Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:8]([NH2:10])=[O:9])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To a solution of (D)-leucinamide hydrochloride (0.25 g, 1.5 mmol), and Et3N (0.43 mL, 3.0 mmol) in CH2Cl2 (150 mL) was added 4-chlorobenzenesulfonyl chloride (380 mg, 1.8 mmol). The resulting solution was stirred at rt for 18 h. The reaction was then diluted with CH2Cl2 (200 mL) and washed with H2O, 0.5 N HCl, brine, and dried over MgSO4, to afford the titled compound (410 mg) as a white solid in 90% yield. MS (ESI), (M+H)+ 305.2; 1H NMR (DMSO-d6) δ 7.77 (d, 2H, J=8.7), 7.62 (d, 2H, J=8.7), 6.90 (br s, 1H), 3.67 (m, 1H), 1.54 (m, 1H), 1.31 (m, 2H), 0.81 (d, 3H, J=7.0), 0.71 (d, 3H, J=7.0).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1c(Cl)ncnc1Nc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1c(Cl)ncnc1Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
6-chloro-N4-phenylpyrimidine-4,5-diamine obtained in step 1 (35 g, 158.6 mmol) was dissolved in N,N-dimethylacetamide (265 ml) at 0° C. Benzoyl chloride (20.5 mL, 174.5 mmol) was added slowly to the resulting solution at 0° C. and warmed to room temperature. The reaction mixture thus obtained was stirred for 4 hours at room temperature and filtered with NaHCO3(aq)/H2O. The collected solid was dried under reduced pressure to obtain the title compound (50.1 g, 97%) as white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[NH:32]1[C:40]2C(=CC=CC=2)[C:34](CCCC(O)=O)=[CH:33]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[NH:32]1[C:33]2[C:2](=[CH:7][CH:6]=[CH:5][CH:34]=2)[C:3]([CH2:4][CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:40]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2c[nH]c3ccccc23)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(1H-indol-3-yl)-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCC3)n2)c1

Procedure:
B14 was prepared following the general procedure reported for B10 using A1 and pyrrolidine. Yield: 96.6 mg (29%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.84-1.96 (m, 4H), 3.43-3.55 (m, 4H), 4.18 (s, 2H), 6.81 (s, 2H), 6.96 (d, J=7.6 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.86 (s, 1H), 8.18 (s, 1H), 9.59 (s, 1H). MS (ES) C14H18N6O2S requires: 334. found: 335 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:10](=O)[C:9]2[CH:8]=[C:7]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:6]3=[CH:5][C:4]=2[CH2:3]1.[BH4-].[Na+].C(O)C.Cl>C(OCC)C>[CH3:1][C:2]1[CH2:10][C:9]2[CH:8]=[C:7]3[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC1Cc2cc3c(cc2C1=O)C(C)(C)CCC3(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC1=Cc2cc3c(cc2C1)C(C)(C)CCC3(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(2,3,5,7-Tetrahydro-2,5,5,8,8-pentamethyl-1H-Benz(f)inden-1-one (14.89 g, 58.08 mmol) and NaBH4 (2.21 g, 58.5 mmol) were stirred in diethylether (200 mL) at 0° C. as ethanol (100 mL) was added slowly. This mixture was allowed to warm slowly to room temperature and then stirred at room temperature overnight. After the reaction period the mixture was poured onto crushed ice and made acidic with HCl. The organic layer was then separated and washed with 1M HCl (1×100 mL). The volatiles were then removed from the organic layer and the residue refluxed in benzene (300 mL) with ptoluenesulfonic acid (0.12 g) using a Dean-Stark apparatus until no more H2O was evolved. The mixture was then washed with 1 M NaHCO3 (2×100 mL) and the volatiles were removed from the organic layer resulting in the isolation of a yellow oil. Recrystallization from MeOH (0° C.) gave the desired product as off-white crystals (10.37 g, 74.3 percent yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:5]=1.BrC1C([F:35])=C(C=C(Br)C=1)C(OC)=O>>[F:35][C:5]1[C:6]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])=[CH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:22]
Reactant: COC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Reactant: COC(=O)c1cc(Br)cc(Br)c1F
Product: COC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F

Procedure:
Prepared in an analogous manner to D7 from methyl 3,5-dibromo-2-fluorobenzoate (D38).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].C([Li])CCC.CN(C)CCN(C)C.[C:25]([C:29]1[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:32]2[O:33][P:34](Cl)[O:35][C:36]3[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:38][C:37]=3[C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>CCCCCC.O1CCCC1>[C:46]([C:39]1[CH:40]=[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]2[O:35][P:34]([C-:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[O:33][C:32]3[C:51]([C:53]([CH3:55])([CH3:54])[CH3:56])=[CH:52][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][C:31]=3[C:37]=2[CH:38]=1)([CH3:49])([CH3:48])[CH3:47].[C-:6]1([P:34]2[O:35][C:36]3[C:41]([C:42]([CH3:43])([CH3:44])[CH3:45])=[CH:40][C:39]([C:46]([CH3:48])([CH3:49])[CH3:47])=[CH:38][C:37]=3[C:31]3[CH:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:32]=3[O:33]2)[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: c1cc[cH-]c1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(C)(C)C)c2op(-[c-]3cccc3)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a solution of 9.5 g (50 mmol) of ferrocene in 250 mL of hexane is added dropwise 67 mL of a 1.6M solution of n-butyl lithium at ambient temperature. The reaction mixture is stirred for 20 minutes and then to the resultant red suspension is added 12.0 g (103 mmol) of N,N,N',N'-tetramethylethylenediamine. A slight exotherm of 10° C. is observed. The reaction mixture is then heated at reflux for two hours during which time an orange suspension forms. The reaction mixture is cooled to room temperature and 100 mL of tetrahydrofuran is then added. The reaction mixture is cooled to -40° C. Then to the cooled reaction mixture is added dropwise a solution of 51.8 g (109 mmol) of 2,4,8,10-tetrakis(tert-butyl)-6-chloro-dibenzo[d,f][1,3,2]dioxaphosphepin in 100 mL of tetrahydrofuran. The reaction mixture is allowed to warm to ambient temperature after the addition is complete. The reaction mixture is then heated at reflux for six hours. After cooling, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue formed is triturate with 150 mL of hexane. The resultant solid is recrystallized from acetonitrile/tetrahydrofuran mixture to give 25 g (47% yield) of a light brown solid.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[CH:4]([CH3:11])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([NH:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5][CH:4]([C:3]([F:12])([F:13])[F:2])[CH3:11])(=[O:18])[CH3:17]
