Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([N:20]=[C:21]=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl>[CH:1]1([NH:7][C:21]([NH:20][C:12]2[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=[C:10]([C:9]([F:8])([F:23])[F:24])[CH:11]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
Cyclohexylamine 4.98 g (49.3 mmol) was added to 120 ml of anhydrous dichloromethane in a 500 ml round bottomed flask. This stirred solution was cooled to 0° C. using an ice water bath. 3,5-Bis(trifluoromethyl)phenyl isocyanate 12.33 g (48.3 mmol) was added drop wise over a period of 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred at ambient temperatures for 18 hours. During this time a heavy precipitate was formed. This solid was collected by filtration on a Buchner funnel, and was re-suspended in 250 ml of dichloromethane. After approximately 30 minutes of stirring, the solid was again filtered on a Buchner funnel and then placed under vacuum at 40° C. to dry for a period of 24 hours to give 15.4 g of a white solid (90% yield). 1H NMR (400 MHz DMSO) δ 9.10 (s 1H) 8.10 (s 2H) 7.53 (s 1H) 6.43 (d 1H) 3.49 (m 1H) 1.81 (t 2H) 1.68 (m 2H) 1.54 (m 1H) 1.25 (m 5H). MS: m/z 355 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:35])[NH:24][C:25]4[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Cl>C1COCC1.O.[OH-].[Li+]>[F:34][C:31]([F:32])([F:33])[C:28]1[N:27]=[CH:26][C:25]([NH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:36])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[O:35])=[CH:30][CH:29]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To 60 mg (0.1 mmol) (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester in THF/H2O (10 mL; 4:1), 5 mL (4M) aqueous Lithium Hydroxide solution was added and the mixture stirred at 60° C. for 5 hours. Acidified with concentrated hydrochloric acid which precipitated the desired compound. Filtered and dried under vacuum to afford (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, which was subsequently dissolved in methanol (5 mL) one equivalent of potassium hydroxide and 2 mL of H2O were added and the resulting mixture was stirred at 40 C for 2 hours. Evaporated to dryness to afford (4-{4-[5-(6-Trifluoromethyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid as the potassium salt: M+1=484.1. HRMS=484.1822. 1H NMR (400 MHz, MeOD) ppm 0.79 (d, J=7.33 Hz, 1 H) 1.11 (td, J=12.44, 2.91 Hz, 3 H) 1.43-1.55(m, 2 H) 1.67-1.78 (m, J=7.14, 7.14, 6.95, 6.57 Hz, 2 H) 1.79-1.89 (m, 3 H) 2.02 (d, J=7.33 Hz, 2 H) 2.14(t, J=7.33 Hz, 1 H) 2.47 (s, 1 H) 7.29 (d, J=8.34 Hz, 2 H) 7.75 (d, J=8.59 Hz, 1 H) 7.88-7.95 (m, 2 H) 8.31(dd, J=8.46, 2.40 Hz, 1 H) 8.43 (dd, J=8.46, 2.15 Hz, 1 H) 8.97 (d, J=2.27 Hz, 1 H) 9.08 (d, J=1.52 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>CC#N.CC(C)=O>[CH:40]([O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:30])=[CH:34][CH:35]=1)([CH3:42])[CH3:41]
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)c2cc1OC
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (1.86 g, 6.80 mmol), prepared essentially as described in the previous step, and (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (2.28 g, 7.22 mmol), prepared essentially as described in Example 1a, in CH3CN (13 mL) was added DIEA (1.24 mL, 7.50 mmol). The homogeneous solution was refluxed for 4 h, allowed to cool to rt, shaken with 1 M K2CO3, and extracted with EtOAc (2×25 mL). The organic layers were combined, washed with 0.5 M NaH2PO4 (1×50 mL), 4 M NaCl (1×25 mL), dried three times (Na2SO4), and concentrated under reduced pressure to give crude title compound as a beige semisolid (3.5 g). Flash chromotography (3:4→1:2 hex/acetone) afforded the title compound as an off-white foam (2.21 g, 72%). 1H-NMR (300 MHz, CDCl3) 9.08 (s, 1H), 7.34 (s, 1H), 7.28-7.22 (m, 3H), 6.83 (m, 2H), 6.46 (br s, 1H), 4.47 (heptet, J=6.1 Hz, 1H), 4.27 (br m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.59 (tt, J=11.0 Hz, 3.7 Hz, 1H), 3.15 (td, J=12.8 Hz, 2.4 Hz, 2H), 2.22-2.06 (m, 2H), 2.04-1.92 (m, 2H), 1.31 (d, J=6.1 Hz, 6H). LC/MS (ESI): calcd mass 450.2, found 451.3 (MH)+. Anal. Calcd for C25H30N4O4: C, 66.65; H, 6.71; N, 12.44. Found: C, 66.41; H, 6.68; N, 12.22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[N:27]=[C:26](O)[CH:25]=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[N:18]=2)[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:30]>>[Br:30][C:26]1[N:27]=[C:22]([C:19]2[N:17]3[N:18]=[C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:14]=[CH:15][C:16]3=[N:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1cccc(-c2cnc3ccc(N4CCC[C@@H]4c4cccc(F)c4)nn23)n1
Reactant: BrP(Br)Br
Product: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(Br)n4)n3n2)c1
Temperature: 175 °C

