Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([Br:25])=[CH:15][N:14]=2)=[O:12])([C:6](=[NH:9])[NH:7][OH:8])[CH3:5])[CH2:3][CH2:2]1.[CH2:26](N(CC)CC)[CH3:27].C(OC(=O)C)(=O)C>CN(C=O)C>[CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[C:16]([Br:25])=[CH:15][N:14]=2)=[O:12])([C:6]2[N:9]=[C:26]([CH3:27])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)(C(=N)NO)C1CC1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)C2CC2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(N-hydroxycarbamimidoyl)-ethyl]-amide (Example 78f, 800 mg, 1.88 mmol) in dry DMF (10 ml) was added triethylamine (190 mg, 262 μl, 1.88 mmol) followed by addition of acetic anhydride (192 mg, 1.88 mmol). The reaction mixture was stirred at room temperature for 1 hours and was then stirred at 125° C. for 30 min under microwave radiation. DMF was removed in vacuo and the residue was dissolved in ethylacetate which was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (492 mg, 47%) as a light yellow oil. MS (ESI, m/z): 449.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[C:28]([CH3:31])([CH3:30])[CH3:29].[CH3:32][N:33]1[C:38](C)([CH3:39])[CH2:37]C(O)[CH2:35][C:34]1([CH3:43])[CH3:42].[NH2-].[Li+].C(O)C>C1(C)C=C(C)C=C(C)C=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11]([O:13][CH:14]2[CH2:35][C:34]([CH3:43])([CH3:42])[N:33]([CH3:32])[C:38]([CH3:39])([CH3:37])[CH2:15]2)=[O:12])=[CH:4][C:3]=1[C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCO
Product: CN1C(C)(C)CC(OC(=O)CCC(C)(c2ccc(O)c(C(C)(C)C)c2)c2ccc(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 160 °C

Procedure:
42.7 g of ethyl 4,4-di-(4-hydroxy-3-t-butyl-phenyl)-valerate and 17.1 g of 1,2,2,6,6-pentamethyl-4-hydroxy-piperidine in 120 ml of mesitylene, with the addition of 100 mg of lithium amide as the catalyst, are heated to 160° C. in a nitrogen atmosphere for 5 hours, whilst stirring. During this time, the ethanol formed distils off in the stream of nitrogen and can be measured in a cold trap. After cooling, 100 ml of toluene are added to the batch and the solution is washed with water, dried with calcium chloride and evaporated in vacuo. The crystalline residue is recrystallised from acetonitrile or chlorobenzene. In this way 1,2,2,6,6-pentamethyl-piperidin-4-yl 4,4-di-(4-hydroxy-3-t-butyl-phenyl)-valerate (stabiliser no. 2) is obtained as a white crystalline powder with a melting point of 203° C.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:16][C@H:15]2[NH2:17])=[CH:10][CH:9]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1.O.[OH-].[Na+].O>CCO>[NH2:17][C@@H:15]1[CH2:16][C@H:14]1[C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: COCCOCOc1ccc([C@@H]2C[C@H]2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H]1C[C@H]1c1ccc(O)cc1

