Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[CH2:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:9]([C:6]2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)=[CH:25][CH:24]=1)[CH3:22]
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2)nc1
Reactant: CCc1ccc(CBr)cc1
Product: CCc1ccc(CN(CCc2ccc(O)c(C)c2)c2ncc(CC)cn2)cc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine and 4-ethyl-benzyl bromide.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine give 2-(imidazol-1-yl)-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:8][C@@H:9]([C:11]1[O:15][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[C:26]([N:28]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]4[N:45]=[CH:46][C:47]([C:48]5[CH:49]=[N:50][C:51]([C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)=[CH:52][CH:53]=5)=[C:24]4[N:23]=3)[CH2:18][CH2:17]2)=[N:13][N:12]=1)[CH3:10])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:43][Si:41]([CH3:42])([CH3:44])[CH2:40][CH2:39][O:38][CH2:37][N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:26]1[N:25]2[N:45]=[CH:46][C:47]([C:48]3[CH:49]=[N:50][C:51]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)=[CH:52][CH:53]=3)=[C:24]2[N:23]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]3[O:15][C:11]([C@H:9]([OH:8])[CH3:10])=[N:12][N:13]=3)[CH2:21][CH2:20]2)[CH:27]=1
Reactant: C[C@@H](OCc1ccccc1)c1nnc(N2CCC(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4ncc(-c5ccc(-c6ccccc6)nc5)c4n3)CC2)o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O)c1nnc(N2CCC(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4ncc(-c5ccc(-c6ccccc6)nc5)c4n3)CC2)o1
Reaction time: 8 h
Yield: 34.2 %

Procedure:
A mixture of (R)-5-(1-(5-(1-(benzyloxy)ethyl)-1,3,4-oxadiazol-2-yl)piperidin-4-yl)-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (105 mg), 20% Pd(OH)2/C (150 mg) in MeOH (4 mL) was stirred under hydrogen (60 psi) overnight. After filtration, washing with EtOAc 4 times and concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-100%) gave the title compound (32 mg, 43%).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH3:8][N:9]([CH3:17])[C:10](=[O:16])[C@H:11]([CH2:13][O:14][CH3:15])[NH2:12]>C(O)C>[CH3:8][N:9]([CH3:17])[C:10](=[O:16])[C@H:11]([CH2:13][O:14][CH3:15])[NH:12][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: COC[C@H](N)C(=O)N(C)C
Solvent: CCO
Product: COC[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a solution of 4-thioxothiazolidin-2-one (1.00 g) in ethanol (20 mL) was added N,N,O-trimethyl-L-serinamide (1.82 g) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (434 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:28][C:29]([C:31]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:40]3[CH2:44][CH2:43][CH2:42][C@H:41]3[C:45](=[O:51])[NH:46][CH:47]3[CH2:50][CH2:49][CH2:48]3)=[O:39])[N:33]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:32]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][O:20]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(OCC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:58])[C@@H:15]([NH:28][C:29]([C:31]2[CH:35]=[C:34]([O:36][CH2:37][C:38]([N:40]3[CH2:44][CH2:43][CH2:42][C@H:41]3[C:45](=[O:51])[NH:46][CH:47]3[CH2:48][CH2:49][CH2:50]3)=[O:39])[N:33]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[N:32]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCO)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h
Yield: 1.1 %

Procedure:
To a solution of 819 mg 4-[(S)-6-Benzyloxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-hexanoyl]-piperazine-1-carboxylic acid butyl ester in 20 ml ethyl acetate were added under argon 100 mg Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 12 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give a mixture of the title compound (8 mg) and unreacted benzyl ether which was subjected to the same hydrogenolysis conditions described above to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([O:21][CH3:22])[CH:5]=1.CC#N>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:24][O:23][CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C(OC)OC)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 35.3 %

Procedure:
5-Nitrophenyl triflate 26 (7 g, 18.7 mmol), palladium (II) acetate (88 mg, 0.39 mmol), 1,1′-bis(diphenylphosphino)ferrocene (430 mg, 0.78 mmol) and hplc grade CH3CN (10 ml) were mixed well in a teflon-lined stainless steel bomb. After adding freshly made, pulverized proton sponge formate (5.1 g, 19.6 mmol), the bomb was sealed and heated at 90° C. for 2 h. The reaction mixture was taken up in EtOAc, passed through a silica gel plug, and then purified on a silica gel column, eluting with 0-30% EtOAc/hexanes to yield 1.5 g (35%) methoxynitrobenzaldehyde acetal 27.
Reaction SMILES: BrC1C=CC(C(=C2CCOCC2)C2C=CC(O)=CC=2)=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=O)=[CH:25][CH:24]=1.[CH3:38][C:39]1([CH3:48])[CH2:44][C:43](=O)[CH2:42][C:41]([CH3:47])([CH3:46])[O:40]1>[Zn].Cl[Ti](Cl)(Cl)Cl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[C:43]2[CH2:42][C:41]([CH3:47])([CH3:46])[O:40][C:39]([CH3:48])([CH3:38])[CH2:44]2)[C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1
Reactant: CC1(C)CC(=O)CC(C)(C)O1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Oc1ccc(C(=C2CCOCC2)c2ccc(Br)cc2)cc1
Agent: [Zn]
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)O1
Yield: 76 %