Procedure:
In step 16-2, a suspension of crude (R)-6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-ol (16-1) (13.3 g, 35.4 mmol) in PBr3 (25 mL) was heated to 175° C. for 35 minutes. While the mixture was hot, it was poured into ice-cold 2N NaOH (1.2 L). The solid was collected by filtration and washed with H2O. The final product was dried under high vacuum overnight to give (R)-3-(6-bromopyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16-2) as a light-yellow solid which was used in the next step without further purification. LC/MS: 438.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)cc1F
Product: Cc1c2n(c3c(-c4ccc(F)cc4F)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (32 mg, 39%), MS (ISP) m/z=331.4 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CN(C=O)C.O>[CH2:20]([O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[O:12][CH3:13])[CH3:21]
Reactant: COc1cc(Br)cc(C)c1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(Br)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of 4-bromo-2-methoxy-6-methyl-benzoic acid (synthesized according to the methods described in sections a) to d) of example 10) (10.7 g, 43.7 mmol) in DMF (90 ml) are added potassium carbonate (12.1 g, 87.3 mmol) and ethyl iodide (17.5 ml, 218 mmol) and the resulting mixture is stirred at room temperature for 2 h. After completion of reaction the reaction mixture is diluted with water (200 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers are washed with water (2×30 ml), brine (2×30 ml), dried over sodium sulfate and concentrated in vacuo yielding 4-bromo-2-methoxy-6-methyl-benzoic acid ethyl ester (10.5 g, 39 mmol, 89%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[O-]Cl.[Na+].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH:19]=[N:20][OH:21])=[CH:17][C:16]=1[CH3:24]>O.C1COCC1.CCOC(C)=O>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[CH:3]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[O:21][N:20]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: C#CC(=O)OCC
Reactant: COCOc1ccc(C=NO)cc1C
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OCOC)c(C)c2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Ethyl propiolate (0.60 mL, 5.88 mmol) and 6% W/V NaOCl solution in water (10.8 mL) were added to a solution of 4-(methoxymethoxy)-3-methylbenzaldehyde oxime (570 mg, 2.92 mmol) in THF (12 mL). The reaction mixture was stirred at 25° C. for 2 h then was diluted with EtOAc. The resulting solution was successively washed with aqueous 10% Na2S2O3 solution, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure to yield the title compound (745 mg, 88% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]([F:15])=[C:13]([CH2:16][CH3:17])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)C>[Br:18][CH:16]([C:13]1[C:14]([F:15])=[C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:10]=[CH:11][N:12]=1)[CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ncnc(Sc2ccc(Cl)cc2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(Cl)Cl
Product: CC(Br)c1ncnc(Sc2ccc(Cl)cc2)c1F
Temperature: 25 °C
Yield: 88.9 %

