Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C(OC([N:35]1[C:39]([C:40]#[N:41])=[CH:38][CH:37]=[C:36]1B(O)O)=O)(C)(C)C>>[C:40]([C:39]1[NH:35][C:36]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][CH:11]=2)=[O:8])=[CH:37][CH:38]=1)#[N:41]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 29 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1) and (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1) to afford an off-white solid. UPLC-MS (Condition 3) tR=1.03 min, m/z=458.1[M+H]+, m/z=456.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (m, J=6.48, 3.06 Hz, 1H) 1.82-1.92 (m, 1H) 2.95 (d, J=11.49 Hz, 1H) 3.26 (dd, J=11.74, 4.65 Hz, 1H) 3.31-3.34 (m, 1H) 3.40-3.50 (m, 1H) 4.19-4.28 (m, 1H) 4.88 (d, J=3.42 Hz, 1H) 6.31 (dd, J=3.67, 2.20 Hz, 1H) 7.01 (dd, J=3.67, 2.20 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.82-7.89 (m, 2H) 8.07 (d, J=2.45 Hz, 1H) 8.76 (d, J=2.45 Hz, 1H) 10.16 (s, 1H) 12.59 (br. s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([F:36])[C:18]=1[C:19]1[N:23]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][NH:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:21]=2[N:20]=1)[C:12]([NH:14][CH3:15])=[O:13].Cl[C:38]([O:40][CH3:41])=[O:39].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:36][C:17]1[CH:16]=[C:11]([C:12](=[O:13])[NH:14][CH3:15])[CH:10]=[C:9]([F:8])[C:18]=1[C:19]1[N:23]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:38]([O:40][CH3:41])=[O:39])[CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:21]=2[N:20]=1
Reactant: CNC(=O)c1cc(F)c(-c2nc3cc(C)ccc3n2C[C@@H]2CNCCO2)c(F)c1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)c(-c2nc3cc(C)ccc3n2C[C@@H]2CN(C(=O)OC)CCO2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
A mixture of (S)-3,5-difluoro-N-methyl-4-(5-methyl-1-(morpholin-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)benzamide trifluoroacetic acid salt (150 mg, 0.37 mmol), methyl chloroformate (0.058 mL, 0.75 mmol), and N,N-diisopropylethylamine (0.072 mL, 0.41 mmol) in DCM (10.00 mL) was stirred at room temperature for 30 min. The mixture was then concentrated under reduced pressure, and the residue was purified on preparative HPLC MS using the short high pH shallow gradient method (mobile phase: 30-50% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 10 min run; XBridge Prep C18 OBD, Waters reverse phase column; column size: 30×50 mm; particle size: 5 μm). This produced to afford (R)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-5-methyl-1H-benzo[d]imidazol-1-yl)methyl)morpholine-4-carboxylate (41.7 mg, 24% yield) as a solid. The solid was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; and particle size: 5 μm). MS m/z 459.3 [M+H]+ (ESI), Rt 1.58 min. 1H NMR (400 MHz, methanol-d4) δ ppm 2.50 (s, 3H) 2.54 (dd, J=4.49, 3.71 Hz, 1H) 2.69-2.84 (m, 1H) 2.96 (s, 3H) 3.25 (td, J=11.91, 2.73 Hz, 1H), 3.55-3.64 (m, 2H), 3.66 (s, 3H), 3.74 (d, J=12.89 Hz, 1H), 3.96 (d, J=12.89 Hz, 1H), 4.16 (dd, J=15.23, 7.42 Hz, 1H), 4.37 (dd, J=15.23, 3.12 Hz, 1H), 7.26 (dd, J=8.59, 1.17 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=8.59 Hz, 1H), 7.64 (d, J=8.59 Hz, 2H). HRMS m/z calcd for C23H25F2N4O4 459.1838 [M+H]+. found 459.1849.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1.[F:32][C:33]([F:40])([F:39])[CH:34]=[CH:35][C:36](O)=[O:37].O>C1COCC1.CN(C=O)C>[Br:31][C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:36](=[O:37])[CH:35]=[CH:34][C:33]([F:40])([F:39])[F:32])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: O=C(O)C=CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(C=CC(F)(F)F)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Yield: 34.8 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol) was added to a solution of 6-amino-4[(3-bromophenyl)amino]quinazoline (158 mg, 0.5 mmol) and 4,4,4,-trifluorobut-2-enoic acid (153 mg, 1.1 mmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 1 hour water (10 mL) was added and after 15 minutes the precipitate was collected by Buchner filtration. The residue was rinsed with water (2×5 mL) and ether (10 mL) and air dried. The solid was suspended in EtOAc, (10 mL) refluxed briefly, and sonicated for 10 minutes, and the solid was collected by Buchner filtration, rinsed with EtOAc (5 mL) and dried in a vacuum oven at 75° C. for 1.5 hours to give N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]4,4,4-trifluorobut-2-enamide 0.4 hydrochloride (76 mg, 33%) as a light yellow solid, mp 273-278° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:43])([CH3:42])[C:40]#[N:41])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:40]([C:39]([C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:11][C:12]=3[CH:13]=2)=[O:25])=[CH:38][CH:37]=1)([CH3:43])[CH3:42])#[N:41]
