Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:31]=1[C:32](O)=[O:33]>>[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:31]=1[C:32]([N:23]1[CH2:24][CH2:25][CH:20]([N:18]2[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]3[C:8]4[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[N:19]2)[CH2:21][CH2:22]1)=[O:33]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: Cc1ccc(C)c(C(=O)O)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(C)ccc4C)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B5) and 2,5-dimethylbenzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>ClC1C=CC=CC=1.CN(C)C1C=CN=CC=1>[ClH:1].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]([NH:18][C:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[NH:28])[CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C(=O)NCCCCc2ccccc2)c1
Reactant: N#CN1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Clc1ccccc1
Product: N=C(Nc1cccc(C(=O)NCCCCc2ccccc2)c1)N1CCCC1
Temperature: 25 °C

Procedure:
To a stirred suspension of the product of step (a), 2.0 g, 0.006 moles, in 35 ml of chlorobenzene was added 4-dimethylaminopyridine. To this was added 1-pyrrolidinecarbonitrile, 1.5 ml; 0.008 moles, and the reaction was heated to reflux for 4hours. The reaction cooled to room temperature and the solvent was decanted. To the residue was added 25 ml of isopropanol and 150 ml of ethyl acetate. A solid crystallized and was collected by filtration. The above solid was then dried at 80° C. for 24 hours to give N-[3-(((4-phenylbutyl)amino)carbonyl)phenyl]-1-pyrrolidinecarboximidamide hydrochloride, 2.3 g, m.p. 197°-198° C.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: COc1ccc(CO)cc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2C#N)cc1
Yield: 81 %

Procedure:
Prepared as in Example 112c from 2,6-dinitrobenzonitrile and 4-methoxybenzyl alcohol to provide 2-nitro-6-(4-methoxybenzyloxy)benzonitrile (2.40 g, 81%). 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 5.26 (s, 2H), 6.93 (m, 2H), 7.35 (dd, J=8.6, 0.7 Hz, 1H), 7.38 (m, 2H), 7.65 (t, J=8.6 Hz, 1H), 7.83 (dd, J=8.2, 0.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-])=O)=[C:6]([NH:8][CH2:9][C:10]2([CH3:26])[CH2:25][CH2:24][CH2:23][C:12]3([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]3)[CH2:11]2)[CH:7]=1.[CH:30](O)=O.C(OC)(OC)OC>CO.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:27]=[CH:30][N:8]([CH2:9][C:10]3([CH3:26])[CH2:25][CH2:24][CH2:23][C:12]4([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]4)[CH2:11]3)[C:6]=2[CH:7]=1
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CNc3cc(Cl)ccc3[N+](=O)[O-])C2)OC1=O
Reactant: O=CO
Agent: [Fe]
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)CN1CC2(CCCC(C)(Cn3cnc4ccc(Cl)cc43)C2)OC1=O
Temperature: 65 °C

