Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=NC=CC=1[C:4]([NH:6][C:7]1[CH:12]=[C:11](C(F)(F)F)[C:10](Cl)=[CH:9][C:8]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[O:18]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:4]1
Reactant: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc2ocnc2c1
Reaction time: 2 h

Procedure:
To a mixture of 0.46 g of 3-chloro-N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 5 ml of tetrahydrofuran and 0.38 g of triphenylphosphine, 0.63 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for two hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.39 g of 6-chloro-2-(3-chloropyridin-4-yl)-5-trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 81”).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH:12]([OH:25])[CH2:13][N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:24])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH2:26]([C@@H:28]1[O:30][CH2:29]1)[Cl:27]>>[CH2:26]([CH:28]1[O:30][CH2:29]1)[Cl:27].[CH2:1]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH:12]([OH:25])[CH2:13][N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]2=[O:24])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: ClC[C@H]1CO1
Agent: CCCCC1CCN(CC(O)CN2C(=O)COc3ccccc32)CC1
Product: ClCC1CO1

Procedure:
Following the method outlined above for (R/S)-4-[3-(4-butylpiperidin-1-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one using (R)-(−)-epichlorohydrine (97% ee), (instead of racemic epichlorohydrin, gave the title compound. The optical purity was determined by HPLC analysis (Chiralpak AD, 250×4.6, 5 μm; hexane/i-PrOH/diethylamine 95:4.7:0.3, 0.5 mL/min) to be 96.3% ee. ([α]D20=−6, c=0.5, EtOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[O:41])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:34]3[CH2:35][CH2:36][CH:37]([C:40]([O:42][CH2:43][CH:44]4[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]4)=[O:41])[CH2:38][CH2:39]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: CN1CCC(COC(=O)C2CCNCC2)CC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CCC(COC(=O)C2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added (1-methylpiperidin-4-yl)methyl piperidine-4-carboxylate hydrochloride (178 mg, 0.64 mmol), DIEA (126 mg, 0.97 mmol), HATU (160 mg, 0.42 mmol). The resulting solution was stirred at room temperature overnight. Water (50 mL) was added. The resulting solution was extracted with DCM (×3) and the organic layers combined. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (3#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (32.0% MeCN up to 50.0% in 8 min); Detector, 254/220. This resulted in 37 mg (16%) of the formic acid salt of (1-methylpiperidin-4-yl)methyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as an off-white solid. LCMS (Method 25) [M+H]+=685.2, RT=1.05 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.2, 6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.36-5.18 (m, 2H), 4.28-4.21 (m, 1H), 3.96-3.88 (m, 3H), 3.25-3.12 (m, 1H), 2.86-2.74 (m, 3H), 2.73-2.66 (m, 1H), 2.15 (s, 3H), 1.92-1.83 (m, 4H), 1.65-1.52 (m, 4H), 1.48-1.38 (m, 1H), 1.29-1.16 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]([OH:45])[CH2:34][C@@H:35]([OH:44])[CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO.O.Cl.CC(O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]([OH:45])[CH2:34][C@@H:35]([OH:44])[CH2:36][C:37]([OH:39])=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O

Procedure:
The crude (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5dihydroxy-heptanoic acid, t-butyl ester (VI-A) was converted to the acid using an excess of KOH/MeOH/Water, followed by lactonization in toluene with catalytic HCl. Chiral HPLC analysis (ChiralCel OF; 1 ml/min; 60° C.; 254 nm; 20% IPA:Hexanes) tR(3R,5R)=26.97 min./tR(3S,5S)=33.8 min. tR(3R,5S)=38.1 min./tR(3S,5R)=61.0 min.) indicated an enantiomeric excess of the syn isomer of 85%, favoring the (R,R) configuration.
Reaction SMILES: C(OC([O:6][CH:7]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH:16]([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])[CH:15]=[CH:14][CH:13]([CH3:31])[CH:12](/[C:32](/[CH3:59])=[CH:33]/[CH:34]=[CH:35]/[C:36]([O:53]C(OCC)C)([CH3:52])[CH2:37][CH:38]2[O:51][CH:39]2[CH:40]([CH3:50])[CH:41]([O:44]C(OCC)C)[CH2:42][CH3:43])[O:11][C:9](=[O:10])[CH2:8]1)C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O1CCCC1.CC(C)CO.C(OCC)(=O)C>[OH:6][CH:7]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH:16]([O:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)=[O:23])[CH:15]=[CH:14][CH:13]([CH3:31])[CH:12](/[C:32](/[CH3:59])=[CH:33]/[CH:34]=[CH:35]/[C:36]([OH:53])([CH3:52])[CH2:37][CH:38]2[O:51][CH:39]2[CH:40]([CH3:50])[CH:41]([OH:44])[CH2:42][CH3:43])[O:11][C:9](=[O:10])[CH2:8]1
Reactant: CCOC(C)OC1CCC(C)C(OC(=O)N2CCN(C)CC2)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(=O)N2CCN(C)CC2)/C=C/C1C
Agent: CCOC(C)OC1CCC(C)C(OC(=O)N2CCN(C)CC2)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CC(C)CO
Solvent: CCOC(C)=O
Product: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)C(OC(=O)N2CCN(C)CC2)C=CC1C
Reaction time: 24.5 h