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: CC(C)(C#N)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(C(C)(C)C#N)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 8.7 %

Procedure:
The title compound was prepared following the procedure described for Example-177 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.265 mmol), oxalyl chloride (0.2 mL), 2-(4-aminophenyl)-2-methylpropanenitrile (Intermediate-22, 0.063 g, 0.397 mmol), THF (5.0 mL), DIPEA (0.103 g, 0.795 mmol) and TEA (0.2 mL). The obtained crude product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.69 (s, 6H), 2.66 (s, 3H), 7.42 (t, J=7.8 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.61 (s, 3H), 7.82 (d, J=9.0 Hz, 2H), 9.45 (s, 1H), 10.11 (s, 1H), 11.58 (s, 1H); MS [M+H]+: 519.32.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:4]([CH3:9])[CH:3]=1
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(Br)ccc1O
Product: COCCOCCOc1ccc(Br)cc1C

Procedure:
Prepared by the method of Example 42 (b) from 4-bromo-2-methylphenol and 2-(2-methoxyethoxy)ethyl tosylate.
Reaction SMILES: [OH2:1].[Si:2](Cl)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:10][SiH:11]([CH3:13])Cl>C(OC(C)C)(C)C>[C:5]([Si:2]([CH3:4])([CH3:3])[O:1][SiH:11]([CH3:13])[CH3:10])([CH3:8])([CH3:7])[CH3:6]
Reactant: O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[SiH](C)Cl
Solvent: CC(C)OC(C)C
Product: C[SiH](C)O[Si](C)(C)C(C)(C)C
Temperature: 32.5 °C

Procedure:
A 1 L round bottom flask was charged with water (95 g) and diisopropyl ether (50 g) and stirred. A solution of tert-butyldimethylsilyl chloride (39.5 g) in isopropyl ether (50 g) was charged to an addition funnel, and added dropwise to the water/IPE mixture at a rate to maintain the reaction temperature between 30-35° C. After complete addition, the reaction temperature was brought to 40° C. and maintained for 1 h. A solution of dimethylchlorosilane (24.8 g) in isopropyl ether (50 g) was then charged to the addition funnel, and this solution was added dropwise at 40-45° C. After complete addition, the reaction mixture was heated to reflux for 1 h and allowed to cool. After aqueous workup (washing with water and aqueous NaHCO3, and drying organic fractions over MgSO4), the product was isolated by fractional distillation under vacuum to yield 39.2 g M(R)M′ product/isopropyl ether solution (70%/20% by GC analysis). This product was found to have an Si—H content of 79 cc H2/g by gasiometric titration.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[C:15]1([C:21]2([NH2:24])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:14][S:13][C:4]1[N:3]=[C:2]([NH:24][C:21]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:23][CH2:22]2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NC1(c2ccccc2)CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1NC1(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 104.2 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (550 mg, 2.36 mmol) and 1-phenylcyclopropanamine (420 mg, 3.16 mmol) in CH3CN (6 mL) at room temperature was added DIEA (0.5 mL, 2.60 mmol). The mixture was stirred at room temperature for 3 h and 50° C. for 3 h. The mixture was diluted with EtOAc, washed with 1N HCl, Sat. NaHCO3, brine, dried and concentrated to give ethyl 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylate (810 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[CH2:11][O:10]2)=[CH:4][N:3]=1.[NH2:12][CH2:13][CH2:14][OH:15].CCOC(C)=O.C1COCC1>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]([OH:10])[CH2:11][NH:12][CH2:13][CH2:14][OH:15])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C2CO2)cnc1Br
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)CNCCO)cnc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (RS)-2-bromo-3-methyl-5-(oxiran-2-yl)pyridine (1.4 g) in THF (6 ml) was added 2-aminoethanol (3.92 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1:1) and the mixture was washed with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(6-bromo-5-methylpyridin-3-yl)-2-(2-hydroxyethylamino)ethanol (1.76 g) as an off-white solid which was used in the next step without further purification. MS (ISP): 277.0 ([{81Br}M+H]+), 275.0 ([{79Br}M+H]+), 258.9 ([{81Br}M+H—H2O]+), 257.0 ([{79Br}M+H—H2O]+).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[S:24])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(-c2ccc3nc(N)[nH]c(=O)c3n2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2ccc3nc(N)[nH]c(=S)c3n2)cc1OC

Procedure:
