Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[OH:38])/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44](Cl)=[O:45].Cl>ClCCl>[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[O:38][C:44]([C:40]3[O:39][CH:43]=[CH:42][CH:41]=3)=[O:45])/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)/C(=N\OC(=O)c1ccco1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 39.3 %

Procedure:
Triethylamine (8.7 ml) was added to an ice-cooled suspension of 2-(2-triphenylmethylamino-4-thiazolyl)- 2-(Z-hydroxyimino)acetic acid (13 g) in 250 ml of anhydrous dichloromethane with stirring. The suspension turned to a clear, faint yellow solution. A solution of 2-furoyl chloride (3.3 g) in 20 ml of anhydrous dichloromethane was dropwise added under ice cooling, the resulting light brown solution was stirred at room temperature for one hour, the mixture was poured into 130 ml of ice-cooled 0.5N hydrochloric acid, and the formed crystals were collected by filtration and washed thrice with 30 ml dichloromethane, affording 5.2 g of the objective compound as colorless crystals.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under atmosphere of argon, to a suspension of sodium hydride (63%, 57.1 g) in anhydrous N,N-dimethylformamide (540 ml) was added a solution of 3,4-dihydroxybenzaldehyde (103.5 g) in anhydrous N,N-dimethylformamide (500 ml) dropwise slowly under cooling with ice. The reaction mixture was stirred for 30 minutes at room temperature, and to the mixture was added benzyl chloride (104 ml) under cooling with ice and it was stirred for 15 hours at room temperature. To the mixture was added water under cooling with ice, and was concentrated under reduced pressure. The residue was diluted by water and it was washed by methylene chloride. The methylene chloride layer was extracted by a 1N aqueous solution of sodium hydroxide. Combined aqueous layers were acidified by 2M hydrochloric acid and it was extracted by ethyl acetate. The organic layer was washed by a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from chloroform to give the title compound (99.4 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[CH3:20][C:21]1([CH3:33])[CH2:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30](Cl)=[O:31])[C:23]=2[O:22]1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:30]([C:29]1[C:23]2[O:22][C:21]([CH3:33])([CH3:20])[CH2:25][C:24]=2[CH:26]=[CH:27][CH:28]=1)=[O:31]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: CC1(C)Cc2cccc(C(=O)Cl)c2O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
To a solution of the product of Example 126A (0.20 g, 1.1 mmol) and Et3N (0.45 mL, 3.2 mmol) in 30 mL THF was added 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carbonyl chloride (Acros, 0.34 g, 1.6 mmol). This mixture was warmed to reflux and allowed to stir for 2 hours. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The residue was diluted with 10 mL EtOAc and washed with 5 mL saturated, aqueous NH4Cl. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 4:1 hexanes:EtOAc) to provide the title compound (0.21 mmol, 0.57 mmol, 53% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.55 (s, 6H), 2.22 (s, 3H), 2.27 (s, 3H), 3.02 (s, 2H), 3.31 (s, 3H), 3.77-3.89 (m, 2H), 4.33-4.50 (m, 2H), 6.85 (t, J=7.5 Hz, 1H), 7.22 (d, J=7.5 Hz, 1H), 8.00 (d, J=8.1 Hz, 1H); MS (DCI/NH3) m/z 361 (M+H); Anal. calculated for C19H24N2O3S: C, 63.31; H, 6.71; N, 7.77. Found: C, 63.19; H, 6.50; N, 7.66.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[O:29])[CH:20]=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:26]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)c1cccc(-c2cccnc2)c1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(-c3cccnc3)c2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-3-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g crude 3-(pyridin-3-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 mg, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added 3-(pyridin-3-yl)benzoyl chloride (1.5 g, 7 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-3-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
A mixture of 3-(3-fluorophenyl)-propylamine (306 mg, 2 mmol), 2-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol), and K2CO3 (200 mg, 1.45 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(3-fluorophenyl)-propyl]-2,3-dihydroisoindol-1-one (391 mg, 73%). GC/MS gave: m/z (rel.int.) 269 (M+, 32), 147 (100), 146 (100), 119 (37), 109 (26) and 91 (45).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)[OH:10])[CH:2]=1.[O:26]=[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41](O)=[O:42])[C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][C:29]([CH3:33])([CH2:30][CH3:31])[C:28](=[O:34])[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=1)[CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:42])=[O:26]
Reactant: CC(C)(C)OC(=O)COc1cccc([C@H](O)CCc2cccnc2)c1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1cccnc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of alcohol 21 (530 mg, 1.54 mmol) in CH2Cl2 (5 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 393 mg, 1.54 mmol, followed by 1,3-dicyclohexylcarbodiimide (381 mg, 1.85 mmol), and 4-(dimethylamino)-pyridine (132 mg, 1.08 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20-60% EtOAc/hexanes) to give (1R)-3-(3-Pyridyl)-1-[3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (860 mg, 96%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 8.46 (m, 2H), 7.50-6.80 (m, 6H), 5.80 (t, J=6.1 Hz, 1H), 5.32 (d, J=5.0 Hz, 1H), 4.54 (s, 2H), 3.38 (d, J=12.8 Hz, 1H), 3.14 (td, J=12.6, 3.0 Hz, 1H) 2.60 (m, 2H), 2.36 (d, J=13.7 Hz, 1H), 2.25 (m, 1H), 2.10 (m, 1H), 1.75 (m, 4H), 1.49 (s, 9H), 1.45 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 0.90 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75MHz) (single diastereomer, mixture of rotamers) 208.2, 175.1, 170.0, 168.2, 167.7, 158.6, 150.2, 148.1, 141.3, 136.6, 130.2, 123.8, 120.1, 115.0, 113.6, 107.9, 82.8, 66.1, 51.7, 47.1, 44.6, 39.2, 37.8, 34.4, 33.0, 29.2, 28.4, 26.7, 25.3, 23.9, 23.5, 21.6, 21.4, 9.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Na+].[CH2:43]=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:43])[CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[CH2:27][CH2:28]3)[CH:17]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C=O
Reactant: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1NC1CCN(c2ccnc(C)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccnc(C)c2)CC1