Procedure:
Following the procedure described for compound 46, zinc powder (0.957 g, 14.6 mmole), TiCl4 (0.800 mL, 7.30 mmole), (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.512 g, 1.85 mmole) and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (52) (0.851 mL, 5.45 mmole), afforded 0.564 g (76%) of 53 as a white foamy solid. 1H NMR (CDCl3): δ 7.41 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.3 Hz, 2H), 4.99 (s, 1H), 2.24 (s, 2H), 2.20 (s, 2H), 1.22 (s, 6H), 1.21 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[C:23]([O:27][C:28](=[O:37])[NH:29][CH:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:37])[NH:29][CH:30]1[CH2:31][CH2:32][CH:33]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:34][CH2:35]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Product: CC(C)(C)OC(=O)NC1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]Br)[CH3:12]>CN(C=O)C.O.CCOCC>[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCCCC(CC)CBr
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)COc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
Sodium hydride (60% dispersion in oil, 17.4 g, 435 mmol) was added in portions to a cold (ice-bath) solution of 4-bromophenol (49.0 g, 283 mmol) in dry DMF (780 cm3). The mixture was stirred at that temperature for 2 h and the ice bath was removed. A solution of 2-ethylhexylbromide (54.4 cm3, 306 mmol) in 150 cm3 of dry DMF was added dropwise through an addition funnel to the reaction mixture and the reaction was stirred at room temperature overnight (21 h). The resultant mixture was diluted with water (400 cm3) and ether (500 cm3). The two phases were separated. The aqueous layer was extracted with ether (3×300 cm) and the organic portion and the ether extracts were dried over anhydrous MgSO4, filtered and the filtrate was collected and evaporated under reduced pressure to leave yellow oil. Column chromatography over silica gel (half amount each time) with light petroleum as eluent afforded R1 (54.1 g, 67%) as colourless oil; λmax(CH2Cl2)/nm 284 (ε/dm3mol−1cm−1 1251), and 291sh (1001); δH(400 MHz; CDCl3) 0.83-0.97 (6 H, m, Me), 1.30-1.57 (8 H, m, CH2), 1.68-1.79 (1 H, m, CH), 3.78-3.84 (2 H, m, ArOCH2), 6.74-6.80 (2 H, m, ArH), and 733-7.40 (2 H, m, ArH); δC(100 MHz; CDCl3) 11.1, 14.1, 23.0, 23.8, 29.1, 30.4, 39.3, 70.7, 112.4, 116.3, 132.1, and 158.5.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33](OC)=[O:34])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CN(C)C1C=CN=CC=1.N1CCCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33]([N:16]4[CH2:17][CH2:13][CH2:14][CH2:15]4)=[O:34])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCNC1
Product: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Yield: 169.9 %

Procedure:
A solution of 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.84 g) (prepared as described in Example 1, parts (a) through (i)) and 4-(dimethylamino)pyridine (0.21 g) in pyrrolidine (5 ml) was heated at 80° for 48 hours under a nitrogen atmosphere. The reaction was diluted with water and acidified with 10% (v/v) hydrochloric acid. The resultant precipitate was collected by filtration and washed with water to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(pyrrolidinocarbonyl)ethyl]indol1-ylmethyl]-3-methoxybenzoic acid as a white powder (0.77 g, 85%): partial NMR (80 MHz, DMSO-d6 : 1.1-2.0 (m, 12H), 2.1(m, 1H, NHCH2CH), 3.9(s, 3H, OCH3), 6.7(d, 1H, Ar), 7.3(s, 1H, H2 -indole), 8.3(t,1H, NH).
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[CH3:16][C:12]1[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([OH:23])=[O:8]
Reactant: Cc1cccc(C(=O)OCc2ccccc2)c1-c1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: Cc1cccc(C(=O)O)c1-c1ccccc1
Yield: 99.8 %