Procedure:
A solution of (trans)-2-(4-((2-methoxyethoxy)methoxy)phenyl)cyclopropanamine (Intermediate L, 62 mg, 0.26 mmol) and p-TsOH.H2O (60 mg, 0.31 mmol) in EtOH (5 mL) was heated at 75° C. for 2 h. The pH of the reaction was adjusted to 7 with NaOH (10% aqueous solution), the mixture was poured into water (10 mL) and extracted with EtOAc (4×10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent a brownish residue was obtained (44 mg, 4-((trans)-2-aminocyclopropyl)phenol contaminated with p-TsOH) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH3:38][O:39][C:40]([NH:42][CH:43]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:44](=[O:45])[CH:43]([NH:42][C:40]([O:39][CH3:38])=[O:41])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: COC(=O)NC(C(=O)O)C(C)(C)C
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of 1-{[4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester (600 mg, 1.115 mmol) in CH3CN (20 mL) was 2-methoxycarbonylamino-3,3-dimethyl-butyric acid (317 mg, 1.673 mmol), DIEA (0.97 mL, 5.575 mmol) and the coupling reagent HOBt (256 mg, 1.673 nunol) and HBTU (634 g, 1.673 mmol). The solution was stirred at rt. overnight. Then it was concentrated, washed with water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give yellowish oil. It was then purified by Prep. HPLC column to give a yellowish oil as product. (410 mg, 47% yield).1H NMR (400 MHz, CD3OD) δ1.03 (s, 9H), 1.22 (t, J=7.09 Hz, 3H), 1.41 (dd, J=9.41, 5.26 Hz, 1H), 1.71 (dd, J=8.19, 5.26 Hz, 1H), 2.17 (m, 1H), 2.50 (m, 1H), 2.77 (m, 1H), 3.33 (s, 3H), 4.03 (s, 3H), 4.04–4.14 (m, 3H), 4.18 (s, 1H), 4.61–4.69 (m, 2H), 4.86 (m, 1H), 5.08 (dd, J=10.27, 1.71 Hz, 1H), 5.25 (d, J=17.11 Hz, 1H), 5.72–5.82 (m, 2H), 7.39 (dd, J=9.29, 2.20 Hz, 1H), 7.51 (m, 1H), 7.63 (m, 1H), 7.69–7.77 (m, 3H), 8.06 (m, 2H), 8.35 (d, J=9.29 Hz, 1H), 8.75 (s, 1H). LC-MS (retention time: 2.857 min.), MS m/z 673 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:38])[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=4)[CH2:20][CH2:19]3)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:38])[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=4)[CH2:20][CH2:19]3)=[S:48])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(CN1CCN(c2ccc(Cl)cc2)CC1)C(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(CN1CCN(c2ccc(Cl)cc2)CC1)C(=S)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1

Procedure:
3-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-methyl-1-[4-(4-nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-propan-1-one (6 mg; 0.011 mmol, prepared in accordance with Example 61) is reacted with Lawesson's reagent (2 mg; 0.005 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (2 mg; 0.004 mmol). The structure was confirmed using Protocol I-B. Calculated mass=570; observed mass=570; HPLC retention time=4.69 min
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>N1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=1[NH:1][S:28]([C:22]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=1)(=[O:30])=[O:29]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC

Procedure:
5.6 g of 2-amino-2',5-dichlorobenzophenone and 5 g of 3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine overnight at 100° C. The pyridine is evaporated off to dryness, water and ethyl acetate containing a small amount of DCM are added and the mixture is extracted. After washing several times with water and drying over sodium sulfate, the extract is evaporated under vacuum and 7.7 g of the expected product are recrystallized from a DCM/AcOEt mixture.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu](C#N)[C:14]#[N:15].O>CN1CCCC1=O>[F:10][C:5]1[C:6]([CH:7]=[O:8])=[CH:9][C:2]([C:14]#[N:15])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(F)c(C=O)cc1Br
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(F)c(C=O)cc1C#N
Temperature: 180 °C
Reaction time: 5.5 h
Yield: 25.8 %

Procedure:
5.33 g of 5-bromo-2-fluoro-4-methoxy-benzaldehyde was dissolved in 73 ml of 1-methyl-2-pyrrolidone, 2.46 g of copper cyanide was added under stirring at 180° C. for 5.5 hours. After cooling to room temperature, water was added to the reaction mixture. The mixture was extracted with ethyl acetate and filtered through Celite. Then, the resulting organic layer was washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography, to give 0.983 g of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]1[O:11][CH2:10]1.FC1C=C(CCO)C=CN=1>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][N:3]=1
Reactant: C1CO1
Reactant: Cc1ccnc(F)c1
Agent: OCCc1ccnc(F)c1
Product: OCCCc1ccnc(F)c1
Yield: 528.6 %

