Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([C:24]([NH:26][CH3:27])=[O:25])=[N:11][C:12]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=3)=[CH:13][CH:14]=2)[C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][N:3]=1.[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=1[O:48][CH3:49].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[OH:23][CH2:22][CH2:21][CH2:20][N:18]1[CH:19]=[C:15]([C:12]2[N:11]=[C:10]([C:24](=[O:25])[NH:26][CH3:27])[C:9]([NH:8][C:6]3[C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][N:3]=[C:2]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[CH:7]=3)=[CH:14][CH:13]=2)[CH:16]=[N:17]1
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1Nc1cc(Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2cc(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)c(C(F)(F)F)cn2)c(OC)c1)OCC
Yield: 11.2 %

Procedure:
A solution of 3-{[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino}-6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 36C, 158 mg, 0.35 mmol) and diethyl (4-amino-3-methoxybenzyl)phosphonate (Compound 1F, 104 mg, 0.38 mmol) in 1,4-dioxane (4.0 mL) was treated with Pd(II)(OAc)2 (3.90 mg, 0.017 mmol), Xantphos (20.1 mg, 0.035 mmol) and Cs2CO3 (226 mg, 0.70 mmol). The mixture was purged with N2 for 2 minutes, sealed and irradiated in a microwave reactor for 40 minutes at 120° C. The cooled reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to a brown residue which was taken purified using a Teledyne ISCO Combiflash® system (0%-5%-10% MeOH/DCM) to afford 27 mg of a brown foam (11%). 1H NMR (400 MHz, CDCl3) δ 10.91 (s, 1H), 8.38 (s, 1H), 8.23 (q, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.86-6.94 (m, 3H), 6.70 (s, 1H), 4.38 (t, J=6.3 Hz, 2H), 3.93-4.05 (m, 4H), 3.88 (s, 3H), 3.66 (q, J=5.5 Hz, 2H), 3.12 (d, J=21.2 Hz, 2H), 3.06 (d, J=5.1 Hz, 3H), 2.79 (t, J=5.2 Hz, 1H), 2.13 (quin, J=6.1 Hz, 2H), 1.21 (t, J=7.0 Hz, 6H).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Br:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[Br:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (10.02 g, 25.75 mol) in methanol (100 mL) and water (100 mL) was treated with lithium hydroxide (15.4 g, 515 mmol). The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1×400 mL). The organic layer was washed with water (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (9.58 g, 99%) as a white solid which was used without further purification: mp 149-150° C.; FAB-HRMS m/e calcd for C15H19BrO4S (M+H)+ 375.0266, found 375.0274.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]4[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.Cl.C1(CC(O)=[O:41])C2C(=CC=CC=2)CC=1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:14]([C:17](=[O:41])[CH2:18][CH2:19][CH:20]4[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:21]4)[CH2:15][CH2:16]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CC(CCCN1CCN(c3cccc4c3OCCO4)CC1)C2
Reactant: O=C(O)CC1=CCc2ccccc21
Agent: Cl
Product: O=C(CCC1Cc2ccccc2C1)N1CCN(c2cccc3c2OCCO3)CC1
Yield: 50 %

Procedure:
4-(benzodioxan-5-yl)-1-[3-(indan-2-yl)-propyl]piperazine and its hydrochloride, m.p. (K): 210° C., by reduction of 4-(benzodioxan-5-yl)-1-[3-(indan-2-yl)propionyl]-piperazine (yield: 50%), which was itself prepared in a yield of 86% from 3-(indan-2-yl)-propionic acid, m.p. (K): 75°-78° C., and N-(benzodioxan-5-yl)piperazine.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>C(N(CC)CC)C>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[C:15]3[C:10](=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:12]=[CH:13][CH:14]=3)[N:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=1)=[O:37]
Reactant: Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1ccccc1F
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1F

