Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[ClH:13].Cl.[F:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26]>C(O)C>[ClH:13].[NH2:26][C:25]1[N:24]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[C:21]([F:22])[C:16]=2[F:15])[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:29]=[C:28]([NH2:30])[N:27]=1
Reactant: N=C(N)NC(=N)Nc1ccc(F)c(F)c1F
Reactant: CCCCCCCCCCC=O
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(F)c(F)c1F

Procedure:
100 ml of ethanol, 4.8 g (28.2 mmol) of 1-undecanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (18.7 mmol) of N1-(2,3,4-trifluorophenyl)-biguanide hydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)), and recrystallized from 80% aqueous acetonitrile to obtain 3.2 g of colorless crystals having a melting point of 210 to 213° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Li+].CC([N-]C(C)C)C.C([Li])CCC.C(NC(C)C)(C)C.[C:29]1([CH:35]2[CH2:40][CH2:39][CH:38]([CH2:41]I)[CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH:1][C@H:2]([CH3:8])[C@@H:3]([CH2:41][CH:38]1[CH2:37][CH2:36][CH:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:40][CH2:39]1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C[C@@H](C)O
Reactant: ICC1CCC(c2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC1CCC(c2ccccc2)CC1)[C@@H](C)O
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
A solution of methyl (3R)-3-hydroxybutyrate (5.6 g, 0.047 mol) in THF (20 mL) is added dropwise to a solution of LDA prepared by dropwise addition of n-butyllithium (49.5 mL, 0.099 mol, 2 M in cyclohexane) to diisopropylamine (10.0 g, 0.099 mol) in THF (20 mL) at −78° C. After stirring at −50° C. to −40° C. for 0.5 h, a solution of 4-phenylcyclohexylmethyl iodide (14.6 g, 0.049 mol) in a mixture of HMPA (10 mL) and THF (15 mL) is added dropwise. The mixture is kept at −20° C. for 48 h, then allowed to warm to 4 ° C. and kept at that temperature for 48 h. The reaction mixture is chilled to 0° C. and quenched by dropwise addition of saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ether and the combined organic phase is washed with ice-cold 0.1 M HCl, then saturated sodium chloride solution and dried over sodium sulfate. Concentration of the organic phase gives 14.6 g of crude product. Column chromatography on silica gel with hexanes-EtOAc (2:1) as eluent affords 4.18 g (31%) of methyl (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoate as a pale yellow oil which solidified on standing.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.5 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) (Example 11b) in chloroform (2 mL) was added pyridine (0.099 mL, 1.226 mmol) followed by benzenesulfonyl chloride (0.059 mL, 0.460 mmol). The reaction mixture was stirred at room temperature for 1 hr. The saturated solution of NH4Cl was added, and layers were separated. Organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at the room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. trans-2-phenyl-N-((1-(phenylsulfonyl)piperidin-4-yl)methyl)cyclopropanamine (10 mg, 0.026 mmol, 8.37% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.76-7.85 (m, 2H), 7.65-7.73 (m, 1H), 7.52-7.66 (m, 2H), 7.15-7.28 (m, 2H), 7.06-7.16 (m, 1H), 6.97-7.05 (m, 2H), 3.77 (d, J=12.13 Hz, 2H), 2.57 (dd, J=1.26, 6.82 Hz, 2H), 2.13-2.35 (m, 3H), 1.72-1.97 (m, 3H), 1.36-1.54 (m, J=3.73, 3.73, 7.33, 7.33, 14.78 Hz, 1H), 1.14-1.35 (m, 2H), 0.90-1.10 (m, 2H); LC-MS Rt=0.76 min; MS (ESI): 370.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Br)[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH:13]([OH:14])[CH2:20][CH2:19][CH:18]=[CH2:17])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(C=O)COC1(C)C
Reactant: C=CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(O)C1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