Procedure:
(8E,12E,14E)-3,16,21-tris-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide (25.1 mg, 30.0 limol) was dissolved in a 1:1 mixed solution of tetrahydrofuran and 2-methyl-1-propanol (1 mL). Pyridinium p-toluenesulfonate (23.7 mg, 94.3 μmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 24.5 hours, and then pyridinium p-toluenesulfonate (8.7 mg, 34.6 μmol) was further added to the reaction mixture. The reaction mixture was stirred for 4.5 hours. The reaction mixture was diluted with ethyl acetate (30 mL), and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (6 mL) and purified water (6 mL) twice, and with brine (6 mL). The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting concentrate was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate; chloroform:methanol=40:1) to obtain the title compound (12.2 mg, 19.6 μmol, 65.3%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][C:13]2[C:8]3=[C:9]([CH2:15][C:16](=O)[N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8]3=[C:9]([CH2:15][CH2:16][N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1Cc2cccc3c2N(C1)C(=O)C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCN(CCC)C1Cc2cccc3c2N(CC3)C1
Yield: 47.8 %

Procedure:
A mixture of 5-(dipropylamino)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (0.75 g) and lithium aluminum hydride (0.21 g) was stirred in ether (20 mL) for 45 minutes. The reaction was quenched with methanol, evaporated and partitioned between ethyl acetate and water. Evaporation of the ethyl gave an oil which was chromatographed on silica gel using ethyl acetate:hexane (1:20) as eluant to give, as the first compound eluted from the column 0.27 g of 5,6-dihydro-N,N-dipropyl-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (compound 87). Continued elution of the column gave 0.34 g of 1,2,5,6-tetrahydro-N,N-dipropyl-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (compound 92).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)=[C:8]([CH3:20])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:14]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)=[O:16])[CH:17]=[CH:18][CH:19]=3)=[C:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2cccc(C(=O)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(C(=O)N3CCN(C)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 1-methylpiperizine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-methylpiperazin-1-yl)methanone (67 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 19.8 mg of 427. MS (Q1) 554.0 (M)+
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[S-:17][C:18]#[N:19].[Na+].O>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([S:17][C:18]#[N:19])[C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCNc1cc(Cl)ccc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CSc1cc(Cl)c(NCCC(=O)O)cc1Cl
Reaction time: 1 h
Yield: 103 %

Procedure:
A solution of 6 ml (0.11 mole) of bromine in 20 ml of acetic acid was added dropwise over 20 min to a stirred mixture of 25 g (0.10 mole) of N-(2,5-dichloropheyl)-β-alanine, 20.5 g (0.25 mole) of sodium thiocyanate and 100 ml of acetic acid at 15°-20°. An additional 80 ml of acetic acid was added to facilitate stirring which was continued for 1 hr. The reaction mixture was poured into 600 ml of cold water. The yellow solid was collected by filtration, washed with water and dried in an oven at 100° for 2 hrs to give 30 g (100%) of N-(2,5-dichloro-4-thiocyanatophenyl)-β-alanine. Two recrystallizations from CH3NO2 gave an analytical sample, m.p. 133°-135°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O>C(Cl)(Cl)Cl>[C:15]1([C:13]2[N:5]=[C:4]([C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[NH:6][CH:12]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccccc1C(=N)N
Reactant: O=C(CBr)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-c1nc(-c2ccccc2)c[nH]1