Procedure:
Methyl 4-[(6-chloro-2-naphthyl)sulfonyl]-1-[[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazineacetate (0.30 g) obtained in Example 138 was dissolved in a 37% aqueous solution of formaldehyde (6.5 ml) and formic acid (3.0 ml) and refluxed for 15 hours. The reaction mixture was cooled, made alkaline by adding a 1N aqueous solution of sodium hydroxide, extracted with dichloromethane, dried and concentrated. The residue thus obtained was crystallized from ethanol to obtain the title compound (95 mg) as colorless crystals.
Reaction SMILES: Cl.CN[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[N:12][CH3:13])[C:6]=1[OH:14].C1C[O:19]CC1>O.CC(OC)(C)C>[CH3:13][NH:12][C:11](=[O:19])[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]=[O:15])[C:6]=1[OH:14]
Reactant: C1CCOC1
Reactant: CN=Cc1cccc(C(=O)NC)c1O
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Product: CNC(=O)c1cccc(C=O)c1O
Temperature: 22.5 °C
Reaction time: 14 h

Procedure:
60 ml of concentrated aqueous hydrochloric acid were added at 20 to 25° C. to 14 g (65 mmol) of the methylamide of Example 3 in a mixture of 120 ml of THF and 100 ml of water. After the reaction mixture had been stirred for approximately 14 hours at 20 to 25° C., it was taken up in MTBE and washed with water. After drying, the solvent was distilled off. 8 g of the title compound, which corresponded to 71% of theory, were obtained from the residue. (m.p.: 129-131° C.)
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:58][C:59]([F:69])([F:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH:64]([NH2:67])[CH2:63][CH2:62]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:67][CH:64]5[CH2:65][CH2:66][N:61]([CH2:60][C:59]([F:69])([F:58])[F:68])[CH2:62][CH2:63]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(CC(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CC(F)(F)F)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N-(2,2,2-trifluoroethyl)piperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.44 (m, 4H) 1.55-1.89 (m, 10H) 2.42 (t, J=8.0 Hz, 2H) 2.94 (br. d., 2H) 3.17 (q, J=10.11 Hz, 2H) 3.31 (s, 3H) 3.78 (m, 1H) 3.94 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 7.47 (d, J=8.0 Hz, 1H) 7.50 (s, 1H) 7.91 (s, 1H) 8.15 (d, J=8.02 Hz, 1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz, 1H). Melting point: 213-215° C. [M+H] calculated for C29H36F5N7O3, 626. found 626.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>CC(C)=O.[OH-].[Na+]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: CCNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCNc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
The 4-(ethylamino)benzene-sulfonamide was dissolved in 7.8 ml of acetone with 7.9 ml of 1N sodium hydroxide added. To this mixture was added 4-chlorophenylisocyanate (1.22 g, 7.9 mmoles), dissolved in 7.8 ml of acetone. This reaction mixture was allowed to stir for 25 minutes at room temperature, then filtered, with a small amount of an acetone:water (1:1) mixture being used to rinse out the flask and wash the filtered solid. The filtrate was acidified with 1N hydrochloric acid (7.9 ml) and stirred for about an hour until the initially separated oil had changed to a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.CS(O)(=O)=O>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][O:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Cc1nc(-c2nc[nH]n2)ccc1Br
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Temperature: 65 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
