Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[C@@H:21]([CH3:25])[NH:20][C:19](=[O:26])[CH2:18][C@@H:17](/[CH:27]=[CH:28]/[CH2:29][CH2:30][S:31][C:32](C2C=CC=CC=2)([C:39]2C=CC=CC=2)C2C=CC=CC=2)[O:16][C:15](=[O:51])[CH2:14][NH:13][C:12](=[O:52])[C@@H:11]([CH:53]([CH3:55])[CH3:54])[NH:10][C:9]1=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=[O:65].C([C@H]1NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCS)OC(=O)CNC(=O)[C@@H](C(C)C)NC1=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C(Cl)(C)=O>C(Cl)Cl>[CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[C@@H:21]([CH3:25])[NH:20][C:19](=[O:26])[CH2:18][C@@H:17](/[CH:27]=[CH:28]/[CH2:29][CH2:30][S:31][C:32](=[O:65])[CH3:39])[O:16][C:15](=[O:51])[CH2:14][NH:13][C:12](=[O:52])[C@@H:11]([CH:53]([CH3:54])[CH3:55])[NH:10][C:9]1=[O:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Agent: CC(C)[C@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](C)NC(=O)C[C@@H](/C=C/CCS)OC(=O)CNC1=O
Agent: CC[SiH](CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)SCC/C=C/[C@@H]1CC(=O)N[C@H](C)C(=O)N[C@H](Cc2ccccc2)C(=O)N[C@H](C(C)C)C(=O)NCC(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a stirred solution of 15 (15 mg, 19 μmol) in CH2Cl2 (0.8 mL) was added Et3SiH (16 μL, 0.1 mmol) and TFA (0.2 mL). After stirring at room temperature for 30 minutes under an inert atmosphere, the reaction mixture was concentrated and the residue dried by high vacuum. Without further purification, the crude thiol 16 was used in next step. At 0° C., to a stirred solution of thiol 16 in CH2Cl2 (0.3 mL) was added DIPEA (17 μL, 0.1 mmol) and AcCl (2 μL, 28 □mol). After 30 minutes the reaction mixture was warmed to rt and stirred for a further 1.5 h, whereupon it was quenched by addition of 1M HCl (1 mL). EtOAc (5 mL) was added to dilute the solution, phases separated, and the aqueous phase extracted with EtOAc (2×1 mL). The combined organic phases were washed with sat. aq NaCl (2 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (eluent: 1-10% IPA/CH2Cl2) to give compound 17 (5 mg, 8 μmol, 45%) as an off white solid.
Reaction SMILES: [Li]C.[CH2:3]([C:7]1[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][CH:10]=[N:11][CH:12]=1)[CH2:4][CH2:5][CH3:6].[CH3:19]C(O)=O.[OH-].[Na+]>CCOCC.C1COCC1.O>[CH2:3]([C:7]1[C:12]([CH3:19])=[N:11][CH:10]=[N:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O
Reactant: CCCCc1cncnc1-c1ccccc1
Agent: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1c(C)ncnc1-c1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
1.4 M MeLi in Et2O (1.54 ml, 2.16 mmol) is slowly added to a solution of 5-butyl-4-phenyl-pyrimidine (436 mg, 2.05 mmol) in Et2O (6 mL) at −30° C. under N2. The reaction mixture is stirred at −30° C. for 30 minutes and then at 0° C. for 45 minutes. Next, a solution of AcOH (0.12 mL) and H2O (0.02 mL) in THF (2 mL) is added, followed by a solution of 2,3-dichloro-5,6-dicyano-1,4-benzophenone (DDQ) (466 mg, 2.05 mmol) in THF (5 mL). The resulting mixture is stirred at room temperature for 5 minutes, recooled to 0° C., and then treated with 3.0 M aqueous NaOH. The mixture is stirred at 0° C. for 5 minutes, diluted with H2O, and extracted twice with Et2O. The combined extracts are dried over Na2SO4 and concentrated. The dark residue is purified by flash chromatography on silica gel. Elution with 2:1 Hex-EtOAc followed by 1:1 hexanes-EtOAc affords 5-butyl-4-methyl-6-phenyl-pyrimidine as a light yellow oil. 1H NMR (CDCl3, 300 MHz) δ 8.95 (s, 1H), 7.45 (m, 5H), 2.67-2.62 (m, 2H), 2.61 (s, 3H), 1.48-1.40 (m, 2H), 1.25 (sext, J=7.2 Hz), 0.82 (t, J=7.2 Hz, 3H) ppm. MS: m/z 227 [M+1].
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>O1CCCC1.ClCCl>[C:32]([NH:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1[nH]cc(N)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1[nH]cc(NC(=O)c2ccccc2)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To 0.15 g (0.328 mmol) of 4-amino-3-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide hydrochloride dissolved in 4.5 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.038 cm3 of benzoyl chloride and 0.091 cm3 of triethylamine. After stirring for 4 hours at a temperature in the region of 20° C., the reaction mixture is diluted with 15 cm3 of dichloromethane and then washed with twice 10 cm3 of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa) to give a solid, which is recrystallized while hot in 5 cm3 of methanol. The recrystallized solid is filtered through a No 3 sinter funnel, washed with twice 2 cm3 of methanol and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 5 hours to give 0.075 g of 4-benzoylamino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-2-carboxamide in the form of a white solid melting at 239.7° C.; ES+: m/z=526: [M+H]+.
Reaction SMILES: O1CCCCC1OCC[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]([O:21]C)=O.Cl.[NH2:24][C:25]([NH2:27])=[NH:26].[CH3:28][O-:29].[Na+]>CO>[O:29]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:28]1[O:21][CH2:19][CH2:11][NH:26][C:25]([NH2:27])=[N:24][C:19]([C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:21]
Reactant: COC(=O)c1cc2ccccc2n1CCOC1CCCCO1
Reactant: C[O-]
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=NC(=O)c1cc2ccccc2[nH]1)NCCOC1CCCCO1