Procedure:
To a solution of 6.1 g (0.0455 mole) of 2-methylbenzamidine in 25 ml of chloroform 3.6 g (0.018 mole) of α-bromoacetophenone were added and the resulting mixture was refluxed for four hours. After cooling and adding 50 ml of chloroform the reaction mixture was first washed with diluted ammonia and then with water and subsequently dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was chromatographed through silica gel by eluting with mixtures of CHCl3 /CH3COOC2H5 containing up to a maximum of 4% (in volume) of CH3COOC2H5. The fractions eluted with CH3Cl3 /CH3COOC2H5 =9/1 (v/v) were collected, the solvent was evaporated off and the residue was crystallized from diethylether/light petroleum. Yield 1.95 g (46.3%) of the title compound M.p. 145°-46° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[F:15][C:16]([F:51])([F:50])[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[O:26][CH:27]=[C:28]([CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][N:44]=[C:43]4[CH2:47][CH2:48][NH2:49])=[CH:34][CH:33]=3)[N:29]=2)=[CH:19][CH:18]=1.O>C1COCC1>[F:51][C:16]([F:50])([F:15])[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[O:26][CH:27]=[C:28]([CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][N:44]=[C:43]4[CH2:47][CH2:48][NH:49][C:8](=[O:10])[CH3:9])=[CH:34][CH:33]=3)[N:29]=2)=[CH:19][CH:18]=1
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (137 μl) and acetic anhydride (74.0 μl) were added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (200 mg) in THF at 0° C., and the mixture was stirred at 0° C. for 1.5 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; dichloromethane to dichloromethane:methanol=20:1) and recrystallized from ethyl acetate-hexane to give the titled compound (123 mg) as colorless needle crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:18][C:19]2[C:28]3[C:23](=[C:24]([C:29]([O:31]C)=O)[CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:33]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:18][C:19]2[C:28]3[C:23](=[C:24]([C:29]([NH2:33])=[O:31])[CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)c1cccc2c(NC(CCN3CCCC3)c3cccc([N+](=O)[O-])c3)ncnc12
Solvent: CO
Product: NC(=O)c1cccc2c(NC(CCN3CCCC3)c3cccc([N+](=O)[O-])c3)ncnc12
Reaction time: 48 h
Yield: 81.4 %

Procedure:
A suspension of methyl 4-{[1-(3-nitrophenyl)-3-pyrrolidin-1-ylpropyl]-amino}quinazoline-8-carboxylate (1 654.83 mg; 3.80 mmol; 1.00 eq.) and ammonia (16.29 ml; 7.00 M; 114.00 mmol; 30.00 eq.) in MeOH was stirred for 2 days. After concentration, the (1.3 g) of 4-{[1-(3-nitrophenyl)-3-pyrrolidin-1-ylpropyl]-amino}quinazoline-8-carboxamide was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[N:5][N:6]([CH2:8]O[Si](C(C)C)(C(C)C)C(C)C)[N:7]=1)[CH3:2].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C(Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:62]=[C:63]1[NH:68][C:67]2[CH:69]=[C:70]([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[S:71][C:66]=2[C:65](=[O:78])[N:64]1[CH:79]1[CH2:84][CH2:83][N:82]([C:85]([O:87][C:88]([CH3:91])([CH3:90])[CH3:89])=[O:86])[CH2:81][CH2:80]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:3]1[N:4]=[N:5][N:6]([CH2:8][N:68]2[C:67]3[CH:69]=[C:70]([C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[S:71][C:66]=3[C:65](=[O:78])[N:64]([CH:79]3[CH2:84][CH2:83][N:82]([C:85]([O:87][C:88]([CH3:90])([CH3:89])[CH3:91])=[O:86])[CH2:81][CH2:80]3)[C:63]2=[O:62])[N:7]=1)[CH3:2]
Reactant: CCc1nnn(CO[Si](C(C)C)(C(C)C)C(C)C)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: BrC(Br)(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nnn(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-ethyl-2-{[(tripropan-2-ylsilyl)oxy]methyl}-2H-tetrazole (1.53 g; compound D30) in DCM is added n-Bu4NF (5.34 ml of 1M solution in THF) and stirred for 30 min at RT. After completion of the reaction (TLC monitoring, eluent system: EtOAc/c-Hexan, 1/6, (v/v)) CBr4 (2.13 g) and PPh3 (1.68 g) are added and the reaction mixture is stirred for 30 min at RT. The reaction mixture is added to a mixture of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (913 mg; compound B50) and potassium carbonate (1.33 g) in DMF and the combined reaction mixture is stirred for 12 h at 80° C. All volatiles are evaporated under reduced pressure and the resulting residue is purified by flash chromatography (silica gel, eluent EtOAc/cyclohexane, 1/6, (v/v)) to give the title compound as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:5][Br:6])=[O:4].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:23]([OH:25])=O)[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC([NH:36][C@H:37]([C:42]([OH:44])=[O:43])[CH2:38]C(C)C)=O)C1C=CC=CC=1>>[Br:1][CH2:2][C:3]([CH2:5][Br:6])=[O:4].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:23]([NH:36][C@H:37]([C:42]([OH:44])=[O:43])[CH3:38])=[O:25])[CH2:19][C:20]1[CH:21]=[CH:5][CH:3]=[CH:2][CH:22]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(CBr)CBr
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
N-Benzyloxycarbonyl-L-leucine bromomethyl ketone (an oil) from N-benzyloxycarbonyl-L-leucine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.[N:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)=[N+:11]=[N-:12].S(Cl)(Cl)=O.C(N(CC)CC)C>O1CCCC1>[N:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]2)=[O:18])=[CH:20][CH:21]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NC1CCC=CCCC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(C(=O)NC2CCC=CCCC2)cc1
Yield: 73 %