Procedure:
131 g of 4-(4-chloro-phenylsulfanyl)-6-ethyl-5-fluoropyrimidine, 103.8 g of N-bromosuccinimide and 7.98 g of azobisisobutyronitrile were dissolved in 850 ml of dichloroethane. The resulting mixture was refluxed for 2 hours, cooled to room temperature, and washed successively with 800 ml of water, 50 g of sodium metabisulfite in 950 ml of water and 500 ml of brine. The resulting solution was concentrated under a reduced pressure and crystallized at 5° C. in 391 ml of isopropanol to obtain the white compound, and the compound was washed with 50 ml of isopropanol at 5° C. to obtain the white title compound (150.7 g, yield: 89%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]([CH3:52])[CH2:27][CH2:28][CH:29]([NH:39][C:40]([NH:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[CH2:48][CH2:47][CH2:46]2)=[O:41])[C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.[C:53]1([NH2:60])[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH2:59].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[NH:60][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([CH:29]([NH:39][C:40]([NH:42][C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[CH2:48][CH2:47][CH2:46]3)=[O:41])[CH2:28][CH2:27][N:26]([CH3:52])[CH3:25])=[CH:38][CH:37]=1
Reactant: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
HATU (250 mg, 0.66 mmol) was added to a solution of 4-[1-(2-dimethylaminoethyl)-3-(indan-5yl)ureidomethyl] benzoic acid (Reference Compound No. 10-1, 250 mg, 0.66 mmol), o-phenylenediamine (140 mg, 1.3 mmol), and N,N-diisopropylethylamine (0.33 mL, 2.0 mmol) in DMF (5.0 mL), and then the mixture was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) was added thereto, and then the whole was washed with brine (50 mL) three times. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. After the residue was purified by silica gel column chromatography (chloroform-methanol), the resulting solid was collected by filtration with ethyl acetate, and then it was dried under reduced pressure to give 230 mg of the title compound as a pale yellow-white solid. (Yield 74%)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:11][CH2:12][CH2:13]Br>>[Br-:11].[Br:11][CH2:12][CH2:13][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: c1ccc2ncccc2c1
Product: BrCC[n+]1cccc2ccccc21
Product: [Br-]

Procedure:
A solution of quinoline (20 ml) in 200 ml of 1,2-dibromoethane was heated under nitrogen at 70°C. for 18 hours. The crystalline solid was filtered, washed with dichloromethane and recrystallized from methanol-ether. Collected 32 g (65 per cent yield) m.p. 205°-207°C. Nmr (D2O) 4.22 (t, 2), 5.63 (t, 2), 7.8 - 8.6 (m, 5), 9.1 - 9.6 (m, 3).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]1[CH:19]=[C:20]([CH2:26][CH:27]([O:31][CH:32]([CH3:34])[CH3:33])[C:28]([O-:30])=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH:32]([O:31][CH:27]([CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([CH2:17][O:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)[CH:19]=1)[C:28]([OH:30])=[O:29])([CH3:33])[CH3:34]
Reactant: OCc1ccc(Oc2ccccc2)cc1
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(Oc2ccccc2)cc1

Procedure:
Using (4-phenoxyphenyl)methanol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(4-methoxy-3-[(4-phenoxybenzyl)oxy]methylphenyl)propanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=1)[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[C:51]([C:50]([F:60])([F:61])[F:49])[CH:52]=2)[CH3:55])=[CH:18][CH:17]=1
Reactant: CC(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 52 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (89 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-trifluoromethyl-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 48%).
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:29](Br)(Br)([F:31])[F:30].O>C1COCC1>[CH2:12]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][C:25](=[C:29]([F:31])[F:30])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(Br)Br
Reactant: O=C1CCC(C(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(OCc1ccccc1)C1CCC(=C(F)F)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 9.5 %

Procedure:
HMPT (7.40 ml, 39.5 mmol) was added to a solution of 4-oxo-cyclohexanecarboxylic acid benzyl ester (1.50 g, 6.59 mmol) and CF2Br2 (1.8 ml, 19.8 mmol) in THF (30 ml) at 0° C., and the reaction mixture was stirred at room temperature for 22 hours. Water was added, followed by extraction with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→75/25) to give 4-difluoromethylene-cyclohexanecarboxylic acid benzyl ester (166 mg, 9%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][CH2:8][S:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([C:25]([NH:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26])[CH2:13]1)(=[O:11])=[O:10]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:29]([O:28][NH:27][C:25]([C@H:14]1[CH2:13][N:12]([S:9]([CH2:8][CH2:7][NH:6][C:2]([O:4][CH3:5])=[O:3])(=[O:11])=[O:10])[CH2:17][CH2:16][N:15]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:26])([CH3:31])([CH3:32])[CH3:30]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)ONC(=O)[C@H]1CN(S(=O)(=O)CCN)CCN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)NCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NOC(C)(C)C)C1
Temperature: 0 °C
Yield: 102.9 %