To a suspension of 3-bromo-2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridine (96.0 g, 0.4 mol) in tetrahydrofuran (780 mL) was added 3,4-dihydro-2H-pyran (72.5 mL, 0.8 mol) and methanesulfonic acid (3.2 mL). The mixture was heated to 65° C. and the resulting yellow solution was allowed to stir at 65° C. for 6 h. The mixture was cooled to ambient temperature, quenched with triethylamine (23 mL), concentrated under reduced pressure and further dried in a high vacuum for 1 h. The resulting oil was dissolved in acetonitrile (250 mL) and the solution was added into water (750 mL) while stirring vigorously. More acetonitrile (80 mL) was added and the mixture was allowed to stir for 1 h. The resulting solids were filtered, washed with 1:4 acetonitrile/water (800 mL) and dried in a vacuum oven for 48 h to afford the product (110 g, 85% yield) as a white solid. The product was further purified by silica gel plug purification (1:1 hexanes/ethyl acetate) to give 88 g of the pure product as a white solid and 16.2 g of less pure product. MS (ESI) m/z 239.1 [M]+, 241.1 [M+2]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21]([O:23]N1C(=O)CCC1=O)=O)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])[CH3:3].[NH:31](C(OC(C)(C)C)=O)[C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH:47][NH:48][C:49]([O:51][CH2:52][C:53]([Cl:56])([Cl:55])[Cl:54])=[O:50])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[C@H:33]([CH2:35][CH3:36])[CH3:34]>C1COCC1.C(OCC)(=O)C>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:21]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH:47][NH:48][C:49]([O:51][CH2:52][C:53]([Cl:54])([Cl:55])[Cl:56])=[O:50])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[C@H:33]([CH2:35][CH3:36])[CH3:34])=[O:23])[CH2:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Reaction time: 4 h

Procedure:
The preceding 30 g of oil in solution in 250 ml of THF are treated with 6.4 ml (50 mM) of NEM and 18.9 (45 mM) of Boc-Asp(OBzl)O Su. The apparent pH is adjusted between 6 and 7 by successive additions of NEM. After 4 hours, the product is isolated by evaporation of the THF, take-up in 400 ml of ethyl acetate followed by the same washings as the preceding homologue (3). The residue after drying and evaporation (36.5 g) is purified by chromatography over a column of silica with dichloromethane as solvent containing from 0 to 1.5% of methanol. 25 g (66%) of product presenting an NMR spectrum in accordance with the expected structure are thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:14](=O)[CH3:15].[BH3-]C#N.[Na+]>>[CH2:14]([N:8]1[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1)[CH3:15]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 74 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (1.15 g, 6.39 mmol), acetaldehyde (3.59 mL, 64.2 mmol) and NaBH3CN (1.95 g, 31 mmol) to afford 984 mg (74%) of 4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine, a yellow solid. Data for 4-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine: Rf 0.85 (11.5:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 7.81 (dd, 1H, J=9.6, 2.6), 7.66 (d, 1H, J=2.7), 6.29 (d, 1H, J=9.2), 4.23 (t, 2H, J=4.7), 3.47 (t, 2H, J=4.7), 3.45 (q, 2H, J=7.2), 1.22 (t, 3H, J=7.0).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][OH:14])[C:9]([F:12])([F:11])[F:10])=[C:4](F)[CH:3]=1.C1COCC1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([C:9]([F:12])([F:11])[F:10])=[N:13][O:14][C:4]=2[CH:3]=1
Reactant: ON=C(c1ccc(Br)cc1F)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: FC(F)(F)c1noc2cc(Br)ccc12
Temperature: 150 °C
Yield: 66.1 %

