Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(=O)C=Cc1cccc(Cl)c1
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)CCc1cccc(Cl)c1
Yield: 54.8 %

Procedure:
1-(3-Chlorophenyl)-1-buten-3-one (20.0 g, 111 mmol) was subjected to hydrogen catalytic reduction in ethanol (200 ml) at room temperature by using platinum oxide (PtO2; 0.30 g) as a catalyst. The catalyst was filtered off and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 11.1 g of 1-(3-chlorophenyl)butan-3-one.
Reaction SMILES: [CH2:1](O)[CH3:2].[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[SH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:8]([S:4][C:5]1[S:13][C:2]2[CH:1]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH3:9]
Reactant: Sc1nc2ccccc2s1
Reactant: CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCSc1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
Ethyl alcohol (0.63 mL, 10.8 mmol), 2-benzothiazolethiol (2.0 g, 11.9 mmol) and triphenylphosphine (3.1 g, 11.9 mmol) were dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. Then added diisopropylazadicarboxylate (2.3 mL, 11.9 mmol) and continued stirring for 1 hr. Upon completion, the reaction mixture was dried in vacuo, filtered through a plug of silica with 5% ethyl acetate in hexane and dried in vacuo again to yield 2-(ethylthio)-1,3-benzothiazole (2.2 g, HPLC RT=3.05 min.). LC-MS m/z=196.
Reaction SMILES: [C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH:10]=2)[NH2:2].C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].C(Cl)(Cl)Cl>O.CO>[C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH:10]=2)[NH2:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(OC)c1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2COC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(OC)c1cc(O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(O)(O1)C2COC(N)=O

Procedure:
6,9-Dihydroxy-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (22 mg) and sodium bicarbonate (12 mg) were dissolved in water (0.5 ml). To the solution was added benzyl chloroformate (0.02 ml) with stirring in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath and subjected to preparative thin layer chromatography. Development was carried out with a mixture of chloroform and methanol to afford 11-benzyloxycarbonyl-6,9-dihydroxy-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (15 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[CH:10][C:9]([C:18](O)=[O:19])=[CH:8][C:7]=1[O:6]2.F[P-](F)(F)(F)(F)F.N1C2C=CC=C(OC(N(C)C)=[N+](C)C)C=2N=N1.[CH:45]([N:48](CC)[CH:49](C)[CH3:50])(C)[CH3:46].C(NCC)C>CN(C)C=O>[CH2:45]([N:48]([CH2:49][CH3:50])[C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:17])[C:14]3[C:5]([O:6][C:7]=2[CH:8]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)=[O:19])[CH3:46]
Reactant: COc1ccc2c(=O)c3ccc(C(=O)O)cc3oc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(Oc1cccc2[nH]nnc12)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccc(OC)cc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A mixture of compound 6i (0.707 g, 2.62 mmol) and O-benzotriazol-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 1.05 g, 2.74 mmol) in N,N-dimethylformamide (10 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.685 mL, 3.92 mmol) and allowed to stir at rt for 15 min. Diethylamine (0.541 mL, 5.23 mL) was added and the resultant mixture was stirred for 2 h. The mixture was poured into ice water. A solid was collected by filtration, washed with water and air dried to give the title compound (0.445 g). MS: m/z 326.0 (MH+). 1H NMR (DMSO-d6): δ 1.07 (br t, 3H), 1.19 (br t, 3H), 3.20 (br q, 2H), 3.48 (br t, 2H), 3.95 (s, 3H), 7.08 (m, 1H), 7.17 (d, 1H, J=2.1 Hz), 7.40 (d of d, 1H, J=1.3 & 8.1 Hz), 7.59 (d, 1H, J=1.2 Hz), 8.12 (d of d, 1H, J=1.3 & 8.9 Hz) and 8.21 (d, 1H, J=8.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=4)[CH:16]=3)[N:11](C3CCCCO3)[N:10]=2)[CH:6]=[N:7][CH:8]=1.Cl.CC(O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(-c2ccc3c(c2)c(-c2cncc(OC)c2)nn3C2CCCCO2)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cncc(-c2ccc3[nH]nc(-c4cncc(OC)c4)c3c2)c1
Temperature: 50 °C

Procedure:
A mixture of 3,5-bis(5-methoxypyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.429 g, 1.029 mmol) and HCl, 5-6 N in IPA (10 mL, 50.0 mmol) was heated at 50° C. for 2.5 h. The reaction was cooled to RT and the solvent was removed in vacuo. The material was basified with 5 N NaOH and diluted with MeOH. The solution was purified by reverse-phase HPLC (Gilson; Gemini-NX 14, C18 110 A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA ACN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo to give a white crystalline solid. m/z: 333.2 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:28][C:29]([F:34])([F:33])[C:30](=O)[CH3:31]>C1(C)C=CC=CC=1>[CH3:31][C@@:30]1([C:29]([F:34])([F:33])[F:28])[NH:10][CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:8][O:9]1
Reactant: NC(CO)c1ccccc1
Reactant: CC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: C[C@@]1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 110 °C
Yield: 84.3 %

