Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7](C)[C:8]([O:10]CC)=[O:9].BrCCCCOCC(OCC)=O.O1CCCCC1[O:32][CH:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:34][CH2:35][CH2:36][N:37](CCCCOCC(OCC)=O)[S:38]([CH3:41])(=[O:40])=[O:39]>>[OH:32][C@H:33]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:34]#[C:35][CH2:36][N:37]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CCOC(=O)C(C)CCCCCBr
Reactant: CCCCCC(CCCN(CCCCOCC(=O)OCC)S(C)(=O)=O)OC1CCCCO1
Agent: CCOC(=O)COCCCCBr
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 8 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of ethyl 4-bromobutoxyacetate (Example M). The product of Step A is thus ethyl 4-{N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamido}butoxyacetate. The subsequent step yields 4-[N-(4-hydroxynonyl)methanesulfonamido]butoxyacetic acid (B).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[CH:11]([O:13][CH2:14][CH2:15][CH2:16]CO)=[CH2:12]>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.CC(C1C(O)=C(C(C)(C)C)C=C(CCC(OCC(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)(COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)COC(CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)=O)C=1)(C)C.CO>[C:1]([O:9][CH2:10][CH2:16][CH2:15][CH2:14][O:13][CH:11]=[CH2:12])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH2:16][CH2:15][CH2:14][O:13][CH:11]=[CH2:12])=[O:5]
Reactant: COC(=O)/C=C/C(=O)OC
Reactant: C=COCCCCO
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1cc(CCC(=O)OCC(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)COC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [Zn+2]
Solvent: CO
Product: C=COCCCCOC(=O)/C=C/C(=O)OCCCCOC=C
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Into a 1 L-volume flask equipped with a distillation unit, 144 g of dimethyl fumarate, 279 g of hydroxybutyl vinyl ether, 0.2 g of zinc acetate and 0.3 g of IRGANOX 1010 as a polymerization inhibitor were charged. The mixture was heated to 140° C. in a nitrogen atmosphere and methanol generated as a by-product was distilled off. When methanol reached 70% of the theoretical amount, the pressure inside of the reaction system was gradually reduced to accelerate the distillation of methanol, and by finally reducing the pressure to about 400 Pa, the theoretical amount of methanol and the residual hydroxybutyl vinyl ether were completely distilled off. The reaction solution was cooled to a room temperature and then 297 g of bis(4-vinyloxybutyl) fumarate was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10](F)=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7].[OH-:18].[K+].Cl.[CH3:21]O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:5](=[C:9]([F:16])[C:10]([O:18][CH3:21])=[C:11]([F:14])[C:12]=1[F:13])[C:6]([OH:8])=[O:7]
Reactant: CO
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COC(=O)c1c(F)c(F)c(OC)c(F)c1C(=O)O
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser, a stirrer and a dropping funnel, 20 ml of a methanol solution of 10 g (0.0397 mol) of the 3,4,5,6-tetrafluorophthalic acid-monomethyl ester prepared in Example 14 was charged, and then 4.6 g (0.083 mol) of potassium hydroxide was added thereto. The mixture was stirred for one hour under reflux. After completion of the reaction, the reaction mixture was neutralized with a 10% of hydrochloric acid aqueous solution and extracted with ethyl acetate. Then, the solvent was distilled off to obtain 8.2 g of 4-methoxy-3,5,6-trifluorophthalic acid-1-methyl ester. (=5-methoxy-3,4,6-trifluorophthalic acid-2-methyl ester.) The yield was 78.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[N-:9]=[N+:10]=[N-:11].[Na+].O>CS(C)=O>[N:9]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:8])=[N+:10]=[N-:11]
Reactant: COC(=O)CCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCCN=[N+]=[N-]
Temperature: 47.5 °C
Reaction time: 5 h

Procedure:
To a solution of methyl-4-bromobutyrate in DMSO (0.6 M) was added with stirring NaN3 (1.5 eq). The suspension was heated (45-50° C., oil bath) with stirring for 5 h. After cooling, H2O was added and the mixture extracted with Et2O. The organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the crude oil used without further purification (99%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.[CH3:46][O:47][C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1O>C1COCC1>[CH3:46][O:47][C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[O:32][CH:33]1[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