Procedure:
A solution containing 7-(((5-chloro-2-nitrophenyl)amino)methyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.100 g, 0.236 mmol) in MeOH (5 mL) was treated with iron (325 mesh) (0.132 g, 2.36 mmol) followed by formic acid (0.090 mL, 2.359 mmol) and trimethyl orthoformate (0.261 mL, 2.359 mmol). The resulting mixture was heated at 65° C. for 18 h. LCMS indicated partial conversion to desired product. Additional iron (0.100 g, 1.79 mmol), formic acid (0.200 mL, 5.22 mmol), and trimethyl orthoformate (0.500 mL, 4.53 mmol) were added, and the reaction was stirred at 80° C. for 3 h. The reaction was cooled to rt and filtered through filter paper. The collected solids were washed with MeOH, and the combined MeOH washings and filtrate were concentrated. The crude product was purified by reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 14 minute run; 40 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1 TFA, gradient: 10-90% solvent A) to afford the title compound (0.071 g, 52% yield) as the TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.88 (br. s., 1H), 7.89 (d, J=8.78 Hz, 1H), 7.56 (d, J=1.51 Hz, 1H), 7.49 (dd, J=1.63, 8.66 Hz, 1H), 7.27 (s, 1H), 4.08 (s, 2H), 3.26-3.40 (m, 1H), 3.06 (d, J=14.05 Hz, 1H), 2.92 (d, J=14.05 Hz, 1H), 2.05 (br. s., 1H), 1.79-1.99 (m, 2H), 1.69 (d, J=14.05 Hz, 1H), 1.58 (br. s., 1H), 1.42 (d, J=13.80 Hz, 1H), 1.28-1.37 (m, 2H), 1.27 (s, 3H), 0.95 (s, 9H). MS (m/z) 404.2 (M+H+).
Reaction SMILES: Cl.C[O:3][C:4](=[O:11])[C@H:5]([CH2:7][C:8](=[O:10])[NH2:9])[NH2:6].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].Cl>CS(C)=O>[NH2:6][C@H:5]([C:4]([OH:11])=[O:3])[CH2:7][C:8](=[O:10])[NH2:9]
Reactant: COC(=O)[C@@H](N)CC(N)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CS(C)=O
Product: NC(=O)C[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
HA-Asn was synthesized as follows. L-asparagine methyl ester hydrochloride (Bachem) was added to an anhydrous DMSO solution (5 mg/mL) of HA-TBA synthesized using HA-Na (99 kDa) as a starting material in Example 1-2 in an amount of 5 molar equivalents relative to the HA unit. Next, DMT-MM was added in an amount of 3-6 molar equivalents relative to the HA unit, and stirring was performed at room temperature overnight. After the reaction solution was reprecipitated with diethyl ether and the precipitate was dissolved in ultrapure water, 5N NaOH solution was added to adjust the pH to at least 12.5, and stirring was performed for an hour to perform carboxy deprotection via ethyl ester hydrolysis. Thereafter, the mixture was neutralized with 5N HCl solution and further dialyzed for purification against an aqueous solution of 0.3 M NaCl, distilled water, and ultrapure water in this order, and then the dialyzate was freeze-dried to give HA-Asn as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[N:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:35]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:36])[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C(Cl)N1CCCC1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)N3CCCC3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
57 mg (0.12 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 7A) and 20 mg (0.15 mmol, 1.3 eq.) of pyrrolidine-N-carbonyl chloride were reacted according to General Method 3. Yield: 24 mg (52% of theory)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH:14]C(=O)C(C)(C)C)[CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(COCc2cccc(F)c2)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(COCc2cccc(F)c2)n1

Procedure:
This material was prepared in analogy to example 86 step B] from N-[6-(3-fluoro-benzyloxymethyl)-pyridin-2-yl]-2,2-dimethyl-propionamide (0.663 g) and 3M aqueous NaOH (4.19 mL) as a brown liquid (0.596 g). MS (ESI): 233.2 (MH+).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cccnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cccnc1-c1ccccc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of palladium acetate (224.5 mg, 1.00 mmol) and triphenylphosphine (1.05 g, 4.00 mmol) in toluene (1000 mL) was stirred at room temperature for 15 minutes. Phenylboronic acid (114 g, 935 mmol), 2-chloro-3-aminopyridine (100 g, 778 mmol), benzaldehyde (83.4 g, 786 mmol), and toluene (500 mL) were then added followed by a solution of sodium carbonate (200 g, 1.89 mol) in water (1500 mL). The mixture was heated to reflux for 18 hours, cooled to room temperature, and the layers were separated. The organic layer was washed with water (500 mL) and 2.5M aqueous hydrochloric acid was added (630 mL). The aqueous layer was separated and washed with toluene (300 mL). The pH was adjusted to 12—13 using 50% aqueous sodium hydroxide and the mixture was extracted with methyl-tert-butyl ether (500 mL). The organic layer was concentrated and the product was crystallized from diisopropyl ether to afford 2-phenyl-3-aminopyridine (128 g, 97% yield). M. p.=67-68° C. 1H NMR (300 MHz, CDCl3) δ3.88 (bs, 2), 7.02-7.11 (m, 2). 7.28-7.53 (m, 3), 7.67-7.71 (m, 2), 8.,13-8.16 (m, 1). 13C NMR (100 MHz, CDCl3) δ122.57, 122.96, 128.14, 128.38, 128.72, 138.54, 139.86, 139.93, 144.93.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:14]([OH:15])[C:13]2[CH:16]=[CH:17][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(Oc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A mixture of 4-fluorophenol (41.3 g, 0.37 M), 4-fluorobenzaldehyde (45.7 g, 0.37 M) and K2CO3 (55 g) in 450 mL DMF was refluxed for 4 h, cooled, poured into ice water (1.5 L) to give a suspension. The mixture was filtered, washed with water, dried at 50° C. under vacuum to generate 78.3 g of the aldehyde 20 as a brownish solid. This compound was slurried in 2-propanol (1 L), then NaBH4 (14 g, 0.378 M) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h, then concentrated. The residue was poured into water (1.5 L) to give a suspension. After filtration, the resulting solid, washed with water, dried at 50° C. under vacuum to give 76 g of 4-fluorophenoxybenzyl alcohol 26 as a yellowish crystal.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCCN1CCCCC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCN5CCCCC5)n4)cc3)cc12