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 1.00 g (3.30 mmol) of methyl 1-[2-(2-tetrahydropyranyl)oxyethyl]-2-indolecarboxylate, 3.15 g (33.0 mmol) of guanidine hydrochloride and a methanol solution of 1.78 g (33.0 mmol) of sodium methoxide. 1-[2-(2-Tetrahydropyranyl)oxyethyl]-2-indoloylguanidine was obtained in an amount of 0.85 g. Thereafter 0.69 g of the thus obtained compound was dissolved in hydrochloric acid/methanol. The solution was stirred at room temperature for 5.5 hours. The reaction mixture was concentrated under reduced pressure and a solvent mixture of methanol and diethyl ether was added to the resulting residue. The precipitates formed were filtered and dried under reduced pressure to give 0.49 g (65%) of 1-(2-hydroxyethyl)-2-indoloylguanidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)=[C:16]=[O:17]>C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:16]([NH:15][C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][N:22]=[CH:23]4)=[O:17])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C=Nc1cccc2cnccc12
Reactant: Cc1ccc(N2CCNCC2)cc1C
Solvent: CCOCC
Product: Cc1ccc(N2CCN(C(=O)Nc3cccc4cnccc34)CC2)cc1C

Procedure:
1-(3,4-Dimethylphenyl)piperazine (194 mg, 1.02 mmol) in diethyl ether (20 mL) was treated with an ethereal solution of 5-isocyanatoisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.29 (d, 1H, J=0.7 Hz), 8.82 (s, 1H), 8.49 (d, J=6.2 Hz, 1H), 7.90-7.93 (m, 1H), 7.76-7.79 (m, 1H), 7.61-7.71 (m, 2H), 7.00 (d, 1H, 8.5 Hz), 6.83 (d, 1H, J=2.4 Hz), 6.73 (dd, 1H, J=8.3 Hz, 2.5 Hz), 3.67 (m, 4H), 3.15 (m, 4H), 2.19 (s, 3H), 2.13 (s, 3H); MS (ESI+) m/z 361 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1)[CH3:2].[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC>CN(C=O)C.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:10]=[CH2:11])=[CH:5][N:4]=1)[CH3:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CCc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1ccc(CC)nc1
Temperature: 100 °C
Yield: 93.3 %

