Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.[C:3](=[NH:8])(OCC)[CH3:4].[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][CH:12]=1>C(O)C>[NH:8]=[C:3]([NH:18][NH:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:20][CH:19]=1)[CH3:4]
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: CCOC(C)=N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccc(C(=O)NNC(C)=N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.6 g (0.20 mol) sodium in 200 mL ethanol are combined at ambient temperature with a solution of 25 g (0.20 mol) ethyl acetimidate hydrochloride in 200 mL ethanol. The sodium chloride precipitated is suction filtered and 33.2 g (0.20 mol) 4-methoxybenzoic acid hydrazide are added to the filtrate. The reaction mixture is stirred overnight at ambient temperature and then cooled. The precipitate formed is separated off and washed with ethanol and diethyl ether. Yield: 33.6 g (81%); melting range=179-181° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH2:37]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:37][CH2:36][NH:35][C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:39])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(O)cc1
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: 63 °C
Reaction time: 5.5 h
Yield: 97.7 %

Procedure:
[4-(4-Hydroxyphenyl)butyl]carbamic acid tert-butyl ester (38 g, 0.143 mole), cesium carbonate (84 g, 0.257 mole), and (2-bromoethyl)carbamic acid benzyl ester 14 (59 g, 0.23 mole) were combined in DMF (200 ml). The mixture was mechanically stirred under nitrogen at 63° C. for 5.5 h, and allowed to stand at room temperature overnight. An additional amount of (2-bromoethyl)carbamic acid benzyl ester 14 (5 g, 0.019 mole) and cesium carbonate (7.1 g, 0.21 mole) were added, and the reaction was further stirred at 65° C. for 1 h. Toluene was then added, and the stirring mixture was allowed to cool to room temperature. The mixture was suction filtered through a medium sintered glass buchner funnel and washed with toluene. The solvents were removed under vacuum at 75° C. The remaining oil was washed with hexanes (2×400 mL), then dissolved in ether (500 ml) and washed with a mixture of water and brine (10:1, 4×100 mL). The remaining solution was suction filtered through a 30 g pad of silica gel and the solvent evaporated. The residue was washed with hexanes (3×400 ml), and then placed under vacuum for 2 h to afford 61.8 g of the product 15 which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.54 (m, 4H), 2.56 (t, 2H), 3.20 (m, 2H), 3.50 (m, 2H), 3.98 (t, 2H), 4.75 (br s, 1H), 5.00 (br s, 1H), 5.09 (s, 2H), 6.80 (d, 2H), 7.06 (d, 2H), 7.34 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH2:34][CH2:35][CH2:36][CH2:37][OH:38].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:34][CH2:35][CH2:36][CH2:37][OH:38])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: NCCCO
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)NCCCO)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (25 mg, 51 μmol) was dissolved in absolute THF (1.5 ml), 3-aminopropanol (11 μl, 152 μmol; 3 eq.) and triethylamine (5.1 mg, 51 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (18 mg, 67% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]2[S:13]C(=O)[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([SH:13])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc2cc(OCc3ccccc3)ccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1cc(OCc2ccccc2)ccc1S
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 6-benzyloxy-1,3-benzoxathiol-2-one (35 g), aqueous sodium hydroxide solution (200 mL; 2 N) and methanol (50 mL) is stirred at ambient temperature for 16 hours and then it is heated at reflux for 30 minutes. The reaction mixture is then evaporated to dryness and the residue is acidified to pH 1 by treatment with concentrated hydrochloric acid (20 mL). The residue is diluted with water (200 mL) and then extracted with diethyl ether (3×200 mL). The combined organic extracts are washed with brine (100 mL), dried over magnesium sulphate, filtered and concentrated in vacuo, to give 5-benzyloxy-2-mercaptophenol, in the form of a yellow oil which solidified on standing overnight.
Reaction SMILES: [CH:1]1([N:4]([CH3:26])[C:5]2[N:25]=[C:8]3[CH:9]=[C:10]([NH:13][C:14]([C:16]4[N:20]([CH3:21])[N:19]=[CH:18][C:17]=4[C:22](O)=[O:23])=[O:15])[CH:11]=[CH:12][N:7]3[N:6]=2)[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH:1]1([N:4]([CH3:26])[C:5]2[N:25]=[C:8]3[CH:9]=[C:10]([NH:13][C:14]([C:16]4[N:20]([CH3:21])[N:19]=[CH:18][C:17]=4[C:22]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:23])=[O:15])[CH:11]=[CH:12][N:7]3[N:6]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CN(c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1)C1CC1
Product: CN(c1nc2cc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)ccn2n1)C1CC1
Yield: 98.1 %

