Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:37][C:18]3=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:26]([O:28]C(C)(C)C)=O)[CH:22]=[C:17]3[C:16]=2[C:38](=[O:41])[NH:39][CH3:40])=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.Cl.[N:52]1[CH:57]=[CH:56][CH:55]=[N:54][C:53]=1[C:58]1([NH2:61])[CH2:60][CH2:59]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:37][C:18]3=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]([C:26](=[O:28])[NH:61][C:58]5([C:53]6[N:54]=[CH:55][CH:56]=[CH:57][N:52]=6)[CH2:60][CH2:59]5)[CH:33]=[CH:34][C:35]=4[CH3:36])[CH:22]=[C:17]3[C:16]=2[C:38]([NH:39][CH3:40])=[O:41])=[CH:11][CH:10]=1
Reactant: NC1(c2ncccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)OC(C)(C)C)ccc3C)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)NC4(c5ncccn5)CC4)ccc3C)cc12
Reaction time: 2 h
Yield: 61 %

Procedure:
TFA (544 μL, 7.06 mmol) was added to a stirring solution of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (65 mg, 0.141 mmol) in DCE (1.4 mL) at rt. It was allowed to stir for 2 hours then concentrated. The white solid was taken up in DMF (1.5 mL) and treated with DIEA (123 μL, 0.706 mmol), 1-(pyrimidin-2-yl)cyclopropanamine hydrochloride (29.1 mg, 0.169 mmol) followed by HATU (81 mg, 0.212 mmol) at rt. The reaction was allowed to stir for 1 hour and then was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/MeOH gradient, and concentrated to give the expected product 2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide (45 mg, 0.086 mmol, 61.1% yield) consistent by LCMS and NMR. 1H NMR (300 MHz, DMSO-d6) d ppm 9.19 (1H, s), 8.66 (2H, d, J=4.76 Hz), 8.45-8.57 (1H, m), 8.40 (1H, d, J=1.83 Hz), 8.10 (1H, d, J=1.83 Hz), 8.00-8.08 (2H, m), 7.85-7.94 (2H, m), 7.35-7.50 (3H, m), 7.26 (1H, t, J=4.76 Hz), 2.83 (3H, d, J=4.39 Hz), 2.31 (3H, s), 1.55-1.67 (2H, m), 1.27-1.39 (2H, m). LC-MS retention time: 1.75 min; m/z (MH'): 522. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:20])([CH3:19])[CH2:7][C:8](C(=O)C)=[C:9]2[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:21][CH2:22][CH2:23][CH3:24].[CH3:25][CH2:26][O:27][C:28]([CH:30](P(OCC)(OCC)=O)[F:31])=[O:29].[CH:40]([N-]C(C)C)(C)[CH3:41].[Li+]>C1COCC1>[F:31]/[C:30](=[C:40](/[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:19])([CH3:20])[CH2:7][CH:8]=[C:9]2[C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[O:21][CH2:22][CH2:23][CH3:24])\[CH3:41])/[C:28]([O:27][CH2:26][CH3:25])=[O:29]
Reactant: CCCOc1cc2c(cc1Br)C(C(C)(C)C)=C(C(C)=O)CC2(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure F-1, 1-(7-bromo-4,4-dimethyl-6-propoxy-1-tert-butyl-3,4-dihydronaphthalen-yl)ethanone (Compound A-39, 34 mg, 0.11 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.17 mL, 0.86 mmol) were reacted with lithium diisopropylamide (0.86 mmol) in THF (2 mL) to produce the title compound as a yellow oil after purification by flash column chromatography (silica gel, 97:3 hexane:ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:20])[N:10]=[N:9]1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:21]([NH:25][C:26]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:10]=[N:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:12]=2[CH3:13])[C:15](=[O:20])[CH2:16]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N=C=O
Reactant: Cc1c(N2CCNCC2=O)nnn1-c1ccccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(N2CCN(C(=O)NC(C)(C)C)CC2=O)nnn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, 4-[1-(2-chlorophenyl)-5-methyl-1H-[1,2,3]triazol-4-yl]-3-oxopiperazine prepared in 1) of Example 51 was dissolved in 1 ml of chloroform and 0.05 ml of tert-butyl isocyanate and 0.1 ml of triethylamine were added thereto followed by stirring at room temperature for 2 hours. After the solvent was evaporated in vacuo, the resulting residue was purified by a preparative thin-layer silica gel chromatography (chloroform:methanol=9:1) to give 5 mg of the title compound as a white solid.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.ClCCl.[CH:11](Cl)(Cl)Cl.[CH2:15]1[CH2:19]OC[CH2:16]1>>[CH:6]([N:3]([CH:15]([CH3:19])[CH3:16])[CH2:4][CH3:5])([CH3:7])[CH3:11]
Reactant: C1CCOC1
Reactant: ClC(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C