Procedure:
This compound was prepared, starting from compound 41 (7.00 g, 6.30 mmol) and ethylene oxide (4.20 mL, 84.1 mmol), according to the procedure developed for compound 42. The purification was performed using colomm chromatography (SiO2, AcOEt/pentane, 6/4, v/v) to give alcohol 48 (5.16 g, 33.3 mmol) as a yellow oil. Yield 53%; Rf (SiO2, AcOEt/pentane 6/4, v/v) 0.52; IR (CCl4) ν 1412, 1613, 2939, 3639 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.84 (m, 2H), 2.72 (t, 2H, J=7.4 Hz), 3.14 (se, 1H), 3.62 (t, 2H, J=6.2 Hz), 6.72 (s, 1H), 6.98 (m, 1H), 8.01 (d, 1H, J=5.1 Hz); MS m/z 155 (M+, 6), 137 (25), 124 (12), 111 (100), 91 (21), 77 (14), 57 (14), 51 (16).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:40])[O:37][C@H:36]([CH2:38]O)[CH2:35][O:34]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][C:33]1([CH3:40])[O:37][C@H:36]([CH2:38][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:35][O:34]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3° C. to 5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hours. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 hour. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 hours at 3° C. to 5° C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40° C. to give (S)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[CH2:18]=O>C(O)=O>[CH3:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: C=O
Reactant: c1ccc2c(c1)CCC2CCC1CCCCN1
Solvent: O=CO
Product: CN1CCCCC1CCC1CCc2ccccc21

Procedure:
45 g. of 1-[2-(2-piperidyl)-ethyl]indane prepared as described above is mixed with 100 ml. of 37% formalin and 200 ml. of 98% formic acid is added while swirling and the solution is then heated overnight on a steam bath. The reaction mixture is worked up by concentrating in vacuo, dissolving in water, filtering, basification and extraction with ether. The ether extracts are dried over potassium hydroxide and after removal of the ether, the product is distilled collecting 42.6 g. (88%), N-methyl-1-[2-(2-piperidyl)ethyl]indane, boiling point 128°-130° C/0.2 mm.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[CH2:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:30][CH3:31]>C1COCC1>[CH2:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2]#[N:3])=[CH:34][CH:33]=1)[CH2:30][CH3:31]
Reactant: CCCc1ccc(C=O)cc1
Reactant: N#CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(C=CCCCCCC#N)cc1
Yield: 67.3 %

Procedure:
This compound was synthesized from 6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) and p-propylbenzaldehyde (2.96 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the product (3.25 g, 67%) as a colorless liquid (bp 144°-148° C./0.05 torr). IR 2290 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.55 (m, 8H), 2.40 (m, 6H), 5.60 (m, 1H), 6.40 (d, 1H), 7.10 (s, 4H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Br[C:15]1[C:16]([NH2:33])=[N:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:33][C:16]1[C:15]([N:1]2[CH2:5][CH2:4][CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[N:20][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(N3CCC(NC(=O)OC(C)(C)C)C3)n2)cc1
Temperature: 100 °C
Yield: 47.3 %

