Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=C)=[O:14].CSC.C(Cl)Cl.C[OH:40]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=[O:40])=[O:14]
Reactant: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Reactant: CO
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)[C@H](COCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo- 2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester (13 g, 29.8 mmol) in methylene chloride /methanol (10:1, 220 mL). Cool to -78° C. and sparge with a mixture of ozone/oxygen for approximately 10 minutes until a blue color persists. Sparge with nitrogen for 10 minutes at -78° C. to remove excess ozone. Treat with methylsulfide (60 mL, 0.82 mol) and allow to warm to room temperature. Stir at room temperature for 2.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (200 mL). Wash with water, saturated sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo to give the intermediate N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester as a foam (13.6 g).
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH:6](O)[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][CH:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[CH2:5][CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: CC1c2ccccc2CC(O)Cc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC1c2ccccc2C=CCc2ccccc21
Temperature: 0 °C

Procedure:
12-Methyl-5,6,7,12-tetrahydrodibenzo[a,d]cycloocten-6-ol (2.7 g., 0.011 mole) in 50 ml. of pyridine was treated with 15 ml. of phosphorous oxychloride. The mixture was heated at reflux for 45 minutes, cooled, and poured carefully into 600 ml. of stirred ice water. The resulting mixture was extracted three times with ether, and the combined ether layers were washed once with water, once with 1 N hydrochloric acid, and twice with water. The washed ether solution was dried over potassium carbonate, filtered, and evaporated in vacuo to give 1.9 g. of colorless oil.
Reaction SMILES: [N:1]([C@H:4]([C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[C:2]=[S:3].[C:26]([NH:29][NH2:30])(=O)[CH3:27]>CCO>[CH3:27][C:26]1[S:3][C:2]([NH:1][C@H:4]([C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:18][CH:19]=2)[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[N:30][N:29]=1
Reactant: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Reactant: CC(=O)NN
Solvent: CCO
Product: Cc1nnc(N[C@@H](Cc2ccc([N+](=O)[O-])cc2)c2csc(-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A solution of (S)-4-[1-isothiocyanato-2-(4-nitrophenyl)-ethyl]-2-phenylthiazole, 39, (332 mg, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol) in EtOH (5 mL) is refluxed for 2 hours. The solvent is removed under reduced pressure, the residue is dissolved in POCl3 (3 mL) and the resulting solution is stirred at room temperature for 18 hours after which the solution is heated to 50° C. for 2 hours. The solvent is removed in vacuo and the residue is dissolved in EtOAc (40 mL) and the resulting solution is treated with 1N NaOH until the pH remains approximately 8. The solution is extracted with EtOAc. The combined aqueous layers are washed with EtOAc, the organic layers combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 0.345 g (93% yield) of the desired product as a yellow solid. 1H NMR (CDCl3) 8.09 (d, J=8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, 1H), 5.23 (m, 1H), 3.59 (m, 2H), 2.49 (s, 3H). ESI+ MS 424 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[N:6][CH:7]=1.[C:11](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:11][O:9][C:8]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[CH:5][N:4]=1)=[O:10]
Reactant: O=C(O)c1ncncc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ncncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