Procedure:
The product was prepared in the same manner as described in example 4 using 5-(2-(cyclopropyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridine-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 197 μmol) and morpholine (68.6 μl, 788 μmol) as starting materials. The reaction affords 2-Methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(cyclopropyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridine-7-yl]-amide (82 mg, 98.1%) as off-white solid. MS: m/z=325.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH:14][C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])=[CH:13][C:8]=2[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:6]=1)[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH:14][C:15]([NH:17][C@@H:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:19])=[O:16])=[CH:13][C:8]=2[NH:7][N:6]=1)[CH3:2]
Reactant: CCOCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
To the solution of (R)-1-(3-(ethoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (130 mg, 0.223 mmol) and trifluoroacetic acid (0.856 ml, 11.17 mmol) in dichloromethane (2.0 ml) was added triethylsilane (39.0 mg, 0.335 mmol). The resulting mixture was allowed to stir at rt for 18 h. The reaction was concentrated in vacuo and submitted for reversed phase HPLC purification to provide the desired product (28.5 mg, 0.063 mmol, 28.1% yield). MS ESI calc'd. for C18H21N5O2 [M+H]+ 340, found 340.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH3:15])=[CH:12][CH:13]=1)[C@@H:6]1[S:17][CH2:18][C@@H:19]([OH:25])[C@H:20]([OH:21])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 88.2 %

Procedure:
If the procedure described in Preparation LXXXIV is followed starting from 0.9 g (2.2.10-3 mol) of 4-acetylphenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 0.8 ml of a solution of sodium methylate in methanol (8% w/v of Na), reacted in 50 ml of methanol for 1 h, 0.55 g (yield: 88%) of the expected product is obtained after lyophilization.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[C:26]([C:28]([O:30]CC)=O)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:14][CH:13]=1.C(O)(=O)C>CCCCCC.O1CCCC1.O>[CH2:6]([N:8]([CH2:9][CH3:10])[C:28]([C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=2)[CH:27]=1)=[O:30])[CH3:7]
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)nc2ccccc12
Reactant: CCNCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)C(=O)c1cc(-c2ccc(C)cc2)nc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 1.6M solution of butyllithium in hexane (22.5 ml) is added, at ambient temperature and under a nitrogen atmosphere, to diethylamine (5.5 ml) in anhydrous tetrahydrofuran (50 ml). After stirring for 15 minutes, the mixture is cooled to 0° C. and ethyl 2-(4-methylphenyl)-quinoline-4-carboxylate (5.25 g) is then introduced slowly. The mixture is stirred for 2 hours at ambient temperature. Acetic acid is then added slowly, at ambient temperature and with stirring, until decolouration takes place and a yellow solution is obtained. Water (100 ml) is then added, the tetrahydrofuran is evaporated off under reduced pressure and the residue is extracted with ethyl acetate (3×100 ml). The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel with a cyclohexane/ethyl acetate mixture (80/20) as the eluant. After recrystallisation from isopropyl ether of the crude product isolated in this way, N,N-diethyl-2-(4-methylphenyl)-quinoline-4-carboxamide (1.1 g), melting at 145° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH:9][OH:10]>>[CH3:1][C:2]1([O:9][O:10][C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(O)CCCCC1
Reactant: OO
Product: CC1(OOC2(C)CCCCC2)CCCCC1

Procedure:
1-methylcyclohexanol (30 g, 0.26 mol) was placed in a 100 mL three necked round bottomed flask and was stirred. The flask was cooled in a brine/ice bath, dropping funnel fitted and fitted with a static N2 supply. The dropping funnel was charged with 98% sulfuric acid (16.14 ml) and water (6.45 ml) giving a 70% sulfuric acid solution. This was added dropwise to the 1-methylcyclohexanol and stirring continued to give a viscous brown mixture. The bath was recharged with ice/brine, dropping funnel rinsed with water and recharged with 35% hydrogen peroxide (6.98 mL, 0.125 mol) and added dropwise. The solution separated into two phases. Cyclohexanol (150 mL) was added and the mixture was transferred to a separating funnel. The aqueous fraction was extracted with another portion of cyclohexane (150 ml) and the combined organic fractions washed with 1M NaOH (2×100 mL), water (2×150 mL), dried and evaporated to give a viscous colourless oil. (12.98 g). The oil was sorbed onto silica gel then placed on a silica gel column and eluted with cyclohexane. After evaporation at reduced pressure 0.7 g colourless oil of di(1-methyl-cyclohexyl)peroxide was obtained. 13C-NMR (CDCl3) δ 22.45, 25.01, 25.95, 35.39, 78.58
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:13])=[CH:3][C:2]2=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1>>[CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:15]3[N:20]=[C:19]([NH:21][C:22]4[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=4[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=3)=[CH:3][C:2]2=1
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Yield: 60.9 %