5 g (21.81 mmol) of racemate (SR)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester are dissolved in 33 ml of THF, placed under argon and cooled to −78° C. 43.62 ml (21.81 mmol) of a 0.5 M 3-butenylmagnesium bromide solution in THF are added dropwise. The mixture is stirred further at room temperature overnight. After a TLC check, about 90 ml of a saturated NH4Cl solution are added to the mixture with cooling, the mixture is stirred further overnight and diluted with about 50 ml of water. The phases are separated, and the aqueous phase is extracted a further twice with EA. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The oily residue is subjected to flash chromatography on silica gel.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=O)[CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=2)[NH:5][C:4](=[S:24])[CH2:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared by heating under reflux overnight a stirred mixture of 3-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5-fluorobenzonitrile and an equal weight of phosphorus pentasulfide in pyridine and workup as in the previous example gave a yellow solid: mp. 240-2420 C dec.; 1H-NMR (DMSO-d6) δ 12.37 (s, 1H), 8.13 (s, 1H), 7.98 (dt, 1H, J=10.4 and 5.4 Hz), 7.81 (d, 1H, J=8.4 Hz), 7.7 (d, 1H, J=1.8 Hz), 7.68 (dd, 1H, J=8.3 and 1.9 Hz), 7.22 (d, 1H, J=8.3 Hz), 2.85 (s, 2H), 1.27 (s, 6H); MS m/z 309 [M−H]− Anal. Calc. For C18H15FN2S 0.10H2O: C, 69.25, H, 4.91, N, 8.97. Found: C, 69.15, H, 4.74, N 8.75.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH2:6][CH:3]3[CH2:4][CH2:5][N:1]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCNC1
Product: COC(=O)c1cccc(N2CCC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 31.4 %

Procedure:
Using N-(pyrrolidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (168 mg, 0.500 mmol) and 3-(methoxycarbonyl)phenylboric acid (180 mg, 1.00 mmol), the same procedure was followed as in Example 2 to give 73.7 mg (31%) of the desired compound as a colorless powder.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.CN1CCOCC1.[CH3:41][S:42]([CH2:45][S:46](Cl)(=[O:48])=[O:47])(=[O:44])=[O:43].C(=O)([O-])O.[Na+]>ClCCl>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][S:46]([CH2:45][S:42]([CH3:41])(=[O:44])=[O:43])(=[O:48])=[O:47])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CS(=O)(=O)CS(=O)(=O)Cl
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)CS(=O)(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reaction time: 1 h

Procedure:
5-(2-Aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (245 mg) and N-methylmorpholine (1.0 mL) were dissolved in dichloromethane (6.0 mL), (methylsulfonyl)methanesulfonyl chloride (0.40 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate to give the title compound (79.4 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][NH2:17])=[N:4][C:5]([CH3:15])=[N:6][C:7]=1[NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[CH:18]1([CH2:23][C@H:24]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:25](O)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:18]1([CH2:23][C@@H:24]([C:25]([NH:17][NH:16][C:3]2[C:2]([F:1])=[C:7]([NH:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][N:14]=3)[N:6]=[C:5]([CH3:15])[N:4]=2)=[O:26])[CH2:28][N:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:37]=[O:38])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1nc(NN)c(F)c(NCc2nccs2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
5-Fluoro-4-hydrazino-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]pyrimidine (80 mg, 0.33 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (Hunigs base salt, 140 mg, 0.33 mmol), and HOAt (45 mg, 0.33 mmol) were dissolved in 3 mL of DMF. NMM (0.1 mL, 0.9 mmol) was added, followed by EDC (65 mg, 0.33 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (72 mg, 45%). LCMS: (M+H)+: 536.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4O[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:24]([C:23]5[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:22]=5[Cl:21])[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: Brc1ccc2c(c1)-c1sc(-c3nnco3)cc1CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Temperature: 160 °C
Yield: 36.3 %

Procedure:
A microwave tube charged with 2-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-[1,3,4]oxadiazole (200 mg; 0.57 mmol), 2-chloro-4-trifluoromethylaniline (0.12 ml; 0.86 mmol), TFA (64 μl; 0.86 mmol) and toluene (1.5 ml) was heated in a microwave at 160° C. for 30 min. The reaction mixture was basified with DIPEA (0.2 ml), volatiles removed in vacuo and the residue purified by prep. LCMS to give 289 as a white solid (109 mg; 36%). δH (400 MHz, CDCl3) 3.13 (t, J=5.2, 2H), 4.29 (t, J=5.2, 2H), 6.89-6.93 (m, 2H), 7.24-7.28 (m, 1H), 7.62-7.67 (m, 2H), 7.80-7.83 (m, 1H), 7.98 (s, 1H), 8.26 (s, 1H). [M+H]+: 527