To a mixture under N2 of triphenylphosphine (3.10 g, 11.825 mmol) and diethylazodicarboxylate (2.06 g, 11.825 mmol) in THF (40 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.937 mmol). After stirring 10 min, 2-methoxy-4-nitrophenol (1.00 g, 5.912 mmol) was added. The reaction stirred 16 h and evaporated under reduced pressure to give an orange oil. The crude product was purified by column chromatography on silica gel using 25% EtOAc/hexane yielding tert-butyl 4-(2-methoxy-4-nitrophenoxy)piperidine-1-carboxylate as a beige solid (1.70 g, 82%). LC/MS (m/z): 3512 (MH+), Rt 3.23 minutes
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)([Cl:19])(=O)=O>CC(O)=O>[NH2:1][C:2]1[C:10]([Cl:19])=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(OC(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.6 %

Procedure:
To a solution of 2-amino-5-trifluoromethoxybenzoic acid (49.0 g, 0.22 mol; see step (ii) above) in HOAc (1200 mL) was slowly added sulfuryl chloride (41.8 g, 0.31 mol). Gas evolution was observed. The resulting heterogeneous mixture was stirred at room temperature for 1 h. Additional HOAc (300 mL) was added to aid stirring, followed by sulfuryl chloride in 5 mL portions until the starting material was consumed based on TLC analysis. The reaction was concentrated in vacuo to give solids that were flushed on a rotary evaporator with EtOAc (2×) followed by Et2O (1×) to remove the HOAc. The resulting solids were further dried to give the HCl salt of the crude sub-title compound (60.5 g, 94%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24](C(O)=O)=[CH:23][CH:22]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CNC[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:63][N:64]([CH3:67])[CH:65]=[O:66]>C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:65]([N:64]([CH3:67])[CH2:63][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:66])=[CH:23][CH:22]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C)c2c1
Reactant: CCOC(=O)CCNC
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a mixture of 4-{[cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methyl]amino}benzoic acid (745 mg) synthesized above, ethyl 3-(methylamino)propanoate (298 mg), 1-hydroxybenzotriazole monohydrate (348 mg), triethylamine (633 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg), and the mixture was stirred at room temperature for overnight then at 50° C. for 3 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55% ethyl acetate/hexane) to give the title object compound (801 mg, 84%) as a pale-brown solid.
Reaction SMILES: C[Al](C)C.CCCCCCC.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C[O:26][C:27]([C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][NH:35]2)=[CH:31][CH:30]=1)=O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>O1CCOCC1.ClCCl>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([NH:12][C:27]([C:29]2[CH:37]=[C:36]3[C:32]([CH:33]=[CH:34][NH:35]3)=[CH:31][CH:30]=2)=[O:26])=[CH:14][C:15]=1[C:21]([F:22])([F:23])[F:24])#[N:18]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: N#Cc1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A 2 N trimethylaluminium solution in heptane (30.8 mmol, 15.41 mL, 3 equiv.) was added dropwise over 10 minutes to a solution of 4-amino-2-trifluoromethylbenzonitrile (30.8 mmol, 5.7 g, 3 equiv.) in dry dioxane (20 mL). The reaction mixture was stirred for a further 30 minutes then a solution of 1H-indole-6-carboxylic acid methyl ester (10.3 mmol, 1.8 g, 1 equiv.) in dioxane was added portionwise over 5 minutes and the reaction mixture was stirred at 106° C. for 16 hours. The solution was poured onto a 1M aqueous sodium tartrate solution (100 mL) and diluted with dichloromethane (50 mL). The organic layer was separated, dried over Na2SO4 and the solvent was removed under vacuum. The residue was dissolved in dichloromethane (10 mL) and sonicated for 5 minutes. The resultant solid was filtered to afford 1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, 2.4 g (71% yield). LC @215 nm; Rt 1.50: 97%, m/z (ES+): 330 (M+H+.); δH (250 MHz; d6-DMSO) 10.89 (1H, s), 8.54 (1H, s), 8.32 (2H, m), 8.17 (1H, s), 8.13 (1H, s), 7.70 (2H, m), 7.62 (1H, t), 6.57 (1H, s).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1)[C:6](=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[Cl:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]Cl>CC(N(C)C)=O.C(OCC)(=O)C>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:16]([CH2:32][CH:31]=[CH:30][CH2:29][Cl:28])[C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:15]
Reactant: ClC/C=C\CCl
Reactant: CCCCN(Cc1nc2ccccc2[nH]1)C(=O)c1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCN(C(=O)c1cccc(F)c1F)C(CC=CCCl)c1nc2ccccc2[nH]1