Procedure:
Using 3-(piperidin-1-yl)-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH:12]([CH3:16])[C:13]([NH2:15])=[O:14])[C:3]1=[O:17]>CC(O)=O.[Zn]>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH:12]([CH3:16])[C:13]([NH2:15])=[O:14])[C:3](=[O:17])[CH2:2]2
Reactant: CC(C(N)=O)N1C(=O)C(Br)(Br)c2cc(Cl)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C(N)=O)N1C(=O)Cc2cc(Cl)ccc21
Reaction time: 1 h

Procedure:
Zinc dust (23.71 g, 0.58 mol) was added to a stirred solution of compound 31 (theoretical: 58.4 mmol) in AcOH (110 ml) at 0° C. After 1 hour, the reaction mixture was filtered through a Celite pad. The filtrate was diluted with AcOEt and cold water. The pH was adjusted to 7 and the layers were separated. The aqueous phase was extracted again with AcOEt. Organic layers were dried over Na2SO4 and concentrated. The beige solid was cristallized in AcOEt and afforded 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide 32 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:48][CH3:49])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21][C@@H:22]1[CH2:26][N:25]([C:27]([NH:29][C@:30]2(C(O)=O)[CH2:32][C@H:31]2[CH:33]=[CH2:34])=[O:28])[C@H:24]([C:38](=[O:47])[N:39]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[CH3:40])[CH2:23]1.C1(N)CC1.[C:54](=[N:56][S:57]([C:60]1(C)[CH2:62][CH2:61]1)(=[O:59])=[O:58])=[O:55]>>[Cl:1][C:2]1[C:3]([O:48][CH3:49])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21][C@@H:22]1[CH2:26][N:25]([C:27]([NH:29][C@:30]2([C:54](=[O:55])[NH:56][S:57]([CH:60]3[CH2:62][CH2:61]3)(=[O:59])=[O:58])[CH2:32][C@H:31]2[CH:33]=[CH2:34])=[O:28])[C@H:24]([C:38]([N:39]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[CH3:40])=[O:47])[CH2:23]1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)N[C@]1(C(=O)O)C[C@H]1C=C
Reactant: CC1(S(=O)(=O)N=C=O)CC1
Agent: NC1CC1
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Yield: 40 %

Procedure:
Compound 118 was synthesized from compound 117 and cyclopropylamine as a white solid in 40% yield, following the procedure as described for compound 56c.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][C:19]3[N:23]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][N:31]([C:33]6([CH2:39][C:40]#[N:41])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[CH:32]=5)[CH:26]=[N:27][C:22]4=[N:21][CH:20]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[C:1]([N:36]1[CH2:37][CH2:38][C:33]([CH2:39][C:40]#[N:41])([N:31]2[CH:32]=[C:28]([C:25]3[CH:26]=[N:27][C:22]4[N:23]([C:19]([CH2:18][C:14]5[CH:13]=[C:12]6[C:17](=[CH:16][CH:15]=5)[N:8]=[CH:9][CH:10]=[CH:11]6)=[CH:20][N:21]=4)[N:24]=3)[CH:29]=[N:30]2)[CH2:34][CH2:35]1)(=[O:2])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: N#CCC1(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CCNCC1
Product: CC(=O)N1CCC(CC#N)(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CC1