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH3:9])[C:3]1=[O:10].[N+:11]([CH2:13]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:12].CC([O-])(C)C.[K+]>CC1OCCC1.CO>[CH3:1][N:2]1[C:7]2=[CH:12][NH:11][CH:13]=[C:6]2[C:5](=[O:8])[N:4]([CH3:9])[C:3]1=[O:10]
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC1CCCO1
Product: Cn1c(=O)c2c[nH]cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,3-Dimethylpyrimidine-2,4(1H,3H)-dione (commercial (40 g, 285 mmol) and 1-(isocyano methylsulfonyl)-4-methylbenzene (commercial) (84 g, 428 mmol) were dissolved in 2-MeTHF (1000 mL) under nitrogen at 30° C. and held for 5 mins. The vessel was then cooled to 0° C. (internal). A solution of KOtBu (commercial) (64.1 g, 571 mmol) in 2-MeTHF (500 mL was added to the solution via a dropping funnel over 0.5 h, such that the internal temperature remained below 5° C. On addition of the KOtBu solution, an orange precipitate formed. An additional portion of 2-MeTHF (455 mL) was charged via dropping funnel over 5 mins. After 40 mins, the dark orange suspension was quenched with sat NH4Cl solution (2×400 mL) charged via dropping funnel over 15 mins. The suspension was then diluted with EtOAc (1 L), the layers were separated and the aqueous extracted with EtOAc (3×1 L). The combined organics were dried (MgSO4) and filtered under reduced pressure. The solvent was removed under reduced pressure to afford a brown semi-solid. The solids were suspended in MeOH (300 mL), sonicated and stirred at room temperature for 15 mins, filtered by reduced pressure filtration and washed with MeOH (100 mL). The solid was dried under vacuum at 50° C. for 24 h. The title compound was obtained as a pale brown amorphous solid (26.34 g, 52%)
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCC=C1CCCCN2.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2([C:51]([F:54])([F:53])[F:52])[O:41][N:40]=[C:39]([C:42]3[S:46][C:45]([CH:47](O)[CH3:48])=[C:44]([CH3:50])[CH:43]=3)[CH2:38]2)[CH:33]=[C:34]([Cl:36])[CH:35]=1>C1(C)C=CC=CC=1>[N:15]([CH:47]([C:45]1[S:46][C:42]([C:39]2[CH2:38][C:37]([C:32]3[CH:31]=[C:30]([Cl:29])[CH:35]=[C:34]([Cl:36])[CH:33]=3)([C:51]([F:54])([F:53])[F:52])[O:41][N:40]=2)=[CH:43][C:44]=1[CH3:50])[CH3:48])=[N+:16]=[N-:17]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: C1=C2CCCCNN2CCC1
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N=[N+]=[N-]
Reaction time: 19 h

Procedure:
Diphenylphosphoryl azide (0.53 ml) and diazabicyclo-[5.4.0]-undec-7-ene (DBU, 0.40 ml) is added to a solution of 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethanol (0.87 g) in toluene (9 ml). After 19 hours at room temperature, the reaction is quenched with a saturated aqueous solution of NH4Cl in water. The reaction mixture is extracted three times with ethyl acetate. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 3-[5-(1-azido-ethyl)-4-methyl-thiophen-2-yl]-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (0.64 g) as a yellow oil. MS (HPLC/MS): 449 (MH+). Retention time: 2.45 min.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[C:21]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([O:31][CH3:32])[CH:26]=4)=[N:23][CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[C:21]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([O:31][CH3:32])[CH:26]=4)=[N:23][CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3ccnc(OC)c3)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2ncc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-methoxy-3-neopentyl-[2,4′-bipyridine]-5-yl)oxy)methyl)phenyl)propanoate (27 mg) in THF (1.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (1.0 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1N hydrochloric acid (1.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (21 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:3]=1.[CH:14]1([C:17](=O)[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.C1C=CC=CC=1>C(O)(=O)C>[CH:14]1([C:17]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]3[C:2]([CH3:1])=[N:3][N:4]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)[C:5]=3[N:7]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Cc1cc(N)n(-c2ccncc2)n1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2-c1ccncc1