Reaction time: 0.08 h

Procedure:
N-butyl-N-(1H-benzoimidazol-2-ylmethyl)-2,3-difluorobenzamide (226 mg, 0.66 mmol) was dissolved in 3 mL dimethylacetamide at room temperature. Sodium hydride (29 mg, 0.72 mmol, 60% oil dispersion) was added and the reaction mixture stirred 5 minutes. Cis-1,4-Dichloro-2-butene was added and the reaction mixture stirred 90 minutes. The reaction mixture was diluted with 10 mL ethyl acetate, placed in a separatory funnel and washed 1×10 mL H2O then 1×10 mL brine. The organic phase was dried over MgSO4, filtered, concentrated, then purified by flash chromatography eluting with 1/1 ethyl acetate/hexane to afford 206 mg 2,3-difluoro-N-butyl-N-[(4-chlorobut-2-enyl)-1H-benzoimidazol-2-ylmethyl]-benzamide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C(Cl)Cl>[C:22]([NH:26][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: CC(C)(C)N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)Nc1nc2ccncc2nc1Cl
Reaction time: 48 h
Yield: 87.9 %

Procedure:
Combined 2,3-dichloropyrido[3,4-b]pyrazine (1 g, 5.00 mmol) and DIPEA (1.75 mL, 10.00 mmol) in DCM (10.00 mL) and cooled to 0° C. and added tert-butylamine (1.590 mL, 15.00 mmol) and stirred for 48 h. The reaction mixture was poured into saturated aqueous NH4Cl and extracted twice with EtOAc. The organic extracts were combined, filtered through MgSO4, and concentrated in vacuo. The residue was redissolved in EtOAc, filtered through a one inch plug of silica, washing with EtOAc, and concentrated gave N-(tert-butyl)-3-chloropyrido[3,4-b]pyrazin-2-amine (1.04 g, 88%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH:11][CH2:12][CH:13]=[CH2:14])[CH:9]=[CH2:10].[13CH4]>C1(C)C=CC=CC=1>[CH2:8]([N:11]([CH2:12][CH:13]=[CH2:14])[C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH:9]=[CH2:10]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CCNCC=C
Agent: [13CH4]
Solvent: Cc1ccccc1
Product: C=CCN(CC=C)C(=O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Maleic anhydride (100 g, 1.02 mol) was dispersed in 400 mL toluene at 40° C. Diallylamine (97% pure, 100 g, 1.00 mol) was added over a period of 30 minutes with cooling so that the reaction temperature was maintained below 40° C. After addition, the reaction mixture was stirred at room temperature for 3 hours. The IR of the reaction mixture showed the absence of the anhydride. A nearly quantitative conversion was obtained. The Carbon-13 data is shown in Table 1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]([NH2:7])[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:15][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCN(CC)CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A solution of 171 mg (0.4 mmol) [2-(4-benzyloxy-phenyl)-1-(diethylamino-methyl)-ethyl]-carbamic acid tert-butyl ester in 2 mL dichloromethane was treated with 0.5 mL 2,2,2-triflouroacetic acid and the resulting solution stirred 3 hours at 25° C. The mixture was concentrated at reduced pressure to a viscous amber oil to which was added 30 mL saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with three 20 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure and the residue purified by column chromatography using ethyl acetate containing 1% methanol as eluent. There was obtained 112 mg (90%) of (S)-3-(4-benzyloxy-phenyl)-N1,N1-diethyl-propane-1,2-diamine as a clear, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][C:18]([CH3:30])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH3:19])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:37][C:38]([F:43])([F:42])[CH:39]1[O:41][CH2:40]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:40][CH:39]([OH:41])[C:38]([F:43])([F:42])[F:37])[C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][C:18]([CH3:30])([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH3:19])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
3.61 g (8.23 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 241A are dissolved in 20 ml of DMF with 3.75 g (11.52 mmol) of caesium carbonate and treated with 2.22 g (11.52 mmol) of 1,1,1-trifluoro-2,3-epoxypropane. This is stirred for 2.5 hrs at 75° C. The suspension is then diluted with 30 ml of ethyl acetate and washed twice with 20 ml water each time. The organic phase is dried over sodium sulphate and filtered. After concentration, the crude product is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate first 5:1, then 1:1). 3.14 g (69% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=O)[C:4](O)=[CH:3][CH:2]=1.[C:10]1([CH3:20])[CH:15]=CC(S(Cl)(=O)=O)=C[CH:11]=1>N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:8]=[CH:7]2)[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1cccccc1O