Procedure:
The title compound was prepared by following general procedure 2. 2-Ethyl-5-bromopyridine (0.6 g, 0.00322 mol) was dissolved in DMF:THF (3:1 6 mL), and to this solution, tributylvinyltin (1.03 mL, 0.00354 mol) and Pd(PPh3)4 (0.048 g, 0.000041 mol) were added at RT under nitrogen and the mixture heated at 100° C. for 30 min. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-ethyl-5-vinylpyridine as a light yellow liquid (0.4 g, 93% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][C:18]3[CH:19]=[N:20][C:21]([OH:24])=[CH:22][CH:23]=3)[CH2:13]2)[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11].[O:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O:54]C(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@@H:14]([O:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[CH:22][CH:23]=3)[C:13]2=[O:54])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: OC1CCOCC1
Reactant: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(O)nc4)C3)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccc(OC5CCOCC5)nc4)C3=O)cc21
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a mixture of (R)-1-(7-fluoro-3-oxo-indan-5-yl)-3-(6-hydroxy-pyridin-3-yloxy)-pyrrolidin-(60 mg), tetrahydro-pyran-4-ol (51 mg) and solvent (THF/DCM/NMP 4:4:1, 5 mL) under argon was added triphenylphosphine (polymer, 0.4 mmol). After 5 minutes DIAD (51 mg) was added. The mixture was shaken at 40° C. for 12 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to provide Example 2-07. 1H-NMR (400 MHz, DMSO) δ 7.99 (1H, dd, J=11.2, 1.8 Hz), 7.97 (1H, d, J=3.1 Hz), 7.78 (1H, d, J=1.8 Hz), 7.54 (1H, dd, J=9.0, 3.1 Hz), 6.78 (1H, d, J=9.0 Hz), 5.23 (1H, dd, J=8.3, 8.3 Hz), 5.08 (1H, m), 3.96 (1H, m), 3.86 (1H, m), 3.86 (2H, m), 3.10 (2H, m), 2.73 (2H, m), 2.70 (1H, m), 2.13 (1H, m), 1.98 (2H, m), 1.60 (2H, m).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.[CH:41]([S:44](Cl)(=[O:46])=[O:45])([CH3:43])[CH3:42]>CC#N.CN(C1C=CN=CC=1)C.CS(C)=O>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:13]2)[CH2:21][CH2:20][N:19]([S:44]([CH:41]([CH3:43])[CH3:42])(=[O:46])=[O:45])[CH2:18][CH2:17]1)#[N:24]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)S(=O)(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-1) (30 mg, 0.068 mmol) in MeCN (0.50 mL) was added DIPEA (0.030 mL, 0.17 mmol) and DMAP (12 mg, 0.10 mmol). To this mixture was added isopropylsulfonyl chloride (0.008 mL, 0.1 mmol). The resulting mixture was allowed to stir at ambient temperature for 1 hour before it was diluted with DMSO (1.0 mL) and purified directly by reverse-phase preparative HPLC (using a gradient elution of 0-100% MeCN/water, with 0.1% v/v HCOOH modifier). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound, Example #37-1. 1H NMR (600 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.47 (s, 1H), 7.54 (br s, 1H), 7.48 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.8 Hz, 2H), 7.15 (br s, 1H), 6.80 (t, J=7.8 Hz, 1H), 3.50-3.56 (m, 2H), 3.19 (s, 2H), 2.98-3.10 (m, 2H), 2.38-2.49 (m, 3H), 2.02-2.08 (m, 2H), 1.15 (d, J=6.6 Hz, 6H). LRMS (ESI) calc'd for C20H26N6O3S [M+H]+: 431. Found: 431.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5](O)=[O:6])[CH2:3]1.C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C=O)C>[CH3:1][N:2]1[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([Cl:14])=[O:6])[CH2:3]1
Reactant: CN1CCCC(C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCCC(C(=O)Cl)C1

Procedure:
The hydrochloride salt of (±)-N-methylnipecotic acid (1.0 g) was suspended in dichloromethane (25 ml) and stirred at room temperature for 2 h with oxalyl chloride (0.58 ml) and DMF (1 drop). The solvent was then evaporated to yield the hydrochloride salt of N-methylnipecotyl chloride as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.B([C:20]1[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]=[C:6]1[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=3)[CH:3]=2)[NH:7]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere, was added tetrakis(triphenylphosphine)palladium(0) (70 mg, 5 mol %). After 15 minutes, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 hours and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give 2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (3.4 g, 76%) as a white powder, mp 177° C.; 1H NMR (CDCl3; 300 MHz): δ 1.38 (s, 9H), 1.59-1.93 (m, 10H), 6.18 (m, 1H), 6.23 (‘t’, 1H, J=3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2O ex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[C:15]1([NH:21][C:22](=[O:25])[NH:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([NH:21][C:22](=[O:25])[NH:23][N:24]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NNC(=O)Nc1ccccc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1

Procedure:
ninhydrin, 4-phenyl semicarbazide hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[Br-:13].[CH3:1][O:2][C:3]1([O:11][CH3:12])[CH:8]2[CH2:7][CH2:6][N+:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH2:10][CH2:9]2)[CH2:4]1
Reactant: CCCCCBr
Reactant: COC1(OC)CN2CCC1CC2
Product: CCCCC[N+]12CCC(CC1)C(OC)(OC)C2
Product: [Br-]
Temperature: 110 °C

Procedure:
A mixture of 3,3-dimethoxyquinuclidine (1.71 g, 10 mmol) and 1-bromopentane (1.51g, 10 mmol) was heated at 110° C. for 15 min. Yield 3.22 g, 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:15]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:25][CH2:24]2)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: CCCCCC1CCC(=O)CC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)c(F)c2)CC1

