:17]([NH:25][C:26]2[NH:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[CH:16]=1
Reactant: Cc1ccc2cc(S)cc(F)c2n1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3cc(F)c4nc(C)ccc4c3)n2)[nH]n1
Temperature: 90 °C
Yield: 49.2 %

Procedure:
To a stirred solution of 8-fluoro-2-methylquinoline-6-thiol (1.21 g, 6.27 mmol) in tBuOH (25 ml) was added 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (1.5 g, 5.22 mmol). The reaction mixture was degassed three times (vacuum/N2) before being heated to 90° C. for 18 hours. The crude mixture was partially concentrated in vacuo. The resulting solid was filtered and washed with ethyl acetate and an aqueous solution of K2CO3. The solid was dried in a pistol under vacuo to afford the title compound as an off-white solid (1.029 g, 49% yield). 1H NMR (DMSO D6, 400 MHz) δ1.42 (3H, br s), 2.73 (3H, s), 4.95 (1H, br s), 6.47 (1H, br s), 7.61 (1H, d), 7.78 (1H, dd), 8.14 (1H, s), 8.39 (1H, d), 10.32 (1H, br s), 11.75 (1H, br s); MS (ES+) 401, (ES−) 399.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([N:21]([CH2:22][CH2:23][CH2:24][CH3:25])[S:33]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCCCNC(CC)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN(C(CC)c1nn2cccc2c(=O)n1Cc1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.1 %

Procedure:
3-Benzyl-2-(1-butylamino-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 33, 28.0 mg, 0.0828 mmol) in CHCl3 (5 mL) was treated with 4-chloro-benzenesulfonylchloride (52.3 mg, 0.248 mmol) and Et3N (23.0 μL, 0.166 mmol), then stirred for 18 h at 25° C. The mixture was concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (3.0 mg, 7.0%) as a colorless film: LC/MS 88% at 4.13 min (ESI+) 513 (M++H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[Br:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][C:30](O)=[O:31])([CH2:22]3)[CH2:20]1)[CH2:26]2>>[Br:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][C:30]([NH:1][N:2]4[C:7](=[O:8])[C:6]5[S:9][CH:10]=[CH:11][C:5]=5[C:4]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:3]4)=[O:31])([CH2:22]3)[CH2:20]1)[CH2:26]2
Reactant: O=C(O)CC12CC3CC(CC(Br)(C3)C1)C2
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Product: O=C(CC12CC3CC(CC(Br)(C3)C1)C2)Nn1nc(-c2ccccc2)c2ccsc2c1=O

Procedure:
The product from Example 29B and 2-(3-bromoadamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.47 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 7.71-7.73 (m, 2H), 7.56-7.59 (m, 4H), 2.32-2.34 (m, 2H), 2.27-2.32 (m, 2H), 2.19-2.25 (m, 2H), 2.17 (s, 2H), 2.12-2.16 (m, 2H), 1.62-1.75 (m, 5H), 1.56-1.60 (m, 1H); MS (APCI+) M/Z 498 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([OH:6])=O.[CH2:12]([CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][NH2:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CCCCCCC>[CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][C:4]([NH:22][CH2:21][CH:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:6]
Reactant: CC(CC(=O)O)CC(C)(C)C
Reactant: CCCCCCCCCCC(CN)CCCCCCCC
Solvent: CCCCCCC
Product: CCCCCCCCCCC(CCCCCCCC)CNC(=O)CC(C)CC(C)(C)C

Procedure:
3.6 g of 3,5,5-trimethylhexanoic acid and 6.8 g. of 2-octyldodecylamine were mixed together in the tube of a microwave machine (Maxidigest™ MX 350 from the company Prolabo; frequency 2450±50 MHz, modulable power 300 W). After irradiation for about 50 minutes at 170° C.±10° C., the reaction mixture was dissolved in heptane and then purified on silica. 7 g of the desired amide were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH:7]([CH2:28][N:29](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].C(OCC)C>[C:1]([O:5][C:6](=[O:44])[CH:7]([CH2:28][NH2:29])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN(Cc3ccccc3)Cc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
The product from step (c) above (4.6 g, 7.62 mmole) in ethanol (75 ml) was hydrogenated in an atmosphere of hydrogen (50 p.s.i., 3.46 bar) over palladium on charcoal (200 mg), at room temperature overnight. The reaction mixture was filtered through a Solkaflok pad, and the filtrate evaporated to dryness to yield the crude product as an oil. This was dissolved in diethyl ether, and extracted into dilute hydrochloric acid (pH 2) (2x). The combined aqueous layers were washed with diethyl ether, then neutralised with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3x). The combined organic phases were dried (Na2SO4) and evaporated to yield the title amine as an oil (2.91 g, 90%). Found: C,64.80; H,9.28; N,6.76. C23H40N2O5 requires C,65.06; H,9.50; N,6.60%.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](I)[CH3:20]>CO>[CH2:19]([S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:20]
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: CCI
Solvent: CO
Product: CCSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1