5-Bromopyrimidine-4-carboxylic acid (prepared according to the procedure described in U.S. Pat. No. 4,110,450) (1.0 eq, 6.14 g, 30.2 mmol) was suspended in CH2Cl2 (100 ml). Oxalylchloride (1.1 eq, 2.9 ml, 33.0 mmol) was added followed by 2 drops of DMF. The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was taken in MeOH (50 ml) and heated. After evaporation of MeOH in vacuo the compound was dissolved in CH2Cl2 and poured on a prepacked silica gel column. The material was eluted using 20% Ethyl acetate in hexanes. Evaporation of the solvent provided methyl-5-bromopyrimidine-4-carboxylate as a light orange crystalline solid (2.54 g, 39% yield). LCMS (ES): 95% pure, m/z 217 [M]+; 219 [M+2]+; 1H NMR (CDCl3, 400 MHz) δ 4.04 (s, 3H), 9.02 (s, 1H), 9.21 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.Cl.NC1NC=C(CCCCCC2[N:34]=[N:35][N:36]([CH2:38][CH2:39][NH:40][C:41]([C:43]3[CH:48]=[CH:47][C:46]([C:49]4C=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:45][CH:44]=3)=[O:42])C=2)N=1>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:34]=[N:35][N:36]([CH2:38][CH2:39][NH:40][C:41](=[O:42])[C:43]3[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:45][CH:44]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: Nc1nc(CCCCCc2cn(CCNC(=O)c3ccc(-c4ccccc4)cc3)nn2)c[nH]1
Agent: Cl
Product: CCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.113 g, 0.408 mmol) was reacted with N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)biphenyl-4-carboxamide hydrochloride (0.106 g, 0.408 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-pentylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), δ 7.67 (d, J=7.5 Hz, 2H), δ 7.27 (s, 1H), δ 7.12 (d, J=7.8 Hz, 2H), δ 4.48 (s, 2H), δ 3.84 (s, 2H), δ 2.55 (m, 4H), δ 2.22 (s, 2H), δ 1.50 (s, 13H), δ 1.23 (s, 8H), δ 0.80 (t, J=5.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 168.3, 150.5, 149.5, 148.2, 147.2, 138.6, 131.5, 128.7, 127.4, 106.4, 84.8, 49.4, 40.2, 35.9, 31.6, 31.0, 29.3, 28.9, 28.1, 27.9, 25.6, 22.6, 14.2; HRMS (ESI) calcd for C29H43N7O3 (M+) 537.3427. found 537.3420, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-pentylbenzamide hydrochloride (0.178 g, 92% yield). 1H NMR (300 MHz, CD3OD) δ 8.41 (s, 1H), δ 7.69 (d, J=7.5 Hz, 2H), δ 7.21 (d, J=7.2 Hz, 2H), δ 6.46 (s, 1H), δ 4.84 (s, 2H), δ 3.90 (s, 2H), δ 2.79 (s, 2H), δ 2.58 (t, J=7.8 Hz, 2H), δ 2.39 (t, J=7.2 Hz, 2H), δ 1.68 (s, 2H), δ 1.55 (s, 4H), δ 1.26 (s, 6H), δ 0.84 (t, J=6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 169.2, 159.5, 158.9, 147.5, 147.3, 131.1, 128.5, 127.6, 127.4, 108.5, 54.2, 51.9, 39.5, 35.6, 31.4, 30.9, 30.6, 28.4, 27.9, 27.6, 26.9, 24.1, 23.5, 22.9, 22.4, 13.3 ppm; HRMS (ESI) calcd for C24H35N7O (M+) 437.2903. found 437.2892.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2I)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:18]1[CH:19]=[C:20]([C:15]2[N:14]3[C:10]([O:11][CH:12]=[CH:13]3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25]
Reactant: Fc1ccc(-c2nc3occn3c2I)cc1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2c(-c3ccc(F)cc3)nc3occn23)cc1F
Temperature: 100 °C
Yield: 83.4 %

Procedure:
A mixture of 6-(4-fluorophenyl)-5-iodo-imidazo[2,1-b]oxazole (10.0 g, 27.4 mmol; Preparation #A.1), 2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (11.9 g, 41.1 mmol; Preparation #B.1), Cs2CO3 (28.6 g, 87.8 mmol), tetrakis(triphenylphosphine)palladium(0) (3.17 g, 2.74 mmol; Strem), DME (150 mL) and water (30.0 mL) was added to a flask with screw-thread top. The flask was sealed and heated at about 100° C. for about 16 h. After cooling to ambient temperature the reaction was concentrated under reduced pressure to remove organic solvent. The resulting mixture was diluted with water (200 mL) and EtOAc (200 mL) then filtered to remove insoluble material. The layers were separated and the aqueous layer was extracted with additional EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude material was purified by silica gel chromatography using DCM to give the title compound (7.80 g, 78%): LC/MS (Table 1, Method b) Rt=2.19 min; MS m/z: 342.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23]OS(C)(=O)=O)=[CH:15]3)=[C:10]([CH2:29][CH3:30])[CH:9]=[C:8]([C:31]([O:33][CH3:34])=[O:32])[C:7]1=[O:35].[N-:42]=[N+:43]=[N-:44].[Na+]>CS(C)=O.O>[N:42]([CH2:23][CH2:22][C:16]1[N:17]([CH3:21])[C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:11]1[N:6]([CH2:5][C:4]3[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:3]=3[O:2][CH3:1])[C:7](=[O:35])[C:8]([C:31]([O:33][CH3:34])=[O:32])=[CH:9][C:10]=1[CH2:29][CH3:30])=[CH:20][CH:19]=2)=[N+:43]=[N-:44]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCOS(C)(=O)=O)n2C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCN=[N+]=[N-])n2C
Temperature: 80 °C
Yield: 72.7 %

Procedure:
To solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(methylsulfonyloxy)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (309.6 mg, 0.53 mmol), prepared according to procedure described in Example 159 Step 10, in DMSO (2 mL) was added NaN3 (100 mg, 1.54 mmol). The reaction mixture was heated at 80° C. for 1.5 h until complete consumption of starting material was observed. The reaction mixture was then diluted with H2O and the product was extracted with DCM (3×10 mL). The combined organics were washed with NaCl (aqueous saturated, 5 mL) and dried over Na2SO4. Upon solvent removal, the residue was purified by column chromatography using EtOAc/hexanes (gradient 0-80%) to afford methyl 6-(2-(2-azidoethyl)-1-methyl-1H-indol-5-yl)-1-(2,4-dimethoxybenzyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (204.0 mg) in 73% yield. The product could not be completely separated from mesylate elimination by-product.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].Br[C:26]#[N:27]>C(#N)C>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:26]([NH2:27])=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: N#CBr
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Solvent: CC#N
Product: CCC(CC)Nc1cc(C)nc2c1nc(N)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine with BrCN in acetonitrile at room temperature overnight. The mixture was quenched with water and adjusted to pH 8.0 with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give crude material. The material was purified through silica gel column chromatography to give the title compound as a brown solid, mp. 158–160° C.; Anal. For C21H29N5 ¼H2O calc. C, 70.85; H, 8.35; N, 19.67; found: C, 71.07; H, 8.30; N, 19.63.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH2:14][OH:15])=[N:9]2)=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH:14]=[O:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(CO)nn1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc(C=O)nn1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A suspension of [1-(4-fluoro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-yl]-methanol (2.20 g, 10.6 mmol) and manganese(IV) oxide (10.3 g, 106 mmol) in dichloromethane (110 mL) was heated at reflux for 1 h. After cooling to ambient temperature it was filtered and concentrated affording the title compound (1.80 g, 33%) as a light yellow solid. MS: m/e=206.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([CH2:14][CH2:15][OH:16])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][S:11]([CH2:14][CH2:15][OH:16])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)CCO)c1
Agent: [Ni]
Solvent: CO
Product: Nc1cccc(CS(=O)(=O)CCO)c1
Yield: 71.8 %

Procedure:
2-(3-Nitro-phenylmethanesulfonyl)-ethanol (0.8 g, 3.3 mmol) (Harms, Wolfgang et al., Ger. Offen. (1995), DE 4402189 A1, 19950727) was placed in a hydrogenation flask and dissolved in methanol (100 mL). After the addition of Raney-Ni (200 mg) the mixture was allowed to shake at a hydrogen pressure of 70 psi at 50° C. for 4 hours. Then the catalyst was removed by filtration and washed with methanol. The methanol solutions were combined and the solvent evaporated under reduced pressure. The crude product was purified by flash-chromatography (eluent system: dichloromethane/methanol—10/1), the desired fractions were combined, dried and evaporated. The residue was washed with diethylether to afford 2-(3-amino-phenylmethanesulfonyl)-ethanol (0.51 g, yield 73%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([Br:32])=[CH:26][C:23]=1[CH:24]=[O:25]>>[Br:32][C:27]1[C:28]([O:30][CH3:31])=[CH:29][C:22]([O:21][CH3:20])=[C:23]([CH:24]([OH:25])[C:9]#[C:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:26]=1
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cc(OC)c(C(O)C#Cc2ccccc2)cc1Br
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,4-dimethoxy-5-bromobenzaldehyde was reacted to give the title compound as a yellow foam (1.43 g, 100%). LCMS (Method B): RT=4.99 min, [M+Na]+=369/371.