Procedure:
in the presence of an organic base such as triethylamine or diisopropylethylamine, and an inert organic solvent such as dichloromethane, chloroform or THF, under an inert atmosphere such as argon at a reduced temperature of from about -20° to about 15° C., to form the sulfonamide I of the invention.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:23]1([N:9]([CH:6]2[CH2:7][CH2:8][N:3]([C:1](=[NH:2])[NH:27][OH:28])[CH2:4][CH2:5]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide (200 mg), hydroxylamine hydrochloride (70 mg), and potassium carbonate (82 mg) in ethanol (0.70 mL) and water (1.00 mL) is heated under reflux for 5 h. The reaction mixture is cooled to room temperature, stirred at this temperature for two days and concentrated in vacuo. The residue is mixed with water and ethyl acetate and the organic phase is separated, dried and concentrated in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA). LC (method 3): tR=1.35 min; Mass spectrum (ESI+): m/z=370 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2.C1(=O)[NH:24]C(=O)C2=CC=CC=C12>CCOCC>[NH2:24][C:1](=[O:5])[C:2]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Solvent: CCOCC
Product: NC(=O)C(=O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 24 °C
Reaction time: 48 h

Procedure:
Oxalyl chloride (4.4 mmol) is added dropwise to a suspension of 2-methyl-5-nitroindole (1.4 mmol) and phthalimide (0.1 g) in ether (10 mL) and the mixture stirred 48 h at 24° C. The reaction vessel is then equipped with a Dewar condenser, chilled to 0° C., and anhydrous ammonia bubbled through the mixture during 1.5 h. The gas and solvent are removed in vacuo. The resulting tan solid is triturated with water, filtered, and the retentate washed with toluene. The solid is dried, affording (2-amino)-1-(5-nitro-1H-indol-3-yl)-ethane-1,2-dione. A portion of this compound (0.59 mmol is taken into THF (15 mL) and treated with borane-THF (2.4 mL of 1 M solution) 16 h at 28° C. The reaction is neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is dried in vacuo, redissolved in ethanol (10 mL) and refluxed in the presence of cesium fluoride (360 mg) and sodium carbonate (312 mg). The mixture is filtered through Celite, evaporated and the residue chromatographed on silica gel using chloroform-methanol-ammonia (8:2:0.2) as eluent affording 2-(2-methyl-5-nitro-1H-indol-3-yl)-ethylamine. This compound is acetylated, hydrogenated and transformed to the carbamic acid methyl ester as above.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH3:9]>CO>[CH2:1]([NH:6][C:7]([NH2:9])=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN=C=S
Reactant: N
Solvent: CO
Product: CCCCCNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Pentylisothiocyanate (10 g, 0.08 mol) was added slowly (about 10 mins) to a mixture of ammonia (50 mL, 0.2 mol) in methanol (7 N) at 0° C. After being stirred at room temperature for 1 h, the solvent was stripped off and the product was obtained as a white solid (10 g, 88.4%), which was used for next step without further purification. LCMS calculated for C6H15N2S: (M+H) 147.1. found 147.1.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].BrCC#N>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH2:2][C:3]#[N:5])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 3 h
Yield: 125.2 %

Procedure:
LDA (2M solution in THF/heptane/ethylbenzene, 97.15 ml, 0.194 mol) was added under an argon atmosphere to THF (300 ml) at −5° C., piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (25 g, 0.097 mol) in THF (100 ml) was then added dropwise and the mixture was stirred for 3 hour at −5° C. Then bromoacetonitrile (23.3 g, 0.194 mol) was added at −5° C. and the mixture was stirred overnight at RT. The solvent was evaporated off, the residue partitioned between AcOEt and water. The layers were separated, the organic layer was washed with brine, dried over sodium sulphate and then concentrated to give 4-cyanomethyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (36 g) as a dark brown oil which was essentially pure and used in the next step without further purification. MS (ESI): 197.3 [(M-Boc)H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[CH:17]=2)(=[O:24])=[O:23])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1