Procedure:
The title compound was prepared in the same manner as described for intermediate 30 using 3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-amine (310 mg, 1.780 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (328 mg, 1.780 mmol), benzene (50 mL), and acetic acid (25 mL). The final product was collected as 3.71 (71% overall). LCMS E-S (M+H)=323.5 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.22 (m, 4 H), 1.41 (t, J=7.07 Hz, 3 H), 2.64-2.69 (m, 4 H), 4.47 (q, J=7.07 Hz, 2 H), 7.74 (s, 1 H), 8.27-8.36 (m, 2 H), 8.66-8.71 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([Li])(C)(C)C.C(=O)=O.CC(C)=O.[N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>O1CCCC1.C1CCCCC1>[CH2:11]([CH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH:10]=2)[CH2:6][CH2:7]1)[CH3:12]
Reactant: CCC1CCc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCC1CCc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Upon cooling by a dry ice-acetone bath, a solution of 6-bromo-1-ethyl-indan 41b (2.52 g, 11.2 mmol) in 15 mL of tetrahydrofuran was added dropwise to a solution of t-butyllithium in cyclohexane (18.1 mL, 1.3 N) under argon atmosphere. Upon completion of the addition, the mixture was stirred for 2 hours in the dry ice-acetone bath. A solution of di-tert-butyl azodicarboxylate in 15 mL of tetrahydrofuran was added dropwise to the above mixture at the same temperature. Upon completion of the addition, the reaction mixture was stirred for another 1.5 hours in the dry ice-acetone bath. Then the dry ice-ethanol bath was removed. The mixture was warmed up to room temperature and stirred for 18 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched by addition of 25 mL of saturated ammonium chloride. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(3-ethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 41c (3.43 g, 81.5%) as a brown oil.
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1>>[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1NCCc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for preparation of Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3,5-bis-trifluoromethylphenylboronic acid (202 mg, 1.24 mmol) were coupled to yield 2-(3,5-bis-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 70 mg (16%), as a pale-yellow solid. mp 230° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 3.11 (m, 2H), 3.42 (m, 2H), 7.31 (app t, 1H, J=7.8 Hz), 7.64 (d, 1H, J=8.1 Hz), 7.73 (d, 1H, J=7.5 Hz), 8.13 (br s, 1H), 8.16 (br t, 1H), 8.28 (br s, 2H), 11.95 (br s, 1H); MS (FAB, MH+) 399; Anal. (C19H12F6N2O.0.2 hexanes) C, H, N.
Reaction SMILES: Cl[CH:2]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].[C:16]1([NH:22][CH2:23][CH2:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(C)C>[CH3:4][CH:3]([CH3:5])[CH:2]([NH:25][CH2:24][CH2:23][NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1
Reactant: NCCNc1ccccc1
Reactant: CC(C)C(Cl)c1cncnc1C(F)(F)F
Solvent: CC(C)O
Product: CC(C)C(NCCNc1ccccc1)c1cncnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.05 g (4.2 mol) of 5-(1-chloro-2-methylpropyl)-4-trifluoromethylpyrimidine and 0.61 (4.2 mol) of N-phenylethylenediamine were added to 10 ml of isopropyl alcohol, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated, then poured into water and extracted with ethyl acetate, and purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.38 g of N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)-propyl]-N′-phenylethane-1,2-diamine. Then, 0.38 g (1 mmol) of N-[2-methyl-1-(4-trifluoromethylpyrimidin-5-yl)-propyl]-N′-phenylethane-1,2-diamine and 0.5 g (5 mmol) of triethylamine were added to 10 ml of dichloromethane, and a dichloromethane solution containing 0.2 g (2 mmol) of phosgene was dropwise added under cooling with ice. After the dropwise addition, stirring was further continued at room temperature for 1 hour to terminate the reaction. After termination of the reaction, the product was poured into water, washed with an aqueous sodium hydrogencarbonate solution, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1 to ethyl acetate) to obtain 0.25 g (yield: 61%) of 1-[2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-3-phenylimidazolin-2-one as colorless crystals (melting point: 126-128° C.).