Procedure:
10.3 g of cis-4,5-diphenyl-imidazolidine-2-thione are suspended in a mixture of 25 ml of methanol and 3.8 ml of ethyl iodide and the suspension is refluxed for 1 hour, with stirring. A further 75 ml of methanol are then added and the mixture is refluxed for 16 hours. The clear reaction solution is evaporated to dryness and the residue is taken up in a mixture of 150 ml of water and 250 ml of ethyl acetate. In order to liberate the base, the mixture is rendered alkaline iwth concentrated aqueous ammonia solution and shaken thoroughly and the organic phase is separated off, dried over sodium sulfate and evaporated. Recrystallisation of the residue from isopropanol/petroleum ether yields cis-2-ethylthio-4,5-diphenyl-imidazoline with a melting point of 95°-96°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].I[CH2:15][C:16]([CH3:18])=[CH2:17]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: C=C(C)CI
Reactant: O=C(CCCl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCl)c1ccccc1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A solution of 3-chloro-1-phenylpropan-1-one (16.8 g, 0.1 mol) in THF (50 mL) was added to a well-stirred suspension of zinc powder (13 g, 0.2 mol) in a mixture of satd aq NH4Cl solution (260 mL) and THF (65 mL). A solution of 3-iodo-2-methylprop -1-ene (36.4 g, 0.2 mol) in THF (50 mL) was added dropwise. The reaction was mildly exothermic, and the mixture began to reflux spontaneously. After refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-phenylpropan-1-one had not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (17 g, yield 76° A)) as an oil. 1H NMR (CDCl3): δ1.28 (s, 3H), 2.31 (m, 2H), 2.54 (m, 2H), 2.68 (d, 1H), 3.15 (m, 1H), 3.58 (m, 1H), 4.78 (m, 1H), 4.93 (m, 1H), 7.27 (t, 1H), 7.38 (m, 4H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2"'-phenyl-2"'-oxoethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (350 mg) in THF (6.2 ml) at -78° C. was added L-Selectride (342 μl, 1 eq.) dropwise over 30 minutes. The reaction was stirred for a further 15 minutes after addition and then quenched by pouring into saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 60% hexane:40% ethyl acetate to give the desired product (216 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].O1CCOCC1>Cl>[CH3:1][NH:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)sc3c2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(S)-tert-butyl 3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (56 mg, 0.12 mmol) was dissolved in 4 ml of 4M HCl in dioxane (16 mmol). The reaction solution was stirred at room temperature for 1 hour. The crude reaction solution was evaporated in vaccuo to give (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (46 mg, 0.12 mmol) as white solid. ES/MS m/z 384.0 (MH+).
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]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=4)=[O:20])[CH:14]=3)[C:9]2=[O:31])[CH2:6][CH2:5][C:4](=[O:32])[NH:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCO.O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][CH2:17][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:31])[N:8]([CH:7]2[CH2:6][CH2:5][C:4](=[O:32])[NH:3][C:2]2=[O:1])[CH2:16]3)=[O:20])=[CH:23][CH:24]=1
Reactant: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc([N+](=O)[O-])cc4)ccc3C2=O)C(=O)N1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 60 °C

Procedure:
To a stirred mixture of 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-nitrophenyl)urea (150 mg, 0.343 mmol) in EtOH (2 mL) was added sodium dithionite (597 mg, 3.43 mmol) in water (2 mL). The resulting mixture was heated to 60° C. for 20 min at which time LC-MS indicated complete disappearance of nitro starting material. The reaction mixture was combined with the crude product from a separate run and concentrated in mew). The residue was dissolved in minimal DMF and chromatographed on a C-18 preparative HPLC column equipped with mass triggered collection. The desired fractions were combined and concentrated in vacuo to provide 1-(4-amino-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a pale yellow solid (90 mg, 40% combined average yield from two separate runs): mp: >400° C.; LCMS: MH+=408.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].P(Br)(Br)[Br:15]>C(OCC)C.O>[Br:15][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(CO)cc1F
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: CS(=O)(=O)c1ccc(CBr)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (3-fluoro-4-methanesulfonyl-phenyl)-methanol (0.269 g, 1.31 mmol) in diethyl ether (5 ml) under an inert atmosphere of Argon is added dropwise phosphorus tribromide (46 μl, 0.434 mmol). After stirring at room temperature overnight, the reaction mixture is diluted with water (2 ml) and the diethyl ether layer separated. This organic portion is placed over NaOH pellets and after 20 minutes, is used as a reagent in solution in diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Cl
Reactant: COc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(-c2cn3cccc(Cl)c3n2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-chloro-2-pyridinamine (4.8 g, 37.4 mmol) and 2-bromo-1-(3-methoxyphenyl)ethanone (8.56 g, 37.4 mmol) in ethanol (30 mL) was added potassium carbonate (5.15 g, 37.4 mmol) and the resultant solution was heated at reflux for 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resultant residue was taken up in dichloromethane, washed with water and then brine. The aqueous layer was extracted with dichloromethane and the combined organics dried over magnesium sulfate. Filtration and concentration followed by recrystallization of the residue from ethyl acetate-hexanes reulted in 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine (6.7 g, 70%) as a tan powder. 1H NMR (CDCl3): δ 8.03 (d, 1 H), 7.89 (s, 1 H), 7.57–7.52 (m, 2 H), 7.33 (t, 1 H), 7.23 (d, 1 H), 6.89 (dd, 1 H), 6.71 (t, 1 H), 3.89 (s, 3 H); 13C NMR (CDCl3): δ 159.94, 146.31, 142.96, 134.61, 129.65, 124.30, 123.58, 123.26, 118.81, 114.33, 112.02, 111.44, 109.91, 55.39; MS m/z 259 (M+1); Anal. Calcd for C14H11ClN2O: C, 64.93; H, 4.29; N, 10.83. Found: C, 64.58; H, 4.51; N, 10.52.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1Cl.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: COc1ccc(Cn2ncc(Cl)c(Cl)c2=O)cc1
Solvent: O
Product: COc1ccc(Cn2ncc(N3CCOCC3)c(Cl)c2=O)cc1