Reactant: CC(C[C@H](N)C(=O)O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@@H](CC(C)C(F)(F)F)C(=O)O
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of the 5,5,5-trifluoroleucine HCl salt (from Step 1 above) in H2O (30 mL) was added 1M aqueous NaOH (60 mL, 60 mmol) followed by acetic anhydride (3.5 mL, 36.7 mmol). The mixture was stirred at room temperature for 30 min to 1 h. After acidification with 6M aqueous HCl (6 mL), the mixture was extracted with EtOAc (6×). The combined EtOAc extracts were washed with brine, dried (MgSO4) and concentrated. The residue was swished with hexanes:Et2O (1:1) to afford N-acetyl-5,5,5-trifluoroleucine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:3]=1[O:4][C@H:5]([CH3:27])[C:6]([NH:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH2:23][CH3:24])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@@H:12]([F:25])[C@@H:11]1[OH:26])=[O:7].[C:35]([NH:42][C@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[C:38]([O:37][C:35]([NH:42][C@H:43]([C:47]([O:26][C@@H:11]1[C@@H:10]([CH2:9][NH:8][C:6](=[O:7])[C@H:5]([O:4][C:3]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:2]=2[Cl:1])[CH3:27])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([CH2:23][CH3:24])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[C@H:12]1[F:25])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:36])([CH3:40])([CH3:41])[CH3:39]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Product: CCc1cn([C@@H]2O[C@H](CNC(=O)[C@@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H]2F)c(=O)[nH]c1=O

Procedure:
Coupling of 1-[5-[2(R)-(2,4-dichloro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil with N-Boc-L-valine in a manner analogous to that described in Example 1(A) gave 1-[3-O-[N-(tert-butoxycarbonyl)-L-valyl]-5-[2(R)-(2,4-dichloro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl]-5-ethyluracil as a white solid, m.p. 110° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[C:6]([S:19](Cl)(=[O:21])=[O:20])=[C:5]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.N.C([N:33](CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[C:6]([S:19](=[O:21])(=[O:20])[NH2:33])=[C:5]([O:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: CCN(CC)CC
Reactant: CCOC(=O)COc1cc(OC)c2c(c1S(=O)(=O)Cl)OC1(CCCCC1)CC2=O
Agent: N
Solvent: ClCCl
Product: CCOC(=O)COc1cc(OC)c2c(c1S(N)(=O)=O)OC1(CCCCC1)CC2=O
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
A solution of ethyl 2-{(5-methoxy-8-chlorosulfonyl -3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-7-yl)oxy}acetate (prepared in Preparation 70) (0.32 g, 0.74 mmol) in dichloromethane (4 ml) is added dropwise to a solution of liquid ammonia (2 ml, 80 mmol) and triethylamine (0.1 ml, 0.7 mmol) in dichloromethane (4 ml) at -25° to -20 ° C. After stirring at the same temperature for 30 minutes, the solvent is removed by distillation. The residue is placed on a silica gel column and eluted with a mixture of acetone and dichloromethane (1:1) to yield the title compound as a crystalline solid (0.173 g, yield 56.5%). Recrystallization from a mixture of ethyl acetate and ether gives a product having a melting point of 188°-190° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[CH2:12](OC(OCC)OCC)C.C(OC(=O)C)(=O)C>>[Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]2[N:9]([CH3:12])[CH:10]=[N:11][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CNc1c(N)cc(Br)nc1Cl
Solvent: CC(=O)OC(C)=O
Product: Cn1cnc2cc(Br)nc(Cl)c21
Temperature: 155 °C

Procedure:
The above crude diamine 2.59-A was dissolved in a mixture of triethylorthoformate:Acetic anhydride (1:1, 9 mL). The reaction mixture was heated to 155° C. for 1 h, cooled to rt and then evaporated. The residue was dissolved in 2.5M NaOH (20 mL) and heated at 50° C. 45 min. The resulting solution was cooled to rt, neutralized with AcOH, and cooled to 0° C. The precipitate was filtered to give 6-bromo-4-chloro-3-methyl-3H-imidazo[4,5-c]pyridine 2.60.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([S:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1.[CH:31](=O)[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([S:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:4]1)[CH3:32]
Reactant: CC=O
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(n2cc(-c3cnc4ccc(Sc5nnc6ccc(C)nn56)cc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
To 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (63 mg, 0.152 mmol) in dichloromethane (3.0 mL) was added acetaldehyde (34 uL, 0.608 mmol). The solution was stirred at room temperature for 15 minutes and then sodium triacetoxyborohydride (80 mg, 0.380) was added. After 1 hour the solution was diluted with dichloromethane (3.0 mL) and washed with sodium bicarbonate (3.0 mL). The aqueous layer was extracted further with dichloromethane (3.0 mL). The combined dichloromethane layers were washed with brine (6 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, dichloromethane:CH3OH:NH4OH, 95:4.995:0.005-80:19.98:0.02) to return 23 mg of 3-[1-(1-ethyl-azetidin-3-yl)-1H-pyrazol-4-yl]-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (34% yield).