A suspension of 2-amino-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)one (100 mg, 0.34 mmol) and phosphorus pentasulfide (163 mg, 0.37 mmol) in pyridine (10 ml) was refluxed for 4 hours. The solvents were evaporated in vacuo. The residue was re-suspended in a small amount of water and filtered off, yielding the title compound which was used without any further purification and which was characterised as follows: MS (m/z): 315 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36][OH:37].[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=1.CCCCCC>N1C=CC=CC=1>[C:47]([O:37][CH2:36][CH:35]=[C:34]([CH3:38])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:39])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:40])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:41])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:42])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:43])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:44])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:45])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH3:1])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C(Cl)c1cccnc1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 Grams of solanesol were dissolved in 50 ml of pyridine and the solution was added with a solution of 4.5 g. of nicotinic acid chloride in pyridine dropwise over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for two hours to complete the reaction. The reaction product was diluted with-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 80 g. of silica gel in n-hexane/ether solvent mixture as elution solvent to obtain white yellow waxy final product. Yield 6.5 g.______________________________________Elementary analysis as C51H77NO2 : C H N______________________________________Theoretical (%): 83.21 10.54 1.90Found (%): 83.18 10.55 1.92______________________________________
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10]CC[C:7]2=[O:12].C([O:17]O)(C)(C)C.C[O-].[Na+].O>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7]([OH:12])=[O:17])[C:11]=1[NH2:10]
Reactant: O=C1CCNc2c(F)cccc21
Reactant: CC(C)(C)OO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)cccc1C(=O)O
Yield: 51.6 %

Procedure:
A solution of 0.25 g (1.5 mmol) of 8-fluoro-2,3-dihydroquinolin-4-one, 0.8 g (6.2 mmol) of 70 percent t-butyl hydroperoxide, 2 mL of 25 percent sodium methoxide in methanol and 3 mL of methanol were stirred at 75° C. for 72 hr. An additional 1 mL of 70 percent t-butyl hydroperoxide and 2 mL of 25 percent sodium methoxide in methanol were added and heating was continued for 72 more hr. The reaction mixture was cooled, poured into water and neutralized with acetic acid. The mixture was extracted with methylene chloride and the organic phase was collected. Evaporation of the solvent gave 0.12 g (51 percent yield) of 3-fluoroanthranilic acid, identical in all respects to an authentic sample.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C1C=CC=CC=1.O.[NH2:22][NH2:23]>O>[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:2]1[NH:23][N:22]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NN
Solvent: O
Solvent: c1ccccc1
Product: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Yield: 83 %

Procedure:
A mixture of 20.8 g (0.1 mole) of 4-chloro-3-nitroquinoline, 40 ml of benzene and 40 ml of hydrazine hydrate is refluxed for 2 hours, then cooled. The separated phase containing hydrazine hydrate is diluted with 150 ml of water. Yellow-white crystals separate. Thus, 16.8 g (83%) of 5-(o-aminophenyl)-4-nitropyrazole are obtained. M.p.: 175°-176° C. (ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:18])[CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.C(Cl)(Cl)Cl.[CH2:30]([O:32][CH2:33][C:34](Cl)=O)[CH3:31]>ClCCl>[CH2:30]([O:32][CH2:33][C:34]1[N:12]([CH2:13][C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:31]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a mixture of 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanol (23.1 mmol, prepared as described in Part D) in dichloromethane (154 mL) and triethylamine (3.54 mL, 25.4 mmol) at 0° C. was added chloroform (100 mL). The mixture was allowed to warm to room temperature and approximately two thirds of the starting material dissolved. To the mixture was slowly added ethoxyacetyl chloride (88% purity, 3.1 g, 24.3 mmol). The solution was stirred at room temperature for 2 hours. More triethylamine (2 mL) and ethoxyacetyl chloride (88% purity, 1.0 g) were added. After an additional 16 hours, the reaction solution was concentrated under reduced pressure. To the residue was added ethanol (190 mL) and triethylamine (13 mL). The resulting solution was heated at reflux for 20 hours and then was concentrated under reduced pressure to yield a yellow solid. The solid was partitioned between dichloromethane (400 mL) and water (100 mL). The organic layer was washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was crystallized from acetonitrile and the crystals were isolated by filtration to provide 4.52 g of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol.
