Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:30]=[C:29]2[C:20]([NH:21][C:22]3[C:27]([S:28]2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:19]2[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=12.[C:35]([O:39][C:40]([NH:42][CH2:43][C:44](O)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]>C1COCC1.CN(C1C=CN=CC=1)C>[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]([O:16][C:17]1[CH:30]=[C:29]2[C:20]([NH:21][C:22]3[C:27]([S:28]2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:19]2[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=12)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reaction time: 0.25 h

Procedure:
Dicyclohexylcarbodiimide (21 g) was added to a solution of 5-hydroxy-12H-benzo[a]phenothiazine (4.2 g) and N-tert-butyloxycarbonyl glycine (8.4 g) in THF (150 ml) followed by the addition of DMAP (0.2 g). The reaction mixture was stirred for 15 minutes, filtered and the filtrate evaporated to dryness. The residue was dissolved in EtOAc, washed with a solution of NaHCO3, dried and evaporated to dryness. The resulting oily residue was chromatographed on silica gel (5% EtOAc/CH2Cl2) to afford 5-tert-butyloxycarbonylamino acetoxy-12H-benzo[a]phenothiazine. m.p. 175° as an intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN(C(C)C)C(C)C.[Br:37][CH2:38][CH:39]=[CH:40][C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH2:22][C:20]1[C:21]2[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[CH:14][N:15]([C@H:23]3[CH2:27][CH2:26][N:25]([C:41](=[O:42])[CH:40]=[CH:39][CH2:38][Br:37])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COc1cc(C#Cc2cn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Reactant: O=C(Cl)C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)C=CCBr)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The crude product (100 mg) of (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 38 (Step 4)) was suspended in chloroform (3.0 ml). DIPEA (117 μl) was added to the suspension, and the mixture was cooled to 0° C. A solution of 4-bromobut-2-enoyl chloride (46 mg) obtained in Example 16 (Step 1) in chloroform (0.3 ml) was added thereto dropwise, and the resulting mixture was stirred at room temperature for 15 minutes. After halting the reaction using a saturated aqueous sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a crude product (140 mg). Physical properties: m/z[M+H]+509.9, 511.9
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[N:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0359 g, 0.108 mmol) in methanol (2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0166 g, 0.113 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0332 g, 67%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[CH:13][CH:14]=[C:15]([F:17])[CH:16]=1)[C:6](/[N:8]=[CH:9]/[N:10](C)C)=O.[CH3:19][NH:20]N>C(O)(=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[C:6]1[N:20]([CH3:19])[N:10]=[CH:9][N:8]=1
Reactant: CNN
Reactant: COC(=O)c1cc(F)ccc1C(=O)/N=C/N(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)ccc1-c1ncnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[1-dimethylamino-meth-(E)-ylidene]-5-fluoro-phthalamic acid methyl ester plus regioiosmer (2.9 g, 11.50 mmol) in acetic acid (10 mL) is added methyl hydrazine (6.0 mL, 113.95 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with EtOAc (250 mL) and the organic layer is washed with H2O (150 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure. The residue is triturated with 1:1 EtOAc:hexanes (200 mL), and filtered to remove the white solid. The mother liquor is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 7.5% MeOH in CH2Cl2 as the eluent to afford 5-fluoro-2-(2-methyl-2H-1,2,4-triazol-3-yl)-benzoic acid methyl ester plus regioisomer (1.5 g, 55%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][OH:44])=[O:40])[CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>ClCCl.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]>[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][OH:44])=[O:40])[CH:26]=[CH:27][C:28]=1[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2F)OC1(C)C
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCO)cc3F)nc(N3CCOCC3)c2C1
Yield: 50 %

Procedure:
Method as described for example 47 using ethyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 27) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-hydroxyethyl)urea (intermediate 32) as starting materials. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane was used as catalyst. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at high pH, yielding the title compound (115 mg, 0.24 mmol, 50%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:15](Cl)=[O:16])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:16])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCNCC
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(OC)c(OC2CCCC2)c1
Yield: 93.8 %

Procedure:
Diethylamine (69.2 g, 0.672 moles) was added dropwise at 5-10° C. to a solution of 3-cyclopentyloxy-4-methoxy benzoyl chloride (57 g, 0.224 moles) obtained as described in example 2, in methylene chloride (250 ml). The mixture was evaporated to dryness, dissolved in ethyl acetate, washed with water, with 2% potassium bisulphate, again with water and sodium bicarbonate, dried on sodium sulphate and brought to dryness. The residue was taken up with petrolatum (250 ml) to give 61.2 g of the title compound (yield: 94%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[CH:10]1([C:20]([O:22]C)=O)[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:5][C:20]([CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH2:19][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:17])[CH2:14][CH2:15]1)=[O:22])[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCC(CC)COC(=O)C1CCC(C(=O)OCC(CC)CCCC)CC1
Temperature: 180 °C