Procedure:
Following a procedure analogous to 61e, 12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (100 mg, 0.57 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (170 mg, 0.57 mmol) were converted to the title compound as an off-white solid (151 mg, 61%). 1HNMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 9.3 (s, 1H), 8.8-8.7 (m, 2H), 8.3 (s, 1H), 7.8 (d, 1H, J=7.8 Hz), 7.5 (t, 1H, J=7.6 Hz), 7.3-7.2 (m, 2H), 7.1 (t, 1H, J=7.6 Hz), 6.9 (d, 1H, J=7.8 Hz), 4.0 (m, 1H), 3.7 (m, 1H), 3.0 (dd, 1H, J=16.3, 4.8 Hz), 2.8 (d, 3H, J=4.0 Hz), 2.7-2.6 (bs, 1H), 2.4 (d, 1H, J=16.3 Hz), 1.9-1.8 (m, 2H), 1.7 (m, 1H), 1.5-1.4 (m, 1H); MS (m/e) 435 (M+1); mp 209-212° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[C:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H+].[B-](F)(F)(F)F.O(CC)CC>ClCCl>[O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C@@H:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC1=C(CC(=O)OC)CCC1=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCC[C@@H]1C(=O)CC[C@@H]1CC(=O)OC
Yield: 99 %

Procedure:
The reaction was carried out analogously to that described in example 6, but using 100 g (446 mmole) of methyl 3-oxo-2-pentyl-1-cyclopentene-acetate, 427 mg (1.34 mmole) of [(COD)Ru(2-methylallyl)2 ], 410 mg (1.34 mmole) of (-)-Me-DuPHOS and 26.5 ml of HBF4.O(C2H5)2 in dichloromethane (0.1M, 2.68 mmole). This corresponds to a catalyst concentration of 0.3 mole %, relative to the substrate. 170 ml of dichloromethane were added, and the mixture was hydrogenated at a temperature of 7.5° C. and a pressure of 5×106Pa for 70 h to obtain methyl (+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate in 99% yield, cis/trans ratio=99.2/0.8 and (+)-cis/(-)-cis ratio=84/16.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[F:27][C:24]([F:25])([F:26])[C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(N2CCNCC2)c(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
3 mmol of 4-(2,4-Bis-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was stirred in 10 ml of 1,4-dioxane saturated with gaseous HCl. After 4 h at room temperature, the reaction mixture was evaporated to dryness to yield the title compound as a colorless solid. MS (m/e): 299.3 (MH+, 100%)
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.COC(C(S(C)(=O)=O)(CCCC(OC(=O)C)CCCC=C)CCCCCCC(OC)=O)=O>>[CH3:32][S:29]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: C=CCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Product: C=CCCCC(CCCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O