Procedure:
tert-Butyl N-pyrrolidin-3-ylcarbamate (43.14 mg, 0.2316 mmol) was added to a stirred solution of 3-bromo-5-(4-(isopropylsulfonyl)phenyl)pyrazin-2-amine (75 mg, 0.2105 mmol) and DIPEA (29.93 mg, 40.34 μL, 0.2316 mmol) in NMP (1 mL) and the reaction mixture heated to 100° C. under microwave conditions for 90 minutes. The reaction mixture was partitioned between EtOAc/water and the layers separated. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 100% EtOAc/Petroleum Ether). The fractions were collected concentrated in vacuo and freeze-dried to give the title compound as a yellow solid (46 mg, 48% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 1.40 (s, 9H), 1.79-1.82 (m, 1H), 2.08-2.17 (m, 1H), 3.30-3.38 (m, 1H), 3.42-3.44 (m, 2H), 3.60-3.71 (m, 2H), 4.06-4.12 (m, 1H), 6.22 (s, 2H), 7.16 (d, 1H), 7.83 (d, 2H), 8.18 (d, 2H) and 8.20 (s, 1H) ppm; (ES+) 462.3.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19](=O)([OH:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH2:1]([S:8][CH:9]([CH:12]([O:13][CH3:14])[O:15][CH3:16])[CH2:10][NH:11][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: CC(C)(C)OC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(OC)C(CNC(=O)OC(C)(C)C)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
2-(Benzylthio)-3,3-dimethoxypropan-1-amine (1 g) was dissolved in tetrahydrofuran (7 mL), and 1N aqueous sodium hydroxide solution (10 mL) was added. A solution of t-butyl bicarbonate (993 mg) in tetrahydrofuran (3 mL) was added dropwise to the reaction solution under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over sodium sulfate. The obtained solution was filtrated through basic silica gel, and concentrated to give the title compound (1.39 g, yield 99%) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: CN1CCN(N)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(Nc2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)CC1
Yield: 34 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (17 mg, 34% yield.) MS/ES+: m/z=429.
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)[C:3]([F:6])([F:5])[F:4].[H][H]>[Pd].C(OCC)(=O)C>[NH2:14][C:9]1[CH:8]=[C:7]([C:2]([F:1])([F:17])[C:3]([F:4])([F:5])[F:6])[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)C(F)(F)F)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)C(F)(F)F)ccc1O
Yield: 83.7 %

Procedure:
A mixture of 1.38 g of 4-(pentafluoroethyl)-2-nitrophenol, 15 ml of ethyl acetate and 0.15 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for four hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was washed with hexane to give 1.02 g of 2-amino-4-(pentafluoroethyl)phenol.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]Cl)[C:4]=2[O:3]1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:17][CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:19][CH:20]=3)[C:4]=2[O:3]1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: CC1(C)Cc2cccc(CCl)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1ccc(OCc2cccc3c2OC(C)(C)C3)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
3.0 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyl chloride and 3.0 g of 1-(4-hydroxyphenyl)-3,3-dimethylurea were dissolved into 20 ml of dried N,N-dimethylformamide, and 2.5 g of anhydrous potassium carbonate was added thereto. After the mixture was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 4.0 g of Compound No. 7 shown in Table 1.
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[CH2:38]2)=[CH:33][CH:32]=1.[Cl-].[NH4+]>C(OCC)C.C(Cl)Cl>[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)([OH:46])[CH2:38]2)=[CH:35][CH:36]=1
Reactant: O=C1CC(c2ccc(F)cc2)c2ccccc21
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Product: OC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC(c2ccc(F)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
A 3.0 M solution of ethylmagnesium bromide (5.9 ml, 0.0177 mol) in diethyl ether was added to a solution of 4-iodo-1-trityl-1H-imidazole (7.22 g, 0.0165 mol, prepared according to K. L. Kirk J. Heterocycl. Chem. 22 (1985) 57) in 70 ml of dry methylene chloride at ambient temperature. After one hour, a solution of 3-(4-fluorophenyl)indan-1-one (2.00 g, 0.00884 mol) in 6 ml of dry methylene chloride was added and stirring was continued for 45 hr. Saturated ammonium chloride solution was added to quench the reaction. The methylene chloride phase was separated and the aqueous phase was extracted twice with methylene chloride. The combined organic extracts were washed with brine, dried and concentrated. The crude 3-(4-fluorophenyl)-1-(1-trityl-1H-imidazol-4-yl)indan-1-ol was purified by flash chromatography using methylene chloride as an eluent.