Procedure:
Methyl chloroformate (132 mg) in CHCl3 (3 ml) was added dropwise to (2R)-4-(2-aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide (400 mg) in pyridine (2.5 ml) with cooling on an ice bath. After stirring on the ice bath for 3 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 3.6% HCl. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 470 mg of (2R)-N-tert-butoxy-1-tert-butoxycarbonyl-4-[2-(methoxycarbonylamino)ethanesulfonyl]-2-piperazinecarboxamide.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:24])[CH2:22][F:23])[CH2:17][CH2:16]1.[C@H:25]1([NH:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH2:45])[CH:41]=3)[N:36]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[F:23][CH2:22][C:21]([N:18]1[CH2:17][CH2:16][CH:15]([NH:14][C:1]([NH:45][C:40]2[CH:41]=[C:42]3[C:37](=[CH:38][CH:39]=2)[N:36]=[C:35]([NH:34][C@H:25]2[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26]2)[CH:44]=[CH:43]3)=[O:12])[CH2:20][CH2:19]1)=[O:24]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(C(=O)CF)CC1
Agent: Cl
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(C(=O)CF)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(4-amino-piperidin-1-yl)-2-fluoro-ethanone hydrochloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=462.6 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:18]([O:20][C:21](=[O:42])[C@H:22]([CH3:41])[CH2:23][C@H:24]([N:38]=[C:39]=[O:40])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[CH3:19]>CN(C=O)C>[C:29]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]=[CH:27][C:26]([CH2:25][C@@H:24]([NH:38][C:39]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]2)=[O:40])[CH2:23][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:42])[CH3:41])=[CH:31][CH:30]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O
Reactant: O=C(O)c1cc[nH]n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a vigorously stirred 1:1 mixture of methylene chloride/8% aqueous NaHCO3 (8 mL) at 0° C. is added triphosgene (28.4 mg, 0.096 mmol). After stirring the mixture at 0° C. for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (100 mg, 0.287 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanate-2-methyl-pentanoic acid ethyl ester. Next, to a solution of 1H-pyrazole-3-carboxylic acid (32.2 mg, 0.287 mmol) in DMF (1 mL) is added diisopropylethylamine (0.05 mL, 0.287 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes the title compound. HPLC Retention time 1.5 minutes (condition A); MS 450.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=7.07Hz, 3H), 1.10 (t, 3H), 1.86 (t, 2H), 2.52 (m, 1H), 2.85 (m, 1H), 2.98 (m, 1H), 3.98 (q, 2H), 4.11 (m, 1H), 6.85 (d, J=2.65Hz, 1H), 7.28 (d, J=8.08Hz, 2H), 7.33 (t, 1H), 7.44 (t, 2H), 7.57 (d, J=8.21Hz, 2H), 7.63 (d, J=7.33Hz, 2H), 8.29 (d, J=2.65Hz, 1H), 8.58 (d, J=9.22Hz, 1H), 13.33 (s, broad, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1.[H-].[Na+].[CH3:14]I.O>CN(C)C=O.CC(OC)(C)C>[CH3:14][N:9]1[CH:10]=[CH:11][C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)=[N:8]1.[CH3:14][N:8]1[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=2)=[CH:11][CH:10]=[N:9]1
Reactant: CI
Reactant: Cc1csc(-c2cc[nH]n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Cc1csc(-c2ccn(C)n2)c1
Product: Cc1csc(-c2ccnn2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %
Yield: 30 %

Procedure:
3-(4-methyl-2-thienyl)-1H-pyrazole (9.0 mmol) was dissolved in 20 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (13.5 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, methyl iodide (18.0 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane:MTBE 100:0 to 90:10) to afford 864 mg 1-methyl-3-(4-methyl-2-thienyl)-1H-pyrazole (54% yield) and 480 mg of 1-methyl-5-(4-methyl-2-thienyl)-1H-pyrazole (30% yield).