Procedure:
A Grignard reagent was prepared from commercially available 2-fluoro-4-bromobiphenyl, and the resulting Grignard reagent was reacted with 4-pentylcyclohexanone in the same manner as in (1-b) and (1-c) to obtain 2-fluoro-4-(trans-4-pentylcyclohexyl)biphenyl. The product was brominated in the same manner as in (29-a) to obtain 2-fluoro-4-(trans-4-pentylcyclohexyl)-4'-bromobiphenyl. A Grignard reagent was prepared therefrom and reacted with 4-pentylcyclohexanone-2,2,6,6-d4 in the same manner as in Example 4 to obtain 2-fluoro-4-(trans-4-pentylcyclohexyl)-4'-(trans-4-pentylcyclohexyl-2,2,6-d3)biphenyl. The phase transition temperatures of this compound are shown in Table 3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:8]([OH:27])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24].[C:28](OCC)(=[O:33])[CH2:29][C:30]([CH3:32])=O.O>C(O)C>[C:8]([NH:1][CH2:2][CH2:3][N:4]1[C:28](=[O:33])[CH2:29][C:30]([CH3:32])=[N:7][CH2:6][CH2:5]1)(=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)O
Reactant: CCOC(=O)CC(C)=O
Reactant: NCCNCCN
Solvent: CCO
Solvent: O
Product: CC1=NCCN(CCNC(=O)CCCCCCCCCCCCCCC(C)C)C(=O)C1

Procedure:
Into an apparatus similar to that in Example 1, were charged 103.1 g (1 mole) of diethylenetriamine and 284.5 g (1 mole) of isostearic acid. At 200° to 210° C., 18 g of water was distilled off to effect the monoamide formation. Then, after the addition of 130.1 g (1 mole) of ethyl acetoacetate, 18 g of water and 46 g of ethanol were distilled off at 150° to 160° C. to obtain 4-isostearamidoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:33][C:34]1[CH:42]=[C:41]2[C:37]([CH2:38][CH2:39][CH:40]2[NH2:43])=[CH:36][CH:35]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:43][CH:40]2[C:41]3[C:37](=[CH:36][CH:35]=[C:34]([Cl:33])[CH:42]=3)[CH2:38][CH2:39]2)=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CCc2ccc(Cl)cc21
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NC1CCc2ccc(Cl)cc21)C1COCCN1c1nc(Cl)ncc1Br

Procedure:
The title compound was prepared in a manner similar to PREPARATION x31 using 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 750 mg, 2.325 mmol), EDC (669 mg, 3.49 mmol), HOBt (534 mg, 3.49 mmol), 6-chloro-2,3-dihydro-1H-inden-1-amine hydrochloride (712 mg, 3.49 mmol), and triethylamine (0.486 mL, 3.49 mmol) in DMF (15 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.95 (m, 1H), 2.36-2.47 (m, 1H), 2.70-2.96 (m, 2H), 3.48-3.80 (m, 3H), 3.86-3.98 (m, 1H), 4.21-4.44 (m, 2H), 4.77-4.93 (m, 1H), 5.28-5.43 (m, 1H), 7.27 (s, 3H), 8.47 (d, J=7.58 Hz, 2H). ESI-MS m/z [M+H]+ calc'd for C18H17Br2Cl2N4O2, 470.99. found 471.3.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].[NH2:14]CC1SC=CC=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH2:14])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: NCc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-acetoxybenzoic acid (8.1 mg, 0.0450 mmol), 5-aminomethyl-thiophene 18d (22.3 mg, 0.0473 mmol), 1-hydroxybenzotriazole (HOBt, 4.7 mg, 0.0348 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 8.5 mg, 0.0443 mmol) was dissolved in DMF (0.6 ml) and stirred overnight at r.t. Work-up (AcOEt/H2O; brine/Na2SO4), concentration, filtration over a silica gel plug (EtOAc) and evaporation gave the intermediate 3-acetoxybenzamide, which was deacetylated by stirring in MeOH (2 ml) and Et3N (0.4 ml) for 1 h at 55° C. Evaporation gave 28.5 mg (103%) of the title 3-hydroxy-benzamide as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][OH:16].[Cl:17][C:18]1[C:23](Cl)=[N:22][CH:21]=[CH:20][N:19]=1>O1CCOCC1>[Cl:17][C:18]1[C:23]([O:16][CH2:15][CH2:14][O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)=[N:22][CH:21]=[CH:20][N:19]=1
Reactant: OCCOc1ccc2ccccc2c1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1nccnc1OCCOc1ccc2ccccc2c1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
Sodium hydride (55% dispersion in mineral oil; 44 mg, 1.0 mmol) was added to a mixture of 2-(2-naphthoxy)ethanol (188 mg, 1.00 mmol) and 2,3-dichloropyrazine (149 mg, 1.00 mmol) in dioxane (0.5 mL), and the reaction mixture was stirred at 40° C. for 15 h. The crude material was used directly in Step 2.