Procedure:
25 g (180 mmol) of (R)-phenylglycinol and then 4 g (16 mmol) of pyridinium para-toluenesulfonate are added to a solution of 25.8 g (230 mmol) of trifluoroacetone in 200 mL of toluene in a three-necked flask on which is mounted Dean-Stark apparatus. The mixture obtained is then heated at 110° C. for 5 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by filtration on silica (eluent: dichloromethane) to give 35.10 g of (R)-2-methyl-4-phenyl-2-trifluoromethyloxazolidine in the form of a colorless liquid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[P:22](Cl)(Cl)=[O:23]>>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[P:22]1(=[O:23])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: Cc1ccccc1P(=O)(Cl)Cl
Product: Cc1ccccc1P1(=O)c2ccccc2CN1c1ccccc1
Yield: 8 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 2-methylphenyl phosphonic dichloride. The reaction of the dilithio compound and the 2-methylphenyl phosphonic dichloride was conducted at 0° C. to yield 1-(2-methylphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.8 g, 8% yield) as a yellow solid having a melting point of 181°-183° C. and the following analysis:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>C(Cl)Cl.CO>[Cl:21][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:36][CH:35]=2)=[N:3][CH:4]=1
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1-c1nc(Cl)ncc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(-c4ccc(F)cc4S(=O)(=O)N(C)C)n3)cc2)CC1
Yield: 44 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-(2,5-dichloropyrimidin-4-yl)-5-fluoro-N,N-dimethylbenzenesulfonamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 44% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.39 (m, 2H), 8.08 (m, 1H), 7.48 (d, 2H, J=8.4 Hz), 7.30-7.20 (m, 4H), 3.41 (s, 2H), 2.82 (s, 6H), 2.40 (bs, 8H), 2.22 (s, 3H); MS (ESI): 519.2 [M+H]+.
Reaction SMILES: C1(P(CC)C2C=CC=CC=2)C=CC=CC=1.[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.[C:25]([NH:28][C:29]([CH:41]1[CH2:44][C:43]([NH:52][C:53](=[O:60])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH2:42]1)([CH2:37][CH2:38][CH:39]=[CH2:40])[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:27])[CH3:26]>ClCCl>[C:25]([NH:28][C:29]([CH:41]1[CH2:44][C:43]([NH:52][C:53](=[O:60])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[CH2:42]1)([CH2:37][CH2:38][CH2:39][CH2:40][B:19]1[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]1)[C:30]([NH:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])(=[O:27])[CH3:26]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Agent: CCP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
While under argon, a solution of bis(1,5-dicyclooctadiene)diiridium(I)dichloride (58 mg, 0.086 mmol) and diphenylphosphinoethane (68 mg, 0.172 mmol) in dichloromethane (10 mL) was cooled to 0° C., and charged with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.66 mL, 11.44 mmol). After stirring for 15 min, a solution of N-(3-(2-acetamido-1-(tert-butylamino)-1-oxohex-5-en-2-yl)-1-(4-chlorophenyl)cyclobutyl)benzamide (1.46 g, −2.8 mmol) in dichloromethane (35 mL) was added in one portion and the resulting solution was allowed to slowly warm to room temperature. After stirring for 16 h dichloromethane (40 mL) added and the organic layer was washed with water and saturated aqueous sodium chloride. The resulting solution was dried over MgSO4, filtered and concentrated to give the crude product as a mixture of diastereomers. Purification by flash column chromatography (20-80% ethyl acetate in heptane) gave two products. The more lipophilic isomer was isolated and used in the next step (590 mg, 0.924 mmol). 1H NMR (CDCl3, 600 MHz) δ 8.65 (s, 1H), 7.97 (s, 1H), 7.67 (d, J=7.2 Hz, 2H), 7.49-7.53 (m, 3H), 7.40-7.43 (m, 4H), 6.17 (s, 1H), 3.37-3.42 (m, 1H), 3.30-3.34 (m, 1H), 2.72-2.80 (m, 2H), 2.39-2.51 (m, 2H), 2.31 (s, 3), 1.66-1.72 (m, 2H), 1.30 (s, 9H), 1.19 (s, 12H), 1.10-1.17 (m, 2H), 0.83-8.89 (m, 1H), 0.72 (t, J=7.8 Hz, 2H). ESI MS found for C35H49BClN3O5 m/z [638.7/640.8 (M+1), 636.7/638.9 (M−1)]
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][CH:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1
Reactant: O=C1NCC2(CCC(COCc3ccccc3)CC2)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCC2(CCC(CO)CC2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 385B (500 mg) in ethanol was added to wet 20% palladium hydroxide on carbon (2500 mg) in a 50 ml pressure bottle. The mixture was stirred at ambient temperature for 3 hours under hydrogen at 30 psi. The mixture was filtered and concentrated to provide the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:37][C@@H:38]([C:43]([NH:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:44])[CH2:39][CH2:40][S:41][CH3:42].CN(C)CCN>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:18]([NH:37][C@@H:38]([C:43]([NH:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:44])[CH2:39][CH2:40][S:41][CH3:42])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)CNC(=O)[C@H](N)CCSC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)CCN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 16.88 g of Boc-L-tyrosine in 50 ml of dry dimethylformamide is added 6.65 ml of N-methylmorpholine. The reaction mixture is cooled to -40° C. and 7.84 ml of isobutylchloroformate is added. The reaction mixture is allowed to warm to 0° C. over a 15 minute period then 13.32 g of methyl D-methionyl-glycinate hydrochloride dissolved in 50 ml of dimethylformamide is added followed immediately by 5.2 ml of N-methylmorpholine. The reaction mixture is stirred for 30 minutes at 0° C. After storage overnight at 5° C., 3 ml of N,N-dimethylethylenediamine is added and the reaction mixture is stirred for 15 minutes at room temperature. The solvent is removed under vacuum at 35° C. and 1 mm of pressure and oily residue is dissolved in a mixture of 100 ml of water and 700 ml of ethyl acetate. The ethyl acetate layer is separated and washed three times with 80 ml of a 0.5 M solution of potassium bisulfate, 2 times with 80 ml of water, 2 times with 80 ml of a 0.5 solution of potassium carbonate, and 3 times with 100 ml of a 10% solution of sodium sulfate then dried over magnesium sulfate. The solvent is removed under pressure. The residue is dissolved in 1.2 liters of 5% ethyl acetate in chloroform and purified by low pressure chromatography on silica gel then reduced to dryness under reduced pressure and recrystallized from ethyl acetate to give methyl Boc-L-tyrosyl-D-methionyl-glycinate which is represented by the following formula
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@@H:34]([CH3:51])[CH2:35][N:36]1[CH:40]=[CH:39][C:38]([C:41]2[CH:48]=[C:47]([F:49])[C:44]([C:45]#[N:46])=[C:43]([Cl:50])[CH:42]=2)=[N:37]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:50][C:43]1[CH:42]=[C:41]([C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:34]([NH:33][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:23]4[N:22]=[CH:21][N:20]([C:1]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:24]=4)[CH:29]=3)=[O:31])[CH3:51])[N:37]=2)[CH:48]=[C:47]([F:49])[C:44]=1[C:45]#[N:46]
Reactant: O=C(O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid (0.875 mmol, 0.368 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.673 mmol, 0.250 g) using HBTU (0.067 mmol, 0.026 g) instead of HOBt. DCM (4 ml) was used as the solvent. The reaction mixture was diluted with DCM and washed with 1 M Na2CO3 and water. The separated organic phase was dried, filtered and evaporated to give 0.511 g of crude product. Another crude batch (931 mg) was combined here and purified first by trituration in ACN and then by flash chromatography to give 0.095 g of the product. 1H-NMR (400 MHz, DMSO-d6): δ 1.18 (d, 3H), 4.13-4.53 (m, 3H), 6.64 (s, 1H), 6.98 (d, 1H), 7.09-7.19 (m, 4H), 7.35-7.51 (m, 9H), 7.52-7.57 (m, 1H), 7.70-7.76 (m, 1H), 7.79-7.86 (m, 2H), 7.92 (s, 1H), 7.95 (s, 1H), 8.06-8.10 (m, 1H), 8.14-8.18 (m, 1H), 13.35 (bs, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[H-].[Na+].[CH3:17][O:18][CH2:19]Cl>CN(C=O)C>[CH3:17][O:18][CH2:19][O:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(C(F)(F)F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 2-nitro-5-trifluoromethylphenol (400 mg) in DMF (4.0 ml), sodium hydride (77 mg) was added at 0° C. in a stream of argon. The mixture was stirred for 30 minutes. After stirring, methoxymethyl chloride (147 μl) was added dropwise thereto. The mixture was stirred for 20 minutes. The reaction mixture was quenched by iced water and extracted with ethyl acetate. The layer containing ethyl acetate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=20:1) to give the title compound (353 mg) having the following physical data.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].O.NN>CO.[Ni]>[NH2:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[C:6](=[O:18])[CH2:7][CH2:8]2
Reactant: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CN(C)CCN1C(=O)CCc2cc(N)ccc21
Temperature: 25 °C

