Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:33]OS(C)(=O)=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:15]=2)[CH2:10][CH2:9]1.[CH3:39][NH:40][CH3:41]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:33][N:40]([CH3:41])[CH3:39])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(COS(C)(=O)=O)cc3Cl)CC2)n1
Reactant: CNC
Product: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(CN(C)C)cc3Cl)CC2)n1

Procedure:
Heat a mixture of methanesulfonic acid 5-chloro-6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyridin-3-ylmethyl ester with an excess of dimethylamine (1M in THF) in a sealed tube at 80° C. for 2 h. Concentrate under reduced pressure then partition between EtOAc and 10% NaOH solution. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the resulting residue using flash chromatography (10:90:1/MeOH:DCM:NH4OH eluent) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=O)[CH2:8]2.Cl.[NH2:17][OH:18]>C(O)C>[F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=[N:17][OH:18])[CH2:8]2
Reactant: O=C1CC2CCCC(C1)N2CC(F)(F)F
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=C1CC2CCCC(C1)N2CC(F)(F)F

Procedure:
A mixture of 9-(2,2,2-trifluoro-ethyl)-9-aza-bicyclo[3.3.1]nonan-3-one (CAS no: 209054-63-7) (6.70 g, 30 mmol) in ethanol (100 mL) and hydroxylamine hydrochloride (2.23 g, 32 mmol) was refluxed for 6 h. The reaction mixture was evaporated totally, the residue extracted with dichloromethane and sodium carbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a light brown solid. (6.4 g, 89%); MS: m/e=237.1 (M+H+).
Reaction SMILES: COC1C=CC(C[N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][C:20]4[N:24]5[N:25]=[C:26]([C:29]6[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=6)[CH:27]=[CH:28][C:23]5=[N:22][N:21]=4)[CH:15]=3)[N:10]=[CH:9]2)=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]3[N:24]([C:20]([CH2:19][C:14]4[CH:15]=[C:16]5[C:11](=[CH:12][CH:13]=4)[N:10]=[CH:9][NH:8][C:17]5=[O:18])=[N:21][N:22]=3)[N:25]=2)[CH:30]=1
Reactant: COc1ccc(Cn2cnc3ccc(Cc4nnc5ccc(-c6cccnc6)nn45)cc3c2=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]cnc2ccc(Cc3nnc4ccc(-c5cccnc5)nn34)cc12
Temperature: 90 °C
Yield: 34.8 %

Procedure:
3-(4-Methoxy-benzyl)-6-(6-pyridin-3-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3H quinazolin-4-one (0.010 mg, 0.021 mmol) was treated with trifluoroacetic acid (1 mL) and anisole (0.1 mL) and heated to 90° C. for 18 hours. The compound was purified via reverse phase HPLC on a C18 column eluting with acetonitrile in water (0.1% TFA) to give 0.0026 g (35%) of 6-(6-pyridin-3-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3H-quinazolin-4-one. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (m, 1H), 8.79 (m, 1H), 8.53 (m, 2H), 8.20 (m, 1H), 8.10 (s, 1H), 8.03 (d, 1H, J=10.0 Hz), 7.89 (d, 1H, J=8.4 Hz), 7.66 (m, 2H), 4.80 (s, 2H). Mass spectrum (LCMS, ESI pos.): Calcd for C19H13N7O; found: 356.3, 357.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:28][CH:30]3[O:32][CH2:31]3)=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: ClCC1CO1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(C(c2ccc(OCC3CO3)c(C)c2)c2cccc3ccccc23)cc1
Temperature: 120 °C