Procedure:
The title compound was prepared from {3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-fluorophenyl isocyanate in substantially the same manner as described in Example 61 with one change: no triethylamine was used; off-white solid:
Reaction SMILES: Br[CH:2]([C:6]1[C:7]([Cl:13])=[N:8][C:9]([Cl:12])=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:12][C:9]1[N:8]=[C:7]([Cl:13])[C:6]([CH:2]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:3]([CH3:5])[CH3:4])=[CH:11][N:10]=1
Reactant: CC(C)C(Br)c1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(NC(c2cnc(Cl)nc2Cl)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-5-(1-Bromo-2-methyl-propyl)-2,4-dichloro-pyrimidine (88.7 mg; 0.312 mmol) (from Example 11b supra) was combined with potassium carbonate (47.4 mg; 0.34 mmol), potassium iodide (14.9 mg; 0.09 mmol) and p-anisidine (38.7 mg; 0.31 mmol) (Aldrich) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and then brine. The organic phase with dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash chromatography (Biotage 12M; 10:90 to 30:70 ethyl acetate-hexanes gradient) gave (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-2-methyl-propyl]-(4-methoxy-phenyl)-amine. (Yield 17.6 mg; 17.3%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:16][CH2:17][CH2:18][OH:19]>C(Cl)Cl>[OH:19][CH2:18][CH2:17][CH2:16][S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Sc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
In 250 ml of methylene chloride was dissolved 22.2 g (200 mmol) of 4-mercaptopyridine and 27.9 ml (200 mmol) of triethylamine. Thereto was added 18.1 g (200 mmol) of 3-bromo-1-propanol. The mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with a 1N aqueous solution of sodium hydroxide and water and dried. Then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 21.3 g of the desired compound (yield: 62.9%, yellow oil).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:14]([OH:20])([C:16]([F:19])([F:18])[F:17])=[O:15]>O=[Pt]=O.O>[C:14]([OH:20])([C:16]([F:19])([F:18])[F:17])=[O:15].[NH2:1][C@@H:2]([CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH2:12]1)[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(C[C@H](N)C(=O)O)cc1
Agent: O=[Pt]=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1CCC(C[C@H](N)C(=O)O)CC1
Reaction time: 48 h

Procedure:
A 250 mL Parr shaker vessel was charged with 1.0 g (5.6 mmol) of (S)-2-amino-3-p-tolylpropanoic acid, 63 mg (0.28 mmol, 5 mol %) of PtO2, and 10 mL of 1:1 TFA:water. The vessel was placed in a Parr hydrogenation shaker, pressurized to 50 psi, and shaken for 2 d. Analysis of the mixture by LC/MS indicated a ca 1:1 mixture of cis:trans isomers. The contents were filtered through a pad of Celite and the spent catalyst washed with additional water. The clear filtrate was evaporated to afford crude TFA salt of (S)-2-amino-3-(4-methylcyclohexyl)propanoic acid which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:20])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[N:6][CH:7]=1.CI.[CH3:23][Si](C)(C)[N-][Si](C)(C)C.[K+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([CH3:23])([CH3:20])[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(Oc1ccc(F)cn1)C(=O)OCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(F)cn1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of benzyl 2-(5-fluoro-2-pyridyloxy)propionate (2.9 g, 10 mmol) and methyl iodide (3.3 mL, 53 mmol) in 40 mL of anhydrous THF at −78° C. was added potassium hexamethyldisilazide (0.5 M in toluene, 32 mL, 16 mmol). The reaction was allowed to warm to room temperature over 3 h and was partitioned between saturated ammonium chloride (150 mL) and EtOAc (150 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 0 to 20% EtOAc in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.63 (d, 1H), 7.44 (ddd, 1H), 7.27 (m, 3H), 7.18 (m, 2H), 6.74 (dd, 1H), 5.09 (s, 2H) 1.64 (s, 6H). LC-MS: m/e 290 (M+H)+ (3.7 min).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([N:22]([CH:29]([CH3:31])[CH3:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:21])[C:15]2[CH:32]=[CH:33][CH:34]=[CH:35][C:14]=2[C:13]([CH3:36])=[N:12]1>C(Cl)Cl>[CH:29]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:21])[CH2:19][N:16]1[C:15]2[CH:32]=[CH:33][CH:34]=[CH:35][C:14]=2[C:13]([CH3:36])=[N:12][CH:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[C:17]1=[O:18])([CH3:31])[CH3:30]
Reactant: CC1=NC(N)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CC1=NC(NC(=O)Nc2ccccc2)C(=O)N(CC(=O)N(c2ccccc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
According to Process A, phenyl isocyanate (0.065 mL, 0.602 mmol) is added to a solution of 2-(3-Amino-5-methyl-2-oxo-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (219 mg, 0.602 mmol), prepared as in Intermediate 24, under nitrogen in DCM (3 mL). The reaction mixture is stirred at ambient temperature overnight and then concentrated in vacuo. The residue is dissolved in ethyl acetate, washed twice with 1N HCl, dried over anhydrous magnesium sulfate, and then concentrated again to a residue. The crude product is purified by reversed-phase HPLC on a C-18 column with 60% acetonitrile in aqueous trifluoroacetic acid (0.1% v/v) over 30 min. at 100 mL/min. Fractions containing the product are combined, frozen and lyophilized to provide the title compound as a white lyophile (92 mg, 0.190 mmol). 1H NMR (300 MHz, CDCl3) δ=1.02-1.25 (m, 6H); 2.59 (s, 3H); 4.08 (d, J=16.9 Hz, 1H); 4.17 (d, J=16.9 Hz, 1H); 4.93-5.00 (m, 1H); 5.56 (d, J=6.3 Hz, 1H); 7.02-7.61 (m, 14H); MS(FAB): [M+H]+ =484.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38].[CH3:41]CN(C(C)C)C(C)C.CI>C(Cl)(Cl)Cl.[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][C:19]3[N:20]([CH3:41])[CH:21]=[C:22]([CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:37]([F:40])([F:38])[F:39]
Reactant: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)c2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: CI
Solvent: ClC(Cl)Cl
Product: Cn1cc(Cc2cn(C)c3ccccc23)c(=O)nc1SCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C#N)c1
Temperature: 60 °C
Yield: 13.5 %