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][NH:36][CH2:37][CH:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:36]([CH2:37][CH:38]([OH:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH3:35])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccccc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(Cc1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.06 gm) from Preparation No. 35 in dry NMP (2 mL) containing diisopropylethylarnine (0.04 mL) is treated with α-(methylaminomethyl)-benzyl alcohol (0.04 gm). The reaction mixture is shaken at room temperature for 3 days then concentrated under reduced pressure. The residue is partioned between dichloromethane and water. The separated organic layer is washed with two additional portions of water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is adsorbed onto silica and purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from ethyl acetate-hexanes to afford 0.05 gm of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=O)[O:6][CH2:5][CH2:4][O:3]1.[Cl:14][C:15]1[CH:33]=[CH:32][C:18]2[O:19][C:20]3[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=3[CH2:22][N:23]([C:24]([NH:26][NH2:27])=[O:25])[C:17]=2[CH:16]=1>>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]([NH:27][NH:26][C:24]([N:23]2[CH2:22][C:21]3[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=3[O:19][C:18]3[CH:32]=[CH:33][C:15]([Cl:14])=[CH:16][C:17]2=3)=[O:25])=[O:12])[O:3][CH2:4][CH2:5][O:6]1
Reactant: COC(=O)CCCC1(C)OCCO1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CC1(CCCC(=O)NNC(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)OCCO1

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[4-(2-methyl-1,3-dioxolan-2-yl)-1-oxobutyl]hydrazide (26) was prepared in the manner described above in Example 18 from methyl 2-methyl-1,3-dioxolane-2-butanoate (25), prepared as described above in Example 25, and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared in the manner described above in Example 1, on a 2 mmol scale to yield 0.47 g (53%) of product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][N:17]=3)[NH:12][C:11]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][Cl:29].O>O1CCCC1>[Cl:29][CH2:28][CH2:27][CH2:26][N:17]1[CH2:16][CH:15]=[N:14][C:13]2[NH:12][C:11]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[C:18]1=2
Reactant: ClCCCBr
Reactant: Fc1ccc(-c2c(-c3ccncc3)[nH]c3nccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2c(-c3ccncc3)[nH]c3c2N(CCCCl)CC=N3)cc1
Temperature: 65 °C
Yield: 39.4 %

Procedure:
To a suspension of sodium hydride (1.03 g, 25.8 mmol, 60% in mineral oil) in dry tetrahydrofuran (20 ml) was slowly added 7-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine (0.75 g, 2.58 mmol) followed by 1-bromo-3-chloropropane (4.05 g, 25.8 mmol). The reaction mixture was heated at 65° C. for 72 h. Water was added slowly to quench the excess sodium hydride and the organics were removed in vacuo. Water was added to the residue and the aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, elating with ethyl acetate, to give 1-(3-chloropropyl)-7-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazineas a solid (0.375 g).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)=[CH:26][N:27]=2)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[N:2]1([O:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:25]3[S:24][C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=4)=[N:27][CH:26]=3)=[CH:36][CH:35]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: On1nnc2ccccc21
Reactant: CCCCCOc1ccc(-c2ncc(-c3ccc(C(=O)O)cc3)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCOc1ccc(-c2ncc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a solution of 1-hydroxybenzotriazole (722 mg) and 4-[2-(4-pentyloxyphenyl)thiazol-5-yl]benzoic acid (1.64 g) in dichloromethane (33 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) (1.28 g), and stirred for 2 hours at ambient temperature. To the reaction mixture was added dichloromethane (500 ml) to be clear solution, then washed with water (200 ml×2) and brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in acetonitrile, and collected by filtration to give 4-[2-(4-pentyloxyphenyl)-thiazol-5-yl]benzoic acid benzotriazol-1-yl ester (1.27 g).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:17]>O1CCOCC1>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([S:13]([NH2:17])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)nc1
Reactant: N
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
6-Morpholin-4-yl-pyridine-3-sulfonyl chloride (1.25 g, 4.8 mmol) was dissolved in a 0.5M solution of ammonia in dioxane (20 mL) and the mixture stirred for 16 hours at room temperature. The mixture was filtered and concentrated in vacuo to afford 6-morpholin-4-yl-pyridine-3-sulfonic acid amide as a white solid 1.1 g (96% yield).