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxyphenyl)-1-naphth-1-yl methane (1.0 gm, 0.002 mol), epichlorohydrin (25 ml) and anhydrous K2CO3 (4.0 gm) was refluxed at 120° C. for 8 hrs. K2CO3 was filtered off and filtrate was concentrated. The residue obtained was dissolved in ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel using hexane-chloroform as the eluent to give the title compound of general formula I, yield 75 gm (66%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH2:16](I)[CH:17]=[CH2:18].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[N:7]2[CH2:18][CH:17]=[CH2:16]
Reactant: C=CCI
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)ccc2c(F)cc(F)cc21
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A suspension of 5,7-difluoro-2(1H)-quinolinone (640 mg, 3.54 mmol) in DMF (15 ml) under argon at 0° C. was treated with sodium hydride (60% in mineral oil, 312 mg, 7.8 mmol) and then it was warmed up at rt. After 0.5 h at rt allyl iodide (0.72 mL, 7.8 mmol) was added. After 0.5 h sodium hydride (60% in mineral oil, 200 mg, 5 mmol) and allyl iodide (0.35 ml, 3.8 mmol) were added. Water (15 ml) was added and the aqueous was extracted using DCM (3×50 ml). The combined organic phases were dried, evaporated and the residue was chromatographed on silica gel, eluting with 0-4% MeOH-DCM to afford 350 mg of the desired compound (45%).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.[F:26][C:27](S(=O)(=O)C1C=CC=CC=1)=[CH2:28]>C1(C)C=CC=CC=1.ClCCl>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:28]=[C:27]([F:26])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: C=C(F)S(=O)(=O)c1ccccc1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1O[C@@H](Cn2cc(F)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.6 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)-oxazolidin-2-one (Reference Example 2) (0.7 g, 1.9 mmol) and (1-fluoroethenyl)-phenylsulfane dioxide (0.7 g, 3.8 mmol) (D. P. Mathews and J. R. McCarthy, JOC 55 (9), 1990, p 2973) were suspended/dissolved in toluene (5 ml) and heated to reflux under stirring for 2 days. The reaction mixture was cooled to room temperature, diluted with dichloromethane, washed with phosphate buffer (pH 7) and dried over sodium sulfate. Chromatography on silica gel with hexanes/acetone (1:1) gave 28 mg (4%) of the title compound as a colourless solid (Rf ˜0.25, TLC:hexanes/acetone, 1:1). The major product was the corresponding 5-fluoro-1,2,3-triazoyl compound with an Rf of ˜0.2.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][NH:3]1.FC(F)(F)C(O)=O.ClC1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[S:37][C:38]([C:41]#[N:42])=[CH:39][N:40]=2)[CH:30]=1.C(N(CC)CC)C>>[O:1]=[C:2]1[CH:7]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]4[S:37][C:38]([C:41]#[N:42])=[CH:39][N:40]=4)[CH:30]=3)[CH2:12][CH2:13]2)[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCCNC2=O)CC1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1cnc(Nc2cc(N3CCN(C4CCCNC4=O)CC3)ncn2)s1
Temperature: 150 °C

Procedure:
51-2 (0.15 g, 0.53 mmol) was first treated with neat trifluoroacetic acid for 30 minutes at room temperature. The trifluoroacetic acid was then evaporated off and the residue was dissolved in n-butanol (3 mL). To this was added 35-1 (0.13 g, 0.53 mmol) and triethylamine (0.27 g, 2.65 mmol). This was heated at 150° C. for 18 hours and then the solid was filtered off, washed with n-butanol and then ethyl ether to afford 51-3. Hi-Res MS: calc: 385.1554 found: 385.1551. 1H-NMR (DMSO-d6): 12.02 (s, 1H); 8.41 (s, 1H); 8.25 (s, 1H); 7.44 (s, 1H); 6.20 (s, 1H); 3.51 (br s, 4H); 3.13 (m, 1H); 3.05 (m, 2H); 2.93 (m, 2H); 2.63 (m, 2H); 1.62–1.83 (complex, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.NC1C=CC(OC2C=CN=C3C=C([C:70]([N:72]4[CH2:76][CH2:75][C@@H:74]([N:77]([CH3:79])[CH3:78])[CH2:73]4)=[O:71])SC=23)=C(F)C=1>>[CH3:78][N:77]([CH3:79])[C@@H:74]1[CH2:75][CH2:76][N:72]([C:70]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:22])=[CH:3][C:2]=3[F:1])[CH:15]=2)=[O:71])[CH2:73]1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Agent: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)C1
Yield: 38 %

Procedure:
Following the procedure described above for the compound 5a (step 5, example 1) but replacing the amine 9 with the compound 26, title compound 5 g was obtained in 38% yield. MS (m/z): 562.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1
Reactant: CCCCCI
Reactant: OCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In DMF (166 ml) was dissolved 2-(4-bromophenoxy)-1-ethanol (19.5 g). To the mixture was added under ice-cooling 65% sodium hydride (5.3 g), and the mixture was stirred at room temperature for 1.5 hours. To the mixture was added dropwise iodopentane (17.7 ml), and the mixture was stirred for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-4-(2-pentyloxyethoxy)benzene (12.0 g).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@H]1OC[C@H](O)CC1)(C1C=CC=CC=1)C1C=CC=CC=1>CCCCC>[CH:1]([C@@H:14]1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Agent: O[C@@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Solvent: CCCCC
Product: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 68.6 %