Procedure:
This compound was prepared as a TFA salt starting from (4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidin-4-yl)acetonitrile using analogous to those for Example 203, Step 4. LCMS: (M+H)=492.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[CH3:32][C@@H:33]1[CH2:37][O:36][C:35](=[O:38])[NH:34]1>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:34]2[C@H:33]([CH3:32])[CH2:37][O:36][C:35]2=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 89.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 180 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (474 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:14](=[O:27])[CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:4].[Li+].[OH-]>O1CCCC1>[C:17]1([O:16][CH2:15][C:14]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C@H:5]2[C:3]([OH:4])=[O:2])=[O:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)COc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)COc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of (2S)-N-[(1-naphthoxy)acetyl]indoline-2-carboxylic acid methyl ester (1.0 g, 2.77 mmol) in tetrahydrofuran (3.3 mL) at 0° C. was added 1.0 N LiOH solution (3.3 mL, 3.3 mmol). After stirring at 0° C. for 2 hours the mixture was concentrated, diluted with water, acidified to pH 3, and extracted with EtOAc. The EtOAc extract was washed with saturated NaCl, dried (Na2SO4), and evaporated to give the title compound (0.918 g, 96%) as an off-white solid. 1H NMR (CD3OD): δ 8.36–8.33 (m, 1H), 8.15 (d, 1H, J=7.8 Hz), 7.81–7.78 (m, 1H), 7.49–7.18 (m, 7H), 7.10–7.04 (m, 1H), 6.92 (d, 1H, J=7.5 Hz), 5.32–4.94 (m, 5H), 3.69–3.34 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)[OH:19])[OH:17])[OH:15])[OH:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(O[C:35](=[O:37])[CH3:36])(=O)C.C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:19][C@@H:18]([C@H:16]([C@@H:14]([C@@H:12]([CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:9][CH:8]=1)[O:13][C:35](=[O:37])[CH3:36])[O:15][C:12](=[O:13])[CH3:11])[O:17][C:7](=[O:10])[CH3:6])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=1)(=[O:2])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)COc2ccc(C(=O)O)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]([C@H](OC(C)=O)[C@@H](COc1ccc(C(=O)O)cc1)OC(C)=O)[C@@H](COc1ccc(C(=O)O)cc1)OC(C)=O
Temperature: 0 °C

Procedure:
2.10 g of 1,6-bis-O-(4-carboxy-phenyl)-D-mannitol were stirred at room temperature for 20 hours in 30 ml of pyridine with 5.1 ml of acetic anhydride. The reaction mixture was worked up extractively with ice-water and methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from methanol and methylene chloride. There was obtained 2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4-carboxy-phenyl)-D-mannitol, MS: m/z 589 ([M-H]-).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]#[C:6][C@@H:7]([O:13]C1CCCCO1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.O1CCCC1.S(=O)(=O)(O)O>O>[OH:13][C@@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6]#[C:5][CH:4]=[O:3]
Reactant: CCCCC[C@@H](C#CC(OCC)OCC)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC[C@H](O)C#CC=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of (4S)-1,1-diethoxy-4-(2-tetrahydropyranyloxy)-2-nonyne (96.0 g., 0.31 mole), tetrahydrofuran (500 ml.), and 30% aqueous sulfuric acid (100 ml.) is stirred at room temperature for 17 hours. The solution is diluted with water and the oily product is extracted with ether. The ether extract is washed with sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of the ether leaves (4S)-4-hydroxy-2-nonynal as a colorless residual oil which is used in the following step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[Cl:11][C:12]1[CH:19]=[C:16]([CH:17]=O)[C:15]([OH:20])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][CH2:17][C:16]=2[CH:19]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: Clc1ccc2c(c1)CNc1ccccc1O2

Procedure:
2-chloro-10,11-dihydrodibenz[b,f][1,4]-oxazepine (42) is prepared in the manner described in Example 40, using 2-chloronitrobenzene and 5-chlorosalicylaldehyde.
Reaction SMILES: Br.[Br:2][C:3]1[C:12]([OH:13])=[C:11]([CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:15])=[N:8]2.[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>ClCCl.N1C=CC=CC=1>[F:21][C:20]([F:23])([F:22])[S:17]([O:13][C:12]1[C:3]([Br:2])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:14])[N:8]=[C:7]([CH3:15])[CH:6]=[CH:5]2)(=[O:18])=[O:16]
Reactant: Cc1ccc2c(Br)c(O)c(C)cc2n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(Br)c(OS(=O)(=O)C(F)(F)F)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-2,7-dimethylquinolin-6-ol-HBr (1.04 g, 3.1 mmol) in dichloromethane (50 mL) and pyridine (10 mL) was added Tf2O (1.1 mL, 6.2 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, quenched with slow addition of NaHCO3 solution at 0° C. The mixture was extracted with dichloromethane. The organic layer was washed with brine and dried with Na2SO4. Concentration gave 5-bromo-2,7-dimethylquinolin-6-yl trifluoromethanesulfonate as a brown solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[I:10]N1C(=O)CCC1=O>CN(C=O)C>[I:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][CH:9]=2)[NH:1][N:2]=1
Reactant: c1ncc2cn[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ncncc12
Temperature: 80 °C

Procedure:
520 mg (4.331 mmol) of 1H-pyrazolo[3,4-d]pyrimidine and 1.461 g (6.496 mmol) of N-iodosuccinimide were dissolved in 10 ml of DMF and the mixture was heated at 80° C. for 3 h. After cooling, the mixture was concentrated on a rotary evaporator and the residue was stirred with dichloromethane, filtered off with suction and dried under high vacuum. 569 mg (53% of theory) of the target compound were obtained.