Procedure:
A mixture of 0.35 g (1.18 mmol) of benzyl-3-methyl-2-phenylbenzoate and 0.25 g of 10% Pd/C in 8 mL of a 4.4% solution of HCO2H in methanol was heated at reflux for 2 h. The reaction mixture was filtered through a thin layer of celite and concentrated to give 0.25 g of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[NH:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:26]([O:25][C:23]([N:15]([CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2ccccc2)nn1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of 3-bromomethyl-6-phenylpyridazine (120 mg, 0.482 mmol) obtained in Reference Example 2-(a) in N,N-dimethylformamide (1.57 ml) were added di-tert-butyl iminodicarboxylate (127 mg, 0.585 mmol) and potassium carbonate (134 mg, 0.970 mmol), followed by stirring at 50° C. for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1 (UV)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (180 mg) as a slightly yellow solid. (Yield: 97%)
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:23])=O>>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:23])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
13.9 g of p-n-decyloxybenzoic acid was heated with excess thionyl chloride for 1 hour under reflux. p-n-Decyloxybenzoic acid chloride was obtained after distilling unreacted thionyl chloride off. 10.6 g of the above prepared p-hydroxybenzoic acid 2-methylbutyl ester was dissolved in 40 ml of pyridine. When the solution was cooled, a toluene solution of said p-n-decyloxybenzoic acid chloride was admixed therewith under stirring to effect reaction at 80° C. for 2 hours. The solution was then acidified by the addition of ice and 6N hydrochloric acid. After the organic layers were washed with water, then with a 2N aqueous sodium hydroxide solution, and again with water, the solvent was distilled off. The residue was recrystallized twice from ethanol to obtain p-n-decyloxybenzoic acid p'-(2-methylbutoxycarbonyl)phenyl ester.
Reaction SMILES: [C:1](OC=O)(=[O:3])C.[Cl:7][C:8]1[C:9]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[CH:10][CH:11]=[C:12]2[C:17]=1[CH2:16][NH:15][CH2:14][CH2:13]2.CN(C1C=CC=CN=1)C>ClCCl>[CH:1]([N:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([Cl:7])[C:9]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:29])([F:30])[F:31])[CH:21]=3)=[CH:10][CH:11]=2)[CH2:16]1)=[O:3]
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1C(F)(F)F
Reactant: CC(=O)OC=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(C=O)CC3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
Formic acetic anhydride (0.21 g) was added to N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.15 g) and dimethylaminopyridine (0.05 g) in dichloromethane. The mixture was stirred at room temperature overnight and quenched with saturated aqueous sodium hydrogen carbonate (20 ml). The organic phase was separated and washed with brine, dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ammonia/methanol/dichloromethane mixtures as eluant) to give the title compound (0.10 g)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>O1CCOCC1>[CH3:1][CH:2]1[CH2:3][C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5][CH:6]=[CH:7]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1C=CC=C(c2ccncc2[N+](=O)[O-])C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of (+/−)-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.) in dioxane (0.1M) was added p-TSA (1.0 equiv.), and the reaction was stirred at 100° C. for 3 h. The solution was cooled to room temperature, then passed through a pad of neutral alumina eluting with EtOAc to yield (+/−)-4-(5-methylcyclohexa-1,3-dienyl)-3-nitropyridine as a yellow oil in 68% yield. LC/MS=217.1 (M+H), LC=3.908 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=O)[NH2:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])([C:15](=[S:27])[NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=S)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-carbamoyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 8.7 mmol) in THF (30 mL) was added Lawesson's reagent (3.5 g, 8.7 mmol) at room temperature. The mixture was heated at 50° C. for 3 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])(=[O:20])=[O:19])[CH2:15][C@H:14]3[C:28]([OH:30])=O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:31][C@@H:32]([CH2:41][CH2:42][CH3:43])[C@H:33]([OH:40])[C:34]([NH:36][CH:37]1[CH2:39][CH2:38]1)=[O:35]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][C@H:16]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])(=[O:19])=[O:20])[CH2:15][C@H:14]3[C:28]([NH:31][C@@H:32]([CH2:41][CH2:42][CH3:43])[C:33](=[O:40])[C:34]([NH:36][CH:37]3[CH2:39][CH2:38]3)=[O:35])=[O:30])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Br)cc2)CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(Br)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-1-[1-(4-bromo-phenyl)-cyclopropanecarbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=680.1 [M+H+].
Reaction SMILES: ClC1C(NC2C=CC=CC=2S(C(C)C)(=O)=O)=NC(NC2C=C3C(CN([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)C3=O)=CC=2OC(C)C)=NC=1.C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C=O)C>[CH2:53]([O:52][C:50]([N:22]1[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23]1)=[O:51])[CH3:54]
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 446-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:7])=[O:6].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>>[CH3:1][O:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:23]=[O:24])(=[O:16])=[O:15])(=[O:6])=[O:7]
Reactant: COCCS(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C(Cl)Cl
Product: COCCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C

Procedure:
A mixture of 2-[(2-methoxyethyl)sulfonyl]benzenesulfonamide (9.5 g, 0.034 mol), n-butylisocyanate (4.7 ml, 0.041 mol) and 1,4-diaza[2.2.2]bicyclooctane (0.1 g) in mixed xylenes (58 ml) was heated to 140° with stirring under nitrogen. Liquid phosgene (2.7 ml, 0.039 mol) was added at a rate to maintain an internal temperature between 125°-135°. When the addition was complete, the solution was refluxed for 2 hours, cooled to room temperature under nitrogen purge and then filtered under a nitrogen atmosphere. Removal of solvent in vacuo gave 2-[(2-methoxyethyl)sulfonyl]benzenesulfonyl isocyanate, which was used immediately in Example 5 below, without further purification.