Procedure:
(1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane (0.05 g, 0.19 mmol) was treated with LiAlH4 (0.036 g, 0.94 mmol) (Procedure I) in dry pentane to yield trans-(3S,6R)-6-benzhydryl-tetrahydro-pyran-3-ol 33b 0.035 g (70%, [α]D=(+)61.7, c=1, MeOH).
Reaction SMILES: [CH2:1]([O:3]C(C1C=CC=CC=1)C=O)C.[CH2:13]([O:20][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:22]=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:1][OH:3])[CH2:22][OH:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=CC(OCc1ccccc1)c1ccccc1
Reactant: CCOC(C=O)c1ccccc1
Product: OCC(CO)(OCc1ccccc1)c1ccccc1

Procedure:
The procedure in Example 6 was repeated except that 2-ethoxy-2-phenylethanal was replaced with 2-benzyloxy-2-phenylethanal, to obtain 2-benzyloxy-2-phenyl-1,3-propanediol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH2:25][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C(C)(Sc1cc2ccccc2[nH]1)c1ccccc1
Product: CCOC(=O)Cn1c(SC(C)(C(=O)OCC)c2ccccc2)cc2ccccc21
Yield: 63 %

Procedure:
Starting from ethyl 2-(1H-indol-2-yl)thio-2-phenylpropionate and ethyl bromoacetate, the title compound was obtained as a pale yellow oily matter (yield: 63 %) according to the method of Example 92.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH2:20])=[NH:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:9])[F:8].CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1)=O.[OH-].[Na+]>CC(O)C>[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:20]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:25]=[CH:24][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:8])[F:9]
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: COc1cccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)c1
Temperature: 25 °C

Procedure:
21.28 g (84.7 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to a solution of 17.4 g (84.7 mmol) of 3-dimethylamino-1-(3-methoxy-phenyl)-2-propen-1-one in 100 ml of 2-propanol. After the addition of 3.72 g (93.2 mmol) of sodium hydroxide, the reaction mixture is boiled under reflux for 21.3 h. After cooling to RT, the product is isolated by filtration and washed with 1-propanol and water. After drying at 60° under HV, N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-methoxy-phenyl)-2-pyrimidineamine is obtained; Rf =0.7 (methylene chloride:methanol =9:1), FAB-MS: 397 (M+ +1), m.p. 103°-104°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.CSC.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][NH2:11])=[CH:6][CH:7]=1
Reactant: N#CCOc1ccc(Br)cc1
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: NCCOc1ccc(Br)cc1
Reaction time: 0.08 h

Procedure:
To a solution of [(4-bromophenyl)oxy]acetonitrile (3.07 g; 14.5 mmol; step 1 above) in anhyd THF (10 mL) at 0° C. was added BH3.DMS (18.1 mL of a 2M solution in THF; 36.2 mmol), dropwise over 5 min. The mixture was heated under reflux for 1.5 h, cooled, and 2M HCl (ca. 50 mL) was slowly added. The acidic mixture was extracted with Et2O (×2) and the extracts set aside. NaOH pellets were added to the aqueous residue until ca. pH 14, and the whole was extracted with Et2O (×3). Combined extracts of the basic mixture were washed (brine), dried over Na2SO4, and concentrated in vacuo, affording the first batch of title compound as a pale yellow liquid. The reserved Et2O extracts (from acidic mixture) were concentrated in vacuo, the residue was heated at near reflux in 15 wt % NaOH (aq) for 15 min, cooled, and extracted with CH2Cl2 (×3). Combined organics were washed (brine) and concentrated in vacuo. The residue was slurried in 4M HCl and insoluble material was removed by filtration. The filtrate was extracted with Et2O (×2), pH was adjusted to ca. pH 14 by addition of NaOH pellets and extracted with Et2O (×5). Combined extracts from the basic mixture were washed (brine), dried over Na2SO4, filtered and concentrated in vacuo, affording a second batch of the title compound, which was combined with the first batch. LC/MS (method D) 1.15 min, m/z 216 (M+H, 79Br), 218 (M+H, 81Br).
Reaction SMILES: Cl.[NH:2]([C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.N1(O)C2C=CC=CC=2N=N1.[NH:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:29].C(N(C(C)C)CC)C>CN(C=O)C>[NH:2]([C:9]1([C:14]([NH:29][NH:28][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCCC1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NNC(=O)C1(Nc2ccccc2)CCCC1