Procedure:
Starting from compound D1 and 3-bromo-benzenesulfonyl chloride the title compound can be obtained analogously as described for compound D4.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([NH:13][CH2:14][C:15]#[N:16])[CH2:7]2.[CH:17](OCCCC)=[O:18]>>[C:15]([CH2:14][N:13]([C@H:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[CH2:7]1)[CH:17]=[O:18])#[N:16]
Reactant: N#CCN[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: CCCCOC=O
Product: N#CCN(C=O)[C@H]1CCc2c(F)cc(F)cc2C1
Reaction time: 19 h

Procedure:
A solution of the (S)-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamino) acetonitrile in butyl formate (8.7 M, 240 mL, 2.10 mol) was heated to reflux and stirred under nitrogen for 19 hours. The solvents were removed under reduced pressure, toluene was added and then evaporated. Drying gave (S)-N-(cyanomethyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)formamide as an oily residue (53.2 g). A stirring mixture of the formamide (53.2 g) and ethyl formate (12.4M, 48.7 mL, 0.604 mol) in 0.925 L of anhydrous THF was cooled to -15° C. A solution of potassium tert-butoxide in THF (1.0 M, 302 mL, 0.302 mol) was added over 20 minutes and the mixture was stirred for 18 hours. Evaporation of the solvent gave potassium (S)-N-(1-cyano-2-oxyvinyl)-N-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)formamide as a residue.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C[Si](N[Si](C)(C)C)(C)C>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:6]2[CH:7]=[N:8][C:9]3[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]2=3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Nc1nc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
Guanine 5 (1.51 g, 9.99 mmol) and (NH4)2SO4 (100 mg) were suspended in HMDS (150 mL) and refluxed for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in CH3CN (150 mL). Triphenylmethyl chloride (2.79 g, 10.0 mmol) was added and the reaction mixture was stirred at 25° C. for 7.0 h. The solution was concentrated under reduced pressure and the residue was purified by use of column chromatography (hexanes/EtOAc=1.5:8.5) to afford 6 (3.54 g, 8.99 mmol) in 90% yield: mp 268-270° C.; Rf(hexanes/EtOAc=1:2) 0.34; UV (EtOH) λmax 254 (ε 13,870), 278 (sh); 1H NMR (DMSO-d6) δ 5.97 (s, 2 H, NH2), 7.09-7.39 (m, 16 H, HC8+C(C6H5)3), 10.45 (br s, 1H, NH); MS m/z 393 (M+). Anal. (C24H19N5O) C, H, N; calcd (%): 73.26, 4.87, 17.80; found (%): 73.20, 4.81, 17.78.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[C:13]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:13][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4]1
Reactant: [BH3-]C#N
Reactant: OCCCC1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(CCCO)CC1
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
Formalin (6.33 g, 211 mmol) is added to a stirred solution of 3-(piperidin-4-yl)-propan-1-ol (3.02 g, 21.1 mmol) in acetonitrile (30 mL) at ambient temperature. The solution is allowed to stir for 20 minutes. Sodium cyanoborohydride (3.31 g, 52.7 mmol) and acetic acid (3 mL) are sequentially added to the reaction mixture and the resultant mixture is stirred for another 2 hours. After concentration, the crude product is dissolved in dichloromethane (150 mL), washed with saturated aqueous NaHCO3 (60 mL×2), dried and concentrated. The crude product is subjected to chromatography on silica gel and eluted with 2 M NH3/CH3OH in dichloromethane 0-15% to give the title compound as an oil (2.70 g).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH2:2][CH3:3].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](O)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)([O:6][CH2:5][CH:4]([CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH3:3])(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC(CO)CCC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(CCC)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 19 h
Yield: 96.9 %

Procedure:
To a mixture of 52 g 2-propylpentanol and 86 g of p-toluenesulfonic acid in 175 ml of chloroform was added at 0°-3° C. and under N2 -atmosphere 48 g of pyridine. The mixture was kept at 0° C. for 30 minutes and at room temperature for 19 hrs. After cooling the reaction mixture, 3M HCl (300 ml) was added. The organic phase was separated and washed with water and brine. Drying with Na2SO4 and evaporation gives 110 g of 2-propylpentyl tosylate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:17](N)=[NH:18]>C(O)C>[F:12][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[F:11])[N:1]=[CH:17][NH:18][C:4]2=[O:5]
Reactant: N=CN
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2cc(F)c(F)cc12
Yield: 86 %