Procedure:
2-Ethylhexyl alcohol (8.1 mol), dimethyl cyclohexane-1,4-dicarboxylate (DMCD, cis 81.8%, trans 18.2%, SK NJC, 3.0 mol) and tetraisopropyl titanate catalyst (0.85 g) were added to a 2.5 L reactor equipped with a stirrer and two condensers and heated to 180° C. Di(2-ethylhexyl)cyclohexane-1,4-dicarboxylate (cis 81%, trans 19%) was obtained with a purity of 99.3% in the same manner as in Example 1.
Reaction SMILES: [CH2:1]([N:8]([C@@H:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][C@H:28]1[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([N:8]([C@@H:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][C@H:28]1[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:9](=[O:10])[CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH:54][S:51]([C:48]3[CH:47]=[CH:46][C:45]([F:44])=[CH:50][CH:49]=3)(=[O:52])=[O:53])=[O:25])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc(-c2cccc(CC(=O)N(Cc3ccccc3)[C@@H]3c4ccccc4CC[C@H]3Cc3ccccc3)c2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NS(=O)(=O)c1ccc(F)cc1)c1cccc(-c2cccc(CC(=O)N(Cc3ccccc3)[C@@H]3c4ccccc4CC[C@H]3Cc3ccccc3)c2)c1
Reaction time: 5 h

Procedure:
To a solution of the product of Example 1 (82.0 mg, 0.145 mmol), 4-fluorobenzene sulfonamide (27.9 mg, 0.160 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP, 74.4 mg, 0.160 mmol), and methylene chloride (12 mL) was added diisopropylethyl amine (0.126 mL, 0.725 mmol). After stirring for 5 h, the reaction was concentrated to dryness and then diluted with ethyl acetate (25 mL). This was then washed with 0.1 N HCl (2×20 mL) and brine (25 mL), dried (magnesium sulfate), and concentrated. The title compound was isolated in quantitative yield as a foam following chromatography on silica gel with ethyl acetate/hexane.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:15][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: O=C1C=CCCC1
Product: O=C1CCCC(NCc2ccccc2)C1

Procedure:
2-Cyclohexenone is reacted with benzylamine to give 3-benzylaminocyclohexanone. Hydrogenolysis of the benzylamino group then gives 3-aminocyclohexanone. Reaction with hexadecanoyl chloride affords 3-hexadecanamidocyclohexanone, which is then reduced with sodium borohydride to produce a cis/trans mixture of 3-hexadecanamidocyclohexanol. Separation by column chromatography then gives the pure isomers. Reaction with bromoethylphosphodichloridate, then with trimethylamine will produce 3-hexadecanamido-cyclohexylphosphocholine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[N:18]=1>O1CCOCC1>[CH3:35][O:34][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([NH:1][C:2]3[CH:11]=[CH:10][C:5]4[O:6][CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[S:12]([NH2:15])(=[O:14])=[O:13])[CH:22]=[CH:21][N:20]=2)[CH:29]=[C:28]([O:30][CH3:31])[C:27]=1[O:32][CH3:33]
Reactant: Nc1ccc2c(c1S(N)(=O)=O)OCCO2
Reactant: COc1cc(Nc2nccc(Cl)n2)cc(OC)c1OC
Solvent: C1COCCO1
Product: COc1cc(Nc2nccc(Nc3ccc4c(c3S(N)(=O)=O)OCCO4)n2)cc(OC)c1OC
Temperature: 120 °C