Procedure:
A mixture of 4,5-dichloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one [P. Matyus, Gy. Rabloczky, L. Jaszlits, J. Kosary, M. Kurthy, A. Papp Behr, D. Zara, E. Karpati, A. Kovacs, WO1992/9212137] (10.15 g, 35.61 mmol) and morpholine (7.66 g, 87.92 mmol) in water (200 ml) was refluxed for 18 h. After cooling, the mixture was extracted with dichloromethane (4×40 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was purified by recrystallization from ethanol (95%).
Reaction SMILES: ClCCl.[CH2:4]([CH:7]1[O:12][CH:11](O)[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]4)=[C:22]([F:35])[C:21]=3[F:36])=[C:16]([F:37])[C:15]=2[F:38])[CH2:9][CH2:8]1)[CH2:5][CH3:6].C([SiH](CC)CC)C>O>[CH2:4]([CH:7]1[CH2:8][CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]4)=[C:22]([F:35])[C:21]=3[F:36])=[C:16]([F:37])[C:15]=2[F:38])[CH2:11][O:12]1)[CH2:5][CH3:6]
Reactant: CCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4O)c(F)c3F)c(F)c2F)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4)c(F)c3F)c(F)c2F)CC1
Reaction time: 3 h
Yield: 44.3 %

Procedure:
Dichloromethane (40 ml) was added to 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(4-propylcyclohexyl)biphenyl-4-yl)tetrahydro-2H-pyran-2-ol (17) (4.2 g) prepared in the second step. Triethylsilane (1.01 g) and a boron trifluoride-diethyl ether complex (1.82 g) were added dropwise to the solution at −30° C. After 3 hours of stirring, water (40 ml) was added to give two layers. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=80/20 by volume), and then by recrystallization (heptane/ethyl acetate=90/10 by volume) to give 2-propyl-5-(2,2′,3,3′-tetrafluoro-4′-(4-propylcyclohexyl)biphenyl-4-yl)tetrahydro-2H-pyran (18) (1.8 g) in 44.3% yield.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[NH:34]N>>[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cccc(NN)c1C
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: Cc1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1C

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (2,3-dimethyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=425.8 (M)+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][C:9](=[O:14])[C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]1=2.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[CH2:11][CH2:10][C:9](=[O:14])[C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]2=3)[CH2:29][CH2:28]1
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Product: O=C1CCC(=O)N(CCCCN2CCN(c3cccc(Cl)c3Cl)CC2)c2ccccc21

Procedure:
Analogously to Example 3b, reaction of 1-(4-chlorobutyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione with 1-(2,3-dichlorophenyl)piperazine afforded the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:32])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH:13]C(OCC1C=CC=CC=1)=O)[CH3:3].CO.[H][H]>[Pd].O>[ClH:1].[CH2:2]([NH:4][C:5](=[O:32])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:31])[C@H:12]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:29])[NH2:30])[NH2:13])[CH3:3]
Reactant: [H][H]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N

Procedure:
A solution of 8.7 g. of Nα -benzyloxycarbonyl-L-arginyl-L-proline N-ethylamide hydrochloride in 100 ml. of methanol is stirred with 500 mg. of 20% palladium on carbon under one inch water pressure of hydrogen for three hours. The catalyst is removed by filtration and the filtrate evaporated under reduced pressure and at 35°-40° C. The residual foam is used without further purification.