Procedure:
To a solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-[({5-[(1-methyl-1H-indol-3-yl)methyl]-4-oxo-1,4-dihydro-2-pyrimidinyl}thio)methyl]benzonitrile (60 mg, 0.103 mmol), DIPEA (0.054 mL, 0.310 mmol) and zinc bromide (23.26 mg, 0.103 mmol) in chloroform (2 mL) was added MeI (0.013 mL, 0.207 mmol). The mixture was heated at 60° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (8.3 mg, 13.51% yield). LCMS: rt=3.78 min, [M+H+]=595
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]([OH:14])[C:12]([CH3:16])([CH3:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O.S(=O)(=O)(O)O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2=NOC(C)(C)C2O)cc1Br
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C2=NOC(C)(C)C2=O)cc1Br
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution 3-(3-bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazol-4-ol (1.80 g, 6.42 mmol) in glacial acetic acid (70 mL), chromium trioxide (640 mg, 6.42 mmol, 1.0 eq), water (4 mL) and concentrated sulfuric acid (0.8 mL) were successively added and the resulting mixture was stirred at 100° C. for 30 min. The reaction was cooled to room temperature and poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate in hexane) to afford the 800 mg of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.29 (d, J=1.0 Hz, 1H), 7.94 (dd, J=1.0, 8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 2.44 (s, 3H), 1.46 (s. 3H), 1.24 (s, 3H); ESI-MS (m/z) 282, 284 [(MH)+, Br79,81].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]1([CH:12]2[C:15]3([CH2:17][O:16]3)[O:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[OH:16][CH2:17][C:15]1([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][O:14]1
Reactant: c1c[nH]nn1
Reactant: c1ccc(C2COC23CO3)cc1
Solvent: ClCCl
Product: OCC1(n2nccn2)OCC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1H-1,2,3-triazole (0.043 g, 0.62 mmol) in dry CH2Cl2 (2 mL) was introduced to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.10 g, 0.62 mmol) in dry CH2Cl2 (2 mL) at −78° C. After 3 hours at −78° C., the reaction was allowed to warm to room temperature; then, the solvent was evaporated in vacuo. The resultant oil was purified by flash chromatography on silica gel (CH2Cl2/EtOAc 95:5). 2-Hydroxymethyl-3-phenyl-2-(1,2,3-triazol-2-yl)oxetane was isolated as a pale yellow solid (0.076 g, 59%): mp 77.0-78.3° C.; IR (CDCl3) 3145, 3031, 2969, 1496, 1452, 1323, 1049 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 2H), 7.41 (m, 2H), 7.35 (m, 3H), 5.41 (dd, J=8.2, 7.7 Hz, 1H), 5.08 (dd, J=8.5, 6.0 Hz, 1H), 4.98 (dd, J=7.0, 6.0 Hz, 1H), 4.15 (dd, J=13.0, 7.6 Hz, 1H), 4.10 (dd, J=13.0, 7.6 Hz, 1H), 2.51 (t, J=7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 135.3, 134.1, 128.8, 128.1, 128.0, 99.7, 68.5, 62.9, 47.9; MS (EI) m/z 200 (M+-CH2O), 185, 104 (100), 78; Anal. calculated for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C, 62.58; H, 5.30; N, 17.94.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([NH:14][C:15]([CH2:17][NH:18]C(=O)OC(C)(C)C)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[NH2:18][CH2:17][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 ml of dichloromethane and 20 ml of trifluoroacetic acid were added to 687 mg (2.74 mmol) of t-butyl phenylcarbamoylmethylcarbamate, and they were stirred at room temperature for 3 hours. Dichloromethane and trifluoroacetic acid were evaporated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue. After the extraction with ethyl acetate and then with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([CH:3]([CH:16]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17]1)[N:4]([CH3:15])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)#[N:2].[NH2:23][OH:24]>C(O)C>[NH2:2][C:1](=[N:23][OH:24])[CH:3]([N:4]([CH3:15])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:16]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17]1
Reactant: CN(C(=O)OCc1ccccc1)C(C#N)C1CCC(CO)C1
Reactant: NO
Solvent: CCO
Product: CN(C(=O)OCc1ccccc1)C(C(N)=NO)C1CCC(CO)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 101.6 %