Solvent: c1ccncc1
Product: Cc1cc2cccccc-2c1

Procedure:
2-Methylazulene was synthesized in accordance with the method described in Japanese Laid-Open Patent Publication No. 207232/1987. Thus, 19.5 g (0.16 mol) of tropolone and 40 g (0.21 mol) of p-toluenesulfonic acid chloride were reacted with each other in pyridine to obtain 37.1 g of tosylated tropolone. This compound was then reacted with 20 g (0.15 mol) of dimethyl malonate and 9.7 g (0.18 mol) of NaOMe in methanol at room temperature for four hours to obtain 14.4 g of 3-methoxy-carbonyl-2H-cyclohepta(b)furan-2-one (compound (2)). To 12 g of the compound (2) were added 200 ml of acetone and 70 ml of diethylamine, and the mixture was refluxed for 30 hours. Water was added to this mixture, and the resulting mixture was extracted with toluene to obtain 39.2 g of methyl-2-methyl-azulenecarboxylate. To this compound was further added 25 ml of phosphoric acid, and reaction was carried out at a temperature of 85 to 90° C. for one hour. The reaction mixture was subjected to decomposition with water, and the resultant was extracted with benzene. The organic phase was dried to obtain 6.5 g of the desired compound, 2-methylazulene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29].CCN(CC)CC>C(Cl)Cl>[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([C@H:11]2[CH2:12][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]2([CH3:17])[CH3:16])=[O:15])[CH2:32][CH2:31]1)[CH3:29]
Reactant: CCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C2(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (2 g, 8.23 mmol) in DCM (50 ml) EDCI (946 mg, 9.876 mmol) and HOBt (756 mg, 9.876 mmol) were added at 0° C., after 10 minutes N-Ethyl piperazine (939 mg, 16.46 mmol) and Et3N (3 mL, 41.15 mmol) were added drop wise and the reaction mass was allowed to stir at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure. The resulting crude residue was stirred in hexane and obtained solid was filtered. Wt: 1.6 g; Yield: 70%. 1H NMR (300 MHz, CDCl3): δ 4.77 (d, 1H, J=8.4 Hz), 3.89-3.78 (m, 1H), 3.6-3.46 (m, 3H), 2.80 (m, 1H), 2.60-2.40 (m, 8H), 1.80 (m, 1H), 1.43 (s, 9H), 1.12 (s, 3H), 1.2 (t, 3H), 0.87 (s, 3H); Mass: [M+1]+ 340 (25%), [M+Na]+ 362 (100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][CH:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:11][CH2:12]1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(c2ncccn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OC1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cooled solution of 1-Pyrimidin-2-yl-piperidin-4-ol (WO2008/8895 A1), (100 mg; 0.55 mmol) and triethylamine (233 μL, 1.67 mmol) in dry dichloromethane (1 mL), was added methanesulfonyl chloride (52 μL, 0.67 mmol). The reaction mixture was stirred at room temperature for 5 hours. Water was added. After extraction with dichloromethane, the combined organic extracts were dried over sodium sulfate and concentrated to afford a crude product that was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[S:23][C:24]([S:27][C:28]4[CH:33]=[CH:32][N:31]=[C:30]([C:34](O)=[O:35])[C:29]=4[F:37])=[CH:25][N:26]=3)=[N:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][C:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([OH:44])[CH2:41][CH2:42][CH3:43].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[F:37][C:29]1[C:30]([C:34](=[O:35])[NH:38][CH2:39][C:40]([OH:44])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:41][CH2:42][CH3:43])=[N:31][CH:32]=[CH:33][C:28]=1[S:27][C:24]1[S:23][C:22]([NH:21][C:18]2[N:19]=[CH:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:16][CH:17]=2)=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Nc3ncc(Sc4ccnc(C(=O)O)c4F)s3)nc2)CC1
Reactant: CCCC(O)(CN)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(NC4CCN(C(=O)OC(C)(C)C)CC4)cn3)s2)c1F)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirring solution of 4-(2-(5-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)pyridin-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinic acid (586 mg, 1.072 mmol), 1-amino-2-phenylpentan-2-ol (479 mg, 2.672 mmol), EDAC (621 mg, 3.239 mmol), HOBt (235 mg, 1.739 mmol) in NMP (7 mL) was added i-Pr2NEt (0.93 mL, 5.339 mmol) and stirred overnight. LCMS showed complete reaction, which was poured into ˜50 mL water and a solid precipitated. The solid was collected by filtration, washed with water and was allowed to air dry. The product was obtained (838 mg, 100%) as a solid: LC/MS (M+H)+: 708. HPLC ret. time (Condition M): 1.95 min.