Procedure:
6-Amino-2,3-dihydro-benzo[1,4]dioxine-5-sulfonic acid amide (87 mg, 0.38 mmol) and (4-chloro-pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine (112 mg, 0.38 mmol) are dissolved in dioxane (1.3 ml). The mixture is heated to 120° C. for 1 h. The reaction mixture is purified by repeated chromatography on silica gel using different solvent mixture, yielding 6-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-ylamino]-2,3-dihydro-benzo[1,4]dioxine-5-sulfonic acid amide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[CH:23]([C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][CH3:6])[NH:12][CH:11]=1)=[O:24]
Reactant: COc1cccc2[nH]ccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc2[nH]cc(C=O)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Add phosphorus oxychloride (1.1 eq.) with vigorous stirring to DMF (cooled in an ice bath). After the addition is complete, allow to stir in the ice bath for ˜10 minutes, then add a solution of 4-methoxy-1H-indole (5 g) in anhydrous DMF with vigorous stirring. Allow to stir at 0° C. After 1 hour, warm to room temperature. After 16 hours, carefully add 4 eq. of 2N NaOH with vigorous stirring. Heat to about 80° C. and then cool. Pour the reaction mixture into cold water with vigorous stirring to give a solid. Collect the solid by filtration and dry in a vacuum oven at room temperature to give the title compound. Acidify the filtrate and extract with EtOAc. Combine the organic layers and wash with 50% brine. Collect the organic layer, dry (MgSO4) filter, and remove the solvent to give the title compound as a light purple solid. Total yield of the title compound is 5.44 g: MS (ES+): m/z 175 (M+H)+, 160 (M-CH3)+; (ES−): m/z 174 (M−H)−.
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:12][C@H:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)[CH2:10]1)C(=O)[O-])(C)C.[ClH:25]>O1CCOCC1.C(OCC)C>[ClH:25].[F:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C@H:11]2[CH2:12][C@H:9]([NH2:5])[CH2:10]2)=[CH:15][C:16]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CC(C)(C)N(C(=O)[O-])[C@H]1C[C@H](Oc2ccc(F)c(C(F)(F)F)c2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@H]1C[C@H](Oc2ccc(F)c(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,1-dimethylethyl(trans-3-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}cyclobutyl)carbamate (3.16 g, 9.05 mmol) in 1,4-dioxane (20 mL) was added hydrochloric acid in 1,4-dioxane (4M, 25 mL, 100 mmol) in one charge. The reaction vessel was sealed and the reaction stirred at ambient temperature for 16 hours. The majority of the solvent was then removed in vacuo leaving a slurry which was diluted with diethyl ether (ca 50 mL) and the solid collected by filtration and dried in vacuo to give the title compound (2.187 g).
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 0.046 mol) prepared as described in example P5a in Xylene (90 g) was added triethylamine (5.6 g, 0.055 mol) followed by addition of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (40.1 g, 0.046 mol) at 70° C. during 2 hours. After complete addition of acid chloride the mixture was stirred 2 hours at 70° C. The solution was washed twice with water and the volatiles were removed from the organic layer under reduced pressure. The resulting crude mass 23.6 g (sticky dark brown oil) was purified by crystallization from a mixture of 16 g xylene and 36 g methylcyclohexene to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (17.0 g, 91.5%) as off white solid. m.p: 115-116° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:15])=[C:9]([C:33](=[O:51])[NH:34][C:35]3[N:40]=[CH:39][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)=[CH:37][N:36]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:33](=[O:51])[NH:34][C:35]3[N:36]=[CH:37][C:38]([C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:48])[F:49])[CH:42]=4)=[CH:39][N:40]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3cccc(C(F)(F)F)c3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ncc(-c3cccc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(4-(piperidin-1-yl)-2-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-ylcarbamoyl)phenylcarbamoyl)benzylthio)propanoate (250 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (3.5 mL), and 2,2,2-trifluoroacetic acid (1.7 mL). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 12.9 mg (6%) of a light yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 11.38 (s, 1H), 11.19 (s, 1H), 9.10 (s, 2H), 8.04-8.20 (m, 3H), 7.62-7.79 (m, 5H), 7.37-7.49 (m, 3H), 3.76 (s, 4H), 3.29 (s, 6H), 2.40-2.44 (m, 2H), 1.68 (m, 4H), 1.53-1.54 (d, J=3.6 Hz, 2H). MS (ES, m/z): 664.00 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:13]=1.[C:20]([O:24][C:25](=[O:45])[NH:26][C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[C:20]([O:24][C:25](=[O:45])[NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:2]3[C:3]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:4][C:5]4[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=4[N:13]=3)=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CC4)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Yield: 101.8 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.125 mmol) and tert-butyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)carbamate (54 mg, 0.150 mmol) in 1,4-dioxane (1 ml), followed by a solution of sodium carbonate (40 mg, 0.3 mmol) in water (0.25 ml) to give a white suspension. This was degassed by bubbling nitrogen for 10 minutes, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (9 mg, 0.013 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with brine (4 ml) and extracted into ethyl acetate (3×4 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a white solid (60 mg, quantitative yield). 1H-NMR (500 MHz, CDCl3) δ 7.14-7.26 (6H, m), 7.08-7.14 (2H, m), 6.93 (2H, d), 4.99-5.27 (1H, br m), 4.80 (2H, s), 3.31 (3H, s), 1.35 (9H, br s), 1.25 (2H, br s), 1.03 (2H, br s). LCMS (Method D): RT=1.44 min, M+H+=472.20.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)[CH2:14][CH3:15].[C:25]([O:28][CH2:29][CH3:30])(=[O:27])[CH3:26]>C1COCC1>[CH2:29]([O:28][C:25](=[O:27])[CH2:26][C:22](=[O:23])[C@H:19]1[CH2:20][CH2:21][C@H:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1)[CH3:30]
Reactant: CCOC(C)=O
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C(=O)CC(=O)OCC)CC1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
THF (1,000 ml) was added to diisopropylamine (162.9 g) in a reaction vessel under an atmosphere of nitrogen. n-Butyllithium was added dropwise, while the solution was kept at −40° C. or lower, and the stirring was continued for 30 minutes. The solution was cooled at −65° C. or lower, and ethyl acetate (141.9 g) and then a THF (200 ml) solution of trans-4-propylcyclohexanecarboxylic acid chloride (2) (189.9 g) prepared in the first step were added dropwise. After the reaction mixture had been slowly warmed up to room temperature with stirring, it was quenched with a saturated aqueous solution of ammonium chloride. Water (1,000 ml) was then added to give two layers. The water layer was extracted with toluene (500 ml) three times, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 300 g, eluent: toluene) to give 3-oxo-3-(trans-4-propyl-cyclohexyl)-propionic acid ethyl ester (3) (220 g) in 90% yield.