Procedure:
A suspension of 1-(2-(dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (320 mg, 1.215 mmol) in dry methanol (10 mL) was treated with Ra—Ni (˜0.05 g) followed by hydrazine hydrate (0.38 mL, 12.2 mmol) at room temperature and the resulting mixture was refluxed for 20 min. The colorless reaction was cooled to room temperature, filtered through a celite pad, washed with methanol (2×10 mL). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95). Yield: 280 mg of colorless oil (98%). 1H NMR (CDCl3) δ: 6.86 (d, J=8.4 Hz, 1H), 6.57 (dd, J=2.7, 8.4 Hz, 1H), 6.51 (d, J=2.1 Hz, 1H), 4.01 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.31 (s, 6H). MS (ESI): 234.2 (M+1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][CH2:11]O.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-:37]>C1(C)C=CC=CC=1>[I:37][CH2:11][CH2:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: [I-]
Reactant: OCCC1Cc2ccccc2C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: ICCC1Cc2ccccc2C1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
A mixture of 2-(indan-2-yl)ethanol (19.3 g), imidazole (12.1 g), triphenylphosphine (34.3 g), and toluene (250 ml) was heated to 90° C. To this mixture, iodide (33.2 g) was added, and the resulting mixture was stirred at 90° C. for 20 min. The mixture was allowed to cool to room temperature. filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:4) to give an oil (28.4 g, 87%).
Reaction SMILES: C(OCC(Cl)=O)C1C=CC=CC=1.[CH2:13]([O:20][CH2:21][C:22]([N:24]=[C:25]=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][C:43]=1[F:49].C1(C)C=CC=CC=1>C(O)C>[CH2:13]([O:20][CH2:21][C:22]([N:24]=[C:25]=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:13]([O:20][CH2:21][C:22]([NH:24][C:25]([NH:46][C:45]1[CH:47]=[CH:48][C:42]([O:41][C:32]2[C:31]3[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=3)[N:35]=[CH:34][CH:33]=2)=[C:43]([F:49])[CH:44]=1)=[S:26])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(COCc1ccccc1)N=C=S
Agent: O=C(Cl)COCc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)COCc4ccccc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
2-(Benzyloxy)ethanoyl isothiocyanate was prepared using commercially available 2-(benzyloxy)ethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-(Benzyloxy)ethanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (33 mg, yield 40%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[CH3:12][OH:13]>>[CH3:12][O:13][C:7]([C:3]1[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:8]
Reactant: CO
Reactant: O=C1OC(=O)c2nccnc21
Product: COC(=O)c1nccnc1C(=O)O
Temperature: 25 °C