Procedure:
To a solution of benzyl cyano(3-(hydroxymethyl)cyclopentyl)methyl(methyl)carbamate (0.540 g, 1.79 mmol) in ethanol (20 mL) was added 50% aqueous solution of hydroxylamine (0.07 mL, 2.15 mmol). The reaction mixture was stirred at 60° C. for 18 hours. The solvent was removed in vacuo to afford 0.610 g (76% yield) of title compound 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.43 (5 H, m), 7.14-7.23 (2 H, m), 5.18 (2 H, br s), 4.87-4.93 (1 H, m), 4.24 (1 H, m), 3.49-3.60 (2 H, m), 2.83-2.94 (3 H, br s), 2.60-2.71 (1 H, m), 2.11-2.49 (2 H, m), 1.60-2.11 (3 H, m), 1.25-1.55 (2 H, m). (+ESI, M+H+) 2 peaks m/z 336.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1([C:14]2([S:17][CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15]2)[CH2:13][O:12]1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:14]1([S:17][CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15]1)([OH:12])[CH2:13][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reactant: c1nc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSC1(C(O)(/C=C/c2ccc(Cl)cc2Cl)Cn2cncn2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
A solution of 38.2 g (0.12 mol) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl) oxirane in 30 ml of dimethylformamide is added dropwise under a nitrogen atmosphere and with stirring at 80° C. to a mixture of 24 g (0.35 mol) of 1,2,4-triazole, 2.7 g (0.02 mol) of potassium tert.-butoxide and 50 ml of dimethylformamide. The mixture is stirred at 80° C. for 6 hours, then the solvent is removed under reduced pressure, and the residue is taken up in ethyl acetate/toluene, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue which remains is chromatographed on silica gel using chloroform as the eluant. In this manner, 12.1 g (26% of theory) of trans-4-(2,4-dichlorophenyl)-2-(1-propylmercaptocyclopropyl)1-(1,2,4-triazol-1-yl)-but-3-en-2-ol are obtained in the form of an oily product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16][C:13]1([F:12])[CH2:15][CH2:14]1)=[O:6]
Reactant: NCC(CC1(F)CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(F)CC1)c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-(1-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=435.1, tR (minutes, Method G)=2.46
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][CH:16]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[NH2:17].C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:17][CH:16]([CH3:15])[CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[N:7]=1
Reactant: Clc1cc(N2CCCCC2)nc(Cl)n1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CC(Cc1c[nH]c2ccccc12)Nc1nc(Cl)cc(N2CCCCC2)n1
Temperature: 150 °C

Procedure:
A mixture of 2,4-dichloro-6-(1-piperidinyl)pyrimidine (80 mg, 0.34 mmol), α-methyltryptamine (59 mg, 0.34 mmol), and potassium carbonate (47 mg, 0.34 mmol) in chlorobenzene (1 mL) was heated at 150° C. in a sealed tube for 16 hours. The solvent was removed and the crude material was purified by preparative TLC, eluting with cyclohexane/ethyl acetate (4:1). 4-Chloro-N-[2-(1H-indol-3-yl)-1-methylethyl]-6-(1-piperidinyl)-2-pyrimidinamine (Rf=0.19) was obtained as a solid (64.5 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 8.29 (br s, 1H), 7.68 (br d, 1H, J=7.5), 7.32 (d, 1H, J=7.8), 7.16 (t, 1H, J=7.8), 7.12 (t, 1H, J=7.8), 6.95 (d, 1H, J=2.1), 5.87 (s, 1H), 4.89 (br d, 1H, J=8.1), 4.36 (sextet, 1H, J=6.6), 3.58-3.50 (m, 4H), 3.07 (dd, 1H, J=14.4, 5.1), 2.83 (dd, 1H, J=14.1, 7.2), 1.70-1.55 (m, 6H), 1.16 (d, 3H, J=6.6).
Reaction SMILES: OC(C(F)(F)F)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:26][CH:25]([NH2:27])[CH2:24]4)[CH2:19][CH:18]=3)=[CH:16][C:11]=2[O:10][CH2:9]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:26][CH:25]([NH:27][C:37]([CH2:36][NH:35][C:33](=[O:34])[C:32]5[CH:40]=[CH:41][CH:42]=[C:30]([C:29]([F:44])([F:28])[F:43])[CH:31]=5)=[O:38])[CH2:24]4)[CH2:19][CH:18]=3)=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1-(4-benzo[1,3]dioxol-5-yl-cyclohex-3-enyl)-azetidin-3-ylamine TFA salt (as prepared in the previous step, 550 mg, 1.10 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet, 272 mg, 1.10 mmol) in DCM (10 mL) was treated with TEA (770 μL, 5.5 mmol) at room temperature. The mixture was treated with EDCI (Aldrich, 252 mg, 1.32 mmol), HOBT (Aldrich 149 mg, 1.10 mmol), and the reaction was stirred at room temperature for additional 6 hours. The reaction was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.