Reaction SMILES: [C:1]([S:9][CH2:10][C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:27]1[C:31](=[O:32])[CH2:30][CH2:29][C:28]1=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:28]1(=[O:33])[N:27]([N:13]([C:11](=[O:12])[CH2:10][S:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[O:16])[C:31](=[O:32])[CH2:30][CH2:29]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=O)CSC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)CNC(=O)CN(C(=O)CSC(=O)c1ccccc1)N1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a 50 ml round bottom flask, 0.37 g (1 mmole) of benzoylmercaptoacetylglycylglycylglycine and 0.126 g (1.1 mmole) of N-hydroxy succinimide are dissolved in approximately 25 mL of tetrahydrofuran and cooled to 5°-10° C. in an ice bath. To this solution, 0.23 g (1.1 mmole) of N,N'-dicyclohexylcarbodiimide is added. The solution is allowed to warm to room temperature and is stirred for 48 hours and the course of the reaction followed by TLC. The precipitate is removed by filtering; the filtered solution is evaporated to dryness under vacuum. The residue is redissolved in 50-60 mL of dichloromethane; this solution is filtered and evaporated to dryness under vacuum. The residue is redissolved in 5-6 mL ethanol with warming and allowed to crystallize for 3-4 hours. The crystals of product succinimidyl-MAGGG are recovered by filtration.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:43]1=[O:58]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:43]1=[O:58])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: COc1cccc(CN2CCCC[C@H](N)C2=O)c1
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(Cc4cccc(OC)c4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-methoxybenzyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 43 (3.1 mg, 0.012 mmol) to give a white solid (7.1 mg, 70% yield). Anal. Calcd. for C45H56N4O7S m/z 796.7. found: 797.7 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.25-7.19 (m, 5H), 7.19-7.11 (m, 8H), 6.85-6.72 (m, 3H), 5.33 (t, J=4.67 Hz, 1H), 5.12 (d, J=6.60 Hz, 1H), 5.04-4.95 (m, 1H), 4.63-4.43 (m, 3H), 3.78 (s, 3H), 3.67 (s, 3H), 3.46 (dd, J=15.12, 11.82 Hz, 1H), 3.24-3.12 (m, 3H), 2.86-2.70 (m, 5H), 2.46-2.37 (m, 3H), 2.02 (d, J=4.95 Hz, 1H), 1.84-1.49 (m, 11H), 1.28-1.23 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH:4]1[NH:9][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][CH2:5]1.Cl.[OH-:19].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH:4]([NH:9][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:5][O:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:19])=[O:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)CC1COC(c2ccccc2)C(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)CC(COC(C(=O)O)c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
5-(2-Methylpropyl)-2-phenyl-3-morpholinone (center phenyl is R, S, other center is S), 0.95 g (0.0041 mole), was suspended in a solution of 50 ml of concentrated hydrochloric acid and 50 ml of water, heated for one hour on a steam bath, cooled to room temperature, and extracted with 100 ml of dichloromethane. The aqueous layer was separated and the pH adjusted with sodium hydroxide to pH 10.5 and 0.84 g (0.0049 mole) of benzyl chloroformate was added dropwise while the pH was maintained at 10.5 with sodium hydroxide. After addition was complete the mixture was extracted with 100 ml of diethylether, the aqueous layer was separated and the pH adjusted to 3 by the addition of a 10% aqueous solution of hydrochloric acid. The mixture was extracted with 200 ml of dichloromethane. The dichloromethane layer was separated, dried over sodium sulfate, evaporated in vacuo and the residue purified by chromatography using silica gel and eluting with 1 l of dichloromethane-methanol (95:5) to give α-[[4-methyl-2[[(phenylmethoxy)carbonyl]amino]pentyl]oxy]benzeneacetic acid (α-carbon is R, S, other stereo site is S), 1.1 g; [α]D25 =-78.9° (C, 0.56, methanol).
Reaction SMILES: N(OCCC(C)C)=O.[CH:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2N)[CH2:11][CH2:10]1.[I:19]CI>C1COCC1.[Cu](I)I>[CH:9]1([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[I:19])[CH2:11][CH2:10]1
Reactant: ICI
Reactant: Nc1cnccc1C1CC1
Agent: I[Cu]I
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Ic1cnccc1C1CC1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
Isoamyl nitrite (2.62 gm, 22.38 mmol) was added to a stirred solution of 4-cyclopropylpyridin-3-amine (I-73b: 1.0 gm, 7.46 mmol) in dry THF (15 mL) under argon atmosphere. This was followed by the addition of diiodomethane (3.0 mL, 22.38 mmol) and copper iodide (1.42 gm, 7.46 mmol). The resulting mixture was refluxed at 80° C. for 1 hour. The reaction mixture was cooled, filtered and the filtrate was partitioned between ethyl acetate and water. The organic layer was concentrated to yield the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 600 mg of the product (34% yield).