Procedure:
A solution consisting of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone oxime (3.2 g, 11.2 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.1 mL, 7.4 mmol) and THF (42 mL) was heated at 150° C. via microwave irradiation for 30 min. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with HCl (1 N aq., 25 mL). The organic layer was then dried (Na2SO4), concentrated, and purified (FCC) to yield the title compound (1.97 g, 66%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[N:8][C:9](=[S:11])[N:10]=1.[Na].Br[C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1>>[N+:19]([C:16]1[S:15][C:14]([S:11][C:9]2[N:10]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[NH:7][N:8]=2)=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: S=C1N=NC(c2cccs2)=N1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: [Na]
Product: O=[N+]([O-])c1cnc(Sc2n[nH]c(-c3cccs3)n2)s1

Procedure:
The title compound was prepared in the manner described in Example 1. Substituting the acid chloride of thiophene-2-carboxylic acid (prepared from the acid and oxalyl chloride) for the benzoyl chloride in Example 1 gave the thiosemicarbazide of thiophene-2-carboxylic acid and then 3-(thien-2-yl)-1,2,4-triazole-5-thione. Reaction of 1.73 g of the sodium salt of the thione with 2.09 g of 2-bromo-5-nitrothiazole as in Example 1 yielded 1 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-(thien-2-yl)-1,2,4-triazole, an orange solid, MP 179°-181° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([CH3:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([O:33][CH3:34])[CH:27]=1)([CH3:25])=[O:24].Cl>COCCO>[CH3:25][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([CH3:21])=[CH:4][N:3]=2)=[C:28]([O:33][CH3:34])[CH:27]=1)([CH3:22])=[O:24]
Reactant: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Reactant: COc1cc(P(C)(C)=O)ccc1N
Agent: Cl
Solvent: COCCO
Product: COc1cc(P(C)(C)=O)ccc1Nc1ncc(C)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 28.9 %

Procedure:
To a solution of 2-chloro-5-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]-pyrimidin-4-amine (0.035 g, 0.11 mmol) in 1 mL of 2-methoxyethanol in a vial was added 4-(dimethylphosphoryl)-2-methyoxyaniline (0.020 g, 0.085 mmol) as the HCl salt. The vial was sealed and the reaction was heated at 90° C. for 16 h. The reaction was quenched with 1N NaOH solution and the solution extracted ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired compound (12 mg, 29% yield). MS/ES+: m/z=489.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1C=CC=CC=1>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCCCNc1ccc2c(c1)CCC2
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCN(C(=O)c1ccc(Cl)cc1)c1ccc2c(c1)CCC2
Yield: 88.5 %

Procedure:
6.3 g of ethyl 5-(indan-5-ylamino)valerate and 3.1 g of ethyl diisopropylamine are reacted in 50 ml of benzene with 4.2 g of p-chlorobenzoyl chloride. The resulting residue (left after filtering off the precipitate and concentrating the filtrate by evaporation) is saponified as described in Example 77b. Recrystallization of the crude product from ethyl acetate/petrol ether (1:2) yields 7.9 g (88.1% of theory) of 5-{p-chloro-[N-(indan-5-yl)]benzamido}valeric acid, MP 132° to 134°.