Procedure:
38.0 g (0.213 mol) of 2-amino-4,5-difluorobenzoic acid and 44.0 g (0.423 mol) of formamidine acetate were suspended in 300 ml of ethanol. The reaction mixture was subsequently stirred under reflux for 16 h. Conventional work-up gave 33.37 g (Y=84%) of 6,7-difluoro-3H-quinazolin-4-one.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=[O:6].[CH2:12]([S:14][C:15]1[C:16]([C:20]2[N:32]([CH3:33])[C:23]3=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:22]3[N:21]=2)=[CH:17][S:18][CH:19]=1)[CH3:13].C(=O)(O)[O-].[Na+].[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([S:14]([C:15]1[C:16]([C:20]2[N:32]([CH3:33])[C:23]3=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]3[N:21]=2)=[CH:17][S:18][CH:19]=1)=[O:6])[CH3:13].[CH2:2]([S:39]([C:15]1[C:16]([C:20]2[N:32]([CH3:33])[C:23]3=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=[C:22]3[N:21]=2)=[CH:17][S:18][CH:19]=1)(=[O:43])=[O:41])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cscc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cscc1-c1nc2cc(C(F)(F)F)cnc2n1C
Product: CCS(=O)c1cscc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.02 g of 3-chloroperoxybenzoic acid (69 to 75%) was added to a mixture of 1.01 g of 2-(4-ethylthiothiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 10 ml of chloroform, under ice cooling, then the mixture was heated to room temperature and stirred for 3 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.51 g of 2-(4-ethylsulfinylthiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (19)) and 0.52 g of 2-(4-ethylsulfonylthiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (20)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
To 1-[2-(methyloxy)phenyl]piperazine (11.0 g, 50.7 mmol) was added concentrated H2SO4 (60 mL) dropwise to and stirred for 4 h at 0° C. KNO3 (7.2 g, 71.2 mmol) was then added and the mixture stirred overnight while allowing to warm to rt. Reaction was then quenched with ice and then 2N NaOH (100 mL) added and extracted three times with EtOAc. Combined organic phases were dried over MgSO4 and loaded directly onto silica gel. Purified by silica gel chromatography in 0-20% MeOH/NH4OH in EtOAc. Yield 5.7 g, 42% yield, of an orange solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.8 (m, 4H) 2.9 (m, 4H) 3.1 (m, 1H) 3.9 (s, 3H) 7.1 (d, J=9.1 Hz, 1H) 7.6 (d, J=2.7 Hz, 1H) 7.9 (dd, J=9.0, 2.7 Hz, 1H).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][C:26]2[C:34]3[O:33][CH:32]=[CH:31][C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClCCl>[ClH:1].[O:33]1[C:34]2[C:26]([O:25][CH:23]3[CH2:24][NH:21][CH2:22]3)=[CH:27][CH:28]=[CH:29][C:30]=2[CH:31]=[CH:32]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: c1ccc(C(c2ccccc2)N2CC(Oc3cccc4ccoc34)C2)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cl
Product: c1cc(OC2CNC2)c2occc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
1-Chloroethyl chloroformate (107 μL, 0.99 mmol) was added to a solution of 1-benzhydryl-3-(benzofuran-7-yloxy)-azetidine (349 mg, 0.98 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture was stirred for 4 hours at room temperature. Ethanol (10 mL) was added and the reaction mixture was stirred for an additional 2 hours at room temperature and 3 hours at 40° C. After concentration to dryness, the residue was taken in a mixture dichloromethane/diethyl ether to afford the title compound as a white solid (193 mg, 87%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[C:25]([O:36][CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=[CH:28][CH:29]=1.[C:38](=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[C:25]([O:36][CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:38])=[O:33])[CH:27]=[CH:28][CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COC(=O)CCc1cccc(O)c1OC
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1OC
Yield: 94.7 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (300 mg) in acetonitrile (10 mL) were added methyl 3-(3-hydroxy-2-methoxyphenyl)propanoate (210 mg) and cesium carbonate (512 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg) as a colorless oil.
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)[CH3:3].S(Cl)([Cl:13])=O>C(Cl)Cl>[ClH:13].[Cl:13][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C(C)O)n1
Solvent: ClCCl
Product: Cc1cccc(C(C)Cl)n1
Product: Cl
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To the crude 2-(1-hydroxyethyl)-6-methylpyridine (1.6 g, 11.7 mmol) in dry DCM (1 5 mL) add with stirring thionyl chloride (2.0 mL, 27 mmol) and continue stirring overnight. Concentrate in vacuo, azeotrope three times with dry chloroform and dry under high vacuum to provide the title compound as a tan solid (1.9 g, 85%). MS (APCI+) m/z 156 (M+H)+.