Procedure:
1-Anilinocyclopentanecarboxylic acid hydrochloride and N-[3-(dimethylaminopropyl)]-N′-ethylcarbodiimide hydrochloride, 1H-1,2,3-benzotriazol-1-ol hydrate, tert-butyl hydrazinecarboxylate, N,N-diethylisopropylamine were stirred in DMF at room temperature to obtain tert-butyl 2-[(1-anilinocyclopentyl)carbonyl]hydrazinecarboxylate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([CH2:8][N:1]2[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: OCC1CCNC1
Product: OCC1CCN(Cc2ccccc2)C1

Procedure:
In a manner similar to Preparation 7 react 3-pyrrolidinemethanol with benzaldehyde to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1.[BH4-].[Na+].C(Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:22][C:20]3[O:21][C:17]([CH3:16])=[CH:18][CH:19]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: Cc1ccc(C=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)o1
Temperature: -20 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (60 mg, 246 μmol) and 5-methylfuran-2-carbaldehyde (111.2 mg, 1.0 μmol) in MeOH (3 ml) was stirred at 45° C. for two days to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (55.8 mg, 1.47 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. Trituration with DCM afforded an off white solid as desired product (61.3 mg, 74% yield). MS +m/z: 338 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[N:13]=1.C(Cl)Cl>C(OCC)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[N:13][C:12]=2[CH:14]=1
Reactant: Nc1nc2cc(Cl)ccc2s1
Reactant: COC(=O)N=C=O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)NC(=O)Nc1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
One part by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution of 2 parts by weight of 2-amino-5-chlorobenzothiazole in 100 parts by weight of methylene chloride and 50 parts by weight of ethyl ether. After stirring the reaction mixture at room temperature overnight, a product was isolated by filtration giving an 85% yield of methyl 4-(5-chlorobenzothiazol-2-yl)allophanate having a melting point of 395°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[C:4]([N:21]([CH2:23][CH2:24][OH:25])[CH3:22])[N:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[CH:28]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCOCC1>[OH:25][CH2:24][CH2:23][N:21]([CH3:22])[C:4]1[CH:5]=[C:6]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH:9]=2)[CH:7]=[C:2]([NH:33][C:29]2[CH:28]=[C:27]([CH3:26])[CH:32]=[CH:31][N:30]=2)[N:3]=1
Reactant: CN(CCO)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(Cl)n1
Reactant: Cc1ccnc(N)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccnc(Nc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)CCO)n2)c1
Temperature: 120 °C
Yield: 51.2 %

Procedure:
To a mixture of tert-butyl 4-(2-chloro-6-(2-hydroxyethyl(methyl)amino)-4-pyridyl)-5,6-dihydro-2H-pyridine-1-carboxylate (220 mg, 0.60 mmol), 4-methylpyridin-2-amine (71.13 mg, 0.66 mmol), sodium tert-butoxide (86.2 mg, 0.90 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (34.9 mg, 0.075 mmol), and RuPhos palladium(II) phenethylamine chloride (43.6 mg, 0.06 mmol) in 1,4-dioxane (3.0 mL) was capped in a small CEM microwave vial, de-gassed with N2, and heated in microwave at 120° C. for 15 min. It was concentrated onto Celite, purified by column chromatography (ISCO), 12 g column, eluded with 0-5% MeOH/DCM to give 135 mg (51%) of the title compound as a yellow gum. LC-MS: m/z=440 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=S)[CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([NH:18][C:19]([NH2:27])=[N:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: FC(F)(F)CNC(=S)Nc1ccnc(CCCOCc2ccccc2)n1
Product: NC(=NCC(F)(F)F)Nc1ccnc(CCCOCc2ccccc2)n1

Procedure:
This thiourea was stirred for 18 hours with yellow mercuric oxide (10 g.) in methanolic ammonia (250 ml.). The mixture was filtered, the filtrate was evaporated to dryness and the residue was extracted with hot CH2Cl2. Evaporation of the CH2Cl2 solution gave 2-(3-benzyloxypropyl)-4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimidine (9.2 g.) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[OH:18])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:30][C:29]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:28]=2[F:27])=[C:4]([F:20])[CH:3]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(OCc2ccc(F)cc2F)c1
Temperature: 25 °C

Procedure:
To a solution of compound 2a (0.59 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmol) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.