Reaction SMILES: C(O[C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])C.[CH2:10]([NH2:13])[CH2:11][NH2:12].C(N(CC)CC)C>CO>[C:5]([C:4]([NH:12][CH2:11][CH2:10][NH2:13])=[O:9])([F:6])([F:7])[F:8]
Reactant: NCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: NCCNC(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
N-1-trifluoroacetylethyldiamine (CF3CONH(CH2)2NH2 is prepared by adding ethyltrifluoroacetate (1.2 ml, 10 mmol) dropwise over one hour to a stirred mixture of ethylenediamine (0.6 g; 10 mmol) and triethylamine (1 ml; 7 mmol) in 20 ml methanol. The solution is stirred overnight. After removal of solvents, the reaction mixture is flash chromatographed on silica using 0-25% methanol in dichloromethane. The fractions containing the desired product are pooled and concentrated to give a colorless product.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].N1C=CN=C1.[Si:60](Cl)([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 30.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (1.04 g) in dry methylene chloride (25 ml) was added an excess of imidazole (280 mg) followed by tert-butyldimethylsilyl chloride (228 mg). After 21 hours of stirring at room temperature, the mixture was quenched by the addition of half-saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (370 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])C(C(F)(F)F)=[CH:10][C:9]=1[NH:23][C:24](=[O:47])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[C:37]([CH2:38][O:39]C3CCCCO3)=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.[C:49](O)([C:51]([F:54])([F:53])[F:52])=O>C(Cl)Cl>[OH:39][CH2:38][C:37]1[N:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:47])[NH:23][C:9]4[CH:10]=[C:49]([C:51]([F:54])([F:53])[F:52])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[N:34]=[N:35][CH:36]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M102) (0.15 g, 0.22 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (31 mg, 30%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[N+:32]([C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br)([O-:34])=[O:33]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[N+:32]([O-:34])=[O:33])[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3ccccc3[N+](=O)[O-])[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide as the starting material and o-nitrobenzyl bromide in place of methyl iodide. The crude product is triturated from 50% EtOAc/hexanes to afford the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=[O:14])=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Si](C)(C)C)=[CH:18][C:17]=1[F:26].C1C(=O)N([Br:35])C(=O)C1>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=[O:14])=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:35])=[CH:18][C:17]=1[F:26]
Reactant: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a solution of 5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester (2.6 g, 6.6 mmol) in dichloromethane (65 mL) at −30° C. was added NBS (1.2 g, 6.6 mmol). The reaction mixture was stirred at −30° C. for 1.5 hours, and then concentrated under reduced pressure The resultant residue was taken up in ethyl acetate and this organic solution was washed with a saturated aqueous solution of sodium bicarbonate, followed by brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound as a brown solid (2.49 g, 95%). LCMS (method B): RT=3.79 min, [M+H]+=400/402.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]=[O:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:35][CH:34]=2)[OH:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccc(CN2CCOCC2)cc1
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Solvent: C1CCOC1
Product: OC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (12.50 mmol) in tetrahydrofuran (100 mL) at 0° C. was dropwise added a 0.25M solution of [4-(4-morpholinylmethyl)phenyl]magnesium bromide in tetrahydrofuran (12.50 mmol, 1.0 eq.) and stirring at 0° C. was continued for 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred 20 min then quenched with saturated aqueous sodium bicarbonate solution (100 mL). After stirring 5 min the reaction mixture was extracted with ethyl acetate (3×75 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to give a thick brown syrup that was purified by column chromatography using 30% acetone/dichloromethane to give the final product as a white solid (1.50 mmol, 12%). MS (ESI) m/z 489.3; HRMS: calcd for C29H29ClN2O3+H+, 489.19395; found (ESI, [M+H]+ Obs'd), 489.1941.