Procedure:
This example describes the preparation of an azidoaryl-substituted cyclooctene by reaction of an acid chloride-substituted phenyl azide with 5-aminocyclooctene. The reactions are illustrated in Scheme 4. 4-Azidobenzoic acid was converted to the corresponding acid chloride (10) with thionyl chloride and triethylamine in dry tetrahydrofuran. An excess of 5-aminocyclooctene was then introduced to the solution of the acid chloride at 0° C. to form the azidoaryl-substituted cyclooctene, 4-azido-N-4-cycloocten-1-yl-benzamide (9), which was purified by recrystallization from diethyl ether/hexane in 73% yield. The product was characterized by proton and carbon-13 nuclear magnetic resonance spectroscopy (1H and 13C NMR), as well as Fourier Transform Infrared (FTIR) spectroscopy. Key features in the characterization of 4-azido-N-4-cycloocten-1-yl-benzamide included the presence of the amide carbonyl in the 13C NMR spectrum at 165.1 parts per million (ppm), and a characteristic azide signal in the IR spectrum at 2120 reciprocal centimeters (cm−1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][NH2:24]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:23][NH2:24])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
Commercially available 3-iodobenzoic acid (7.41 g, 29.9 mmol) was dissolved in THF (121 mL), and the mixture was stirred at room temperature for 45 minutes after adding 1,1′-carbonyldiimidazole (5.33 g, 32.9 mmol). The mixture was further stirred at room temperature for 2 hours after adding hydrazine.monohydrate (5.3 mL, 109 mmol). The mixture was then concentrated under reduced pressure, and recrystallized from methanol and water to give 3-iodobenzohydrazide (6.08 g, 78%).
Reaction SMILES: [CH3:1][NH2:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[CH2:33][C@@:31]2([CH3:32])[C@@H:27]([CH2:28][CH2:29][C@@H:30]2[OH:34])[C@@:26]2([CH:35]=[CH2:36])[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:37])=[CH:22][C:23]=1[CH2:24][CH2:25]2>>[CH3:1][NH:2][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[CH2:33][C@@:31]2([CH3:32])[C@@H:27]([CH2:28][CH2:29][C@@H:30]2[OH:34])[C@@:26]2([CH:35]=[CH2:36])[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:37])=[CH:22][C:23]=1[CH2:24][CH2:25]2
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCCl)C[C@@]1(C)[C@H]2CC[C@@H]1O
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCCNC)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with methylamine (40% in water, 3 ml/mmol) with the addition of sodium carbonate analogously to instructions 17.2, 155 mg of product mixture 30b yields 152 mg of amine 31b as a colorless solid (GC-MS: m/z theor.: 411, pract.: 411).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][C:9]=1[F:16])#[N:7]>CN(C)C=O>[CH2:1]([NH:5][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([C:6]#[N:7])=[C:9]([F:16])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: N#Cc1ccc(CBr)cc1F
Solvent: CN(C)C=O
Product: CCCCNCc1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
4.64 ml n-butylamine was dissolved in 30 ml dimethylformamide. 667 mg commercially available 4-cyano-3-fluorobenzylbromide, dissolved in 10 ml dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature for thirty minutes. The solvent was removed in vacuo and the residue purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate=1:4=>ethyl acetate:methanol=4:1 to obtain 360 mg 4-Butylaminomethyl-2-fluoro-benzonitrile.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[C:10](=[O:23])[O:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)=[N:13][C:8]=2[CH:7]=1)(=[O:4])[CH2:2][CH3:3].CN(C)C=[O:29].O.Cl>C(N(CC)CC)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]([NH:13][C:8]2[CH:7]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:25]=[CH:24][C:9]=2[C:10]([OH:11])=[O:23])=[O:29])=[CH:15][CH:16]=1)([OH:22])=[O:21]
Reactant: CCC(=O)Nc1ccc2c(=O)oc(-c3ccc(C(=O)O)cc3)nc2c1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccc(C(=O)O)cc2)c1

Procedure:
A mixture of 5 g of 7-(propionamido)-2-(4-carboxyphenyl)-4H-3,1-benzoxazine-4-one, 50 ml of dimethylformamide, 10 ml of water and 8 ml of triethylamine was heated at 80°-90° C. for a period of 10 hours. After being allowed to cool, the mixture was treated with dilute hydrochloric acid to adjust its pH between 2 and 3. The precipitating crystal was filtered, washed with water, and recrystallized from isopropyl alcohol to produce 4.1 g of 2-(4-carboxybenzamido)-4-propionamidobenzoic acid having a melting point in the range of 284° to 286° C. (decompose).