Procedure:
The synthesis of this compound is carried out as in Example 3, Step D, except that the methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxy-16-heptadecenoate.
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.C1COCC1.[N:28]([CH2:31][C:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)=[O:33])=[N+:29]=[N-:30].Cl>C1(C)C=CC=CC=1.C1COCC1>[N:28]([CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33])=[N+:29]=[N-:30]
Reactant: CC1(C)OCc2cc(C(=O)CN=[N+]=[N-])ccc2O1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CN=[N+]=[N-])ccc2O1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
(R)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole solution in toluene (1M, 7.5 ml) was added to THF (75 ml) and the solution was diluted to 0° C. Borane-THF complex (1M solution in THF, 125 ml) was added and the mixture was stirred under nitrogen for 15 min. A solution of 2-azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (24.7 g) in THF (250 ml) was added dropwise over 1.5 h at 5° C. The mixture was stirred for a further 1 h and then cautiously treated with 2M HCl (100 ml). The reaction mixture was extracted with ether and the organic layer was washed with 2M HCl, NaHCO3, brine, dried (MgSO4). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with ether-petroleum ether(40–60° C.) (1:9; 1:1) to give the title compound (16.99 g). ES+ve 250 (MH)+.
Reaction SMILES: C(NCC1C=CC=CC=1N1C(C(O)=O)=CC(C(F)(F)F)=N1)(OC(C)(C)C)=O.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:40]([C:41]2[O:42][CH:43]=[CH:44][CH:45]=2)=[CH:39][C:38]([C:46]([F:49])([F:48])[F:47])=[N:37]1)#[N:29].[BH4-].[Na+].Cl.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O>[NH2:29][CH2:28][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[C:40]([C:41]2[O:42][CH:43]=[CH:44][CH:45]=2)=[CH:39][C:38]([C:46]([F:49])([F:48])[F:47])=[N:37]1
Reactant: N#Cc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Agent: CC(C)(C)OC(=O)NCc1ccccc1-n1nc(C(F)(F)F)cc1C(=O)O
Agent: Cl
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
Part C: 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethylpyrazol-5-yl-carboxylic acid: To a solution of 1-(2-cyanophenyl)-5-furyl-3-trifluoromethylpyrazole (1.5 g, 4.67 mmol) in DMF (20 mL) was portion by portion added NaBH4 (0.71 g, 18.7 mmol) and then CoCl2 (0.61 g, 4,67 mmol) at 0° C. After the resulting mixture was stirred at room temperature for 18 hours, a black suspension was cooled to 0° C. and carefully acidified with 6N HCl (20 mL). The resulting mixture was stirred at room temperature for 3 hours, and neutralized with 1N NaOH to pH 14. The mixture was diluted with EtOAc (100 mL), and filtered through a pad of sand (top layer) and Celite (bottom layer). The filtrate was separated and the organic layer was washed with brine (5×10 mL), dried over Na2SO4, and concentrated to give 1-(2-(aminomethyl)phenyl)-5-furyl-3-trifluoromethylpyrazole (1.4 g, 91.5%). 1H NMR (CD3OD) δ7.69-7.61 (m, 2H), 7.52 (d, J=1.5 Hz, 1H), 7 47 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.34 (dd, J=1.8 Hz, J=3.6 Hz, 1H), 5.75 (d, J=3.3 Hz, 1H), 3.40 (s, 2H); ESMS(+): 308 (M+H, 100);
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:27]=[CH:26][C:11]2[NH:12][C:13]([CH:15]3[CH2:18][N:17]([C:19]4[CH:24]=[CH:23][N:22]=[C:21](Cl)[N:20]=4)[CH2:16]3)=[N:14][C:10]=2[CH:9]=1.C(OC(N1CC(C(O)=O)C1)=O)(C)(C)C.C(OCC)(=O)C>CC(N(C)C)=O.O>[Cl:7][C:8]1[CH:27]=[CH:26][C:11]2[NH:12][C:13]([CH:15]3[CH2:16][N:17]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[N:20]=4)[CH2:18]3)=[N:14][C:10]=2[CH:9]=1
Reactant: C1COCCN1
Reactant: Clc1ccc2[nH]c(C3CN(c4ccnc(Cl)n4)C3)nc2c1
Agent: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Clc1ccc2[nH]c(C3CN(c4ccnc(N5CCOCC5)n4)C3)nc2c1
Temperature: 75 °C
Yield: 84 %

Procedure:
A mixture of morpholine (0.19 mL, 2.19 mmol) and 5-chloro-2-(1-(2-chloropyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole, as prepared according to Example 1a, but using 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid in place of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester, (0.069 g, 0.22 mmol) in DMA (1 mL) under argon was heated to 75° C. for 5 h, then cooled to RT. Ethyl acetate and water were added, the resulting layers were separated, and the organic layer was washed with water (2×), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography to give 4-(4-(3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-2-yl)morpholine (0.068 g, 0.18 mmol, 84% yield) as a white solid. [M+1] 371. IC50 (uM) 0.645.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=3)[CH:13]=2)=[CH:5][CH:4]=1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[OH:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=3)[CH:13]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cn2cc(-c3ccc(CO)o3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3ccc(CO)o3)ccc2n1
Yield: 95.9 %

Procedure:
400 mg of ethyl 6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 346 mg of 6-[5-(hydroxymethyl)furan-2-yl]imidazo[1,2-a]pyridine-2-carboxylic acid in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH:12][C:13]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[N:15]2[N:14]=1)(=[O:11])=[O:10].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>CN(C=O)C>[C:24]([N:12]([C:13]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[N:15]2[N:14]=1)[S:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:11])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)n2nc(NS(=O)(=O)c3c(Cl)cccc3Cl)nc2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N(c1nc2nc(C)cc(C)n2n1)S(=O)(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 37.1 %

Procedure:
A solution of 0.50 g (1.3 mmol) of 2,6-dichloro-N-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidin-2-yl)benzenesulfonamide, 2.12 ml (22.5 mmol) of acetic anhydride and 0.18 ml (1.3 mmol) of triethylamine in 4 ml of DMF was heated at 85° C. for 3 days. After cooling to room temperature, the product separated from solution and was collected by filtration and dried in vacuo to yield 0.20 g (39 percent) of the desired product as a solid, mp 219°-222° C. The product was characterized by IR and NMR spectroscopy.