Procedure:
A solution of 12.0 g (79.95 mmol) of 2,3-pyrazine dicarboxylic anhydride in 282 mL of MeOH was heated to 65° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. To the obtained residue was added water followed by slow addition of solid NaHCO3. After gas evolution ceased, the aqueous layer was extracted with EtOAc (1×). The aqueous layer was then acidified to pH 2 by addition of conc. HCl. The aqueous layer was extracted with EtOAc (2×) and the combined organics from the second extraction washed with brine (1×). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 12.41 g (85% crude yield) of 3-(methoxycarbonyl)pyrazine-2-carboxylic acid (Compound 6) as a white powder that was used without further purification: 1H NMR (DMSO, 300 MHz): δppm 8.91 (d, J=2.7 Hz, 1H), 8.89 (d, J=2.7 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:19])[NH:17][CH3:18])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34]([NH2:36])=[O:35])[C:28]([Cl:41])=[CH:27][N:26]=1>CC(O)C.Cl>[C:34]([C:33]1[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=1[NH:31][C:29]1[C:28]([Cl:41])=[CH:27][N:26]=[C:25]([NH:1][C:2]2[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:5]([C:10]3[CH:11]=[CH:12][C:13]([C:16](=[O:19])[NH:17][CH3:18])=[CH:14][CH:15]=3)=[CH:6][C:7]=2[O:8][CH3:9])[N:30]=1)(=[O:35])[NH2:36]
Reactant: NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(N)cc2C(=O)OC)cc1
Agent: Cl
Solvent: CC(C)O
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4C(N)=O)n3)cc2C(=O)OC)cc1
Temperature: 150 °C

Procedure:
To the solution of methyl 4-amino-5-methoxy-4′-(methylcarbamoyl)biphenyl-2-carboxylate (Intermediate 27, 117 mg, 0.37 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)benzamide (Intermediate 3, 316 mg, 1.12 mmol) in 3 mL of i-PrOH is added 5 drops of conc. aqueous HCl. The reaction mixture is heated at 150° C. in a microwave reactor for 30 min, followed by concentration and purification by silica gel chromatography (MeOH/DCM: 1/9) to afford methyl 4-(4-(2-carbamoylphenylamino)-5-chloropyrimidin-2-ylamino)-5-methoxy-4′-(methylcarbamoyl)biphenyl-2-carboxylate; ESMS m/z 561.2 (M+H+).