Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:28]([NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>O1CCCC1>[CH2:47]([N:46]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COc1ccc(C=O)cc1

Procedure:
To a 100 mL solution of freshly distilled tetrahydrofuran (THF) was added p-formylphenoxyacetic acid (K & K Labs) (MW 180, 0.540 g, 3.0 mmol), triethyl amine (MW 101.19, 0.333 g, 3.3 mmol) and trimethylacetyl chloride (MW 120.57, 0.398 g, 3.3 mmol). After 20 minutes of heating at reflux, dioctadecylamine (Fluke) (MW 522.01, 1.723 g, 3.3 mmol) was added. The reaction was refluxed overnight.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2[C:45](OC=1C1C=CC=CC=1)=[C:44]1[N:54](C(C)C)[N:55]=[CH:56][C:43]1=CC=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:54]([CH:44]([CH3:45])[CH3:43])[N:55]=[CH:56][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: CC(C)n1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Product: CC(C)n1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 81 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-1-isopropyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a white solid (37.3 mg, 81%). LCMS (Method H): RT=4.70 min, [M+H]+=550.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(CCC2COc3ccccc3O2)C1
Reaction time: 16 h
Yield: 115.8 %

Procedure:
First 1.96 g (12.5 mmol) of piperidine-3-carboxylic acid ethyl ester and then 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.34 g (10 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.82 g (100%) of crude product are obtained which are filtered over 190 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.70 g (96.6%) of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]piperidine-3-carboxylic acid ethyl ester are then obtained in the form of a pale yellow oil. The 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 162°-165°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7](=O)[CH2:8][N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH2:10][CH2:11][C:5]=2[CH:4]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(C)cc1)CC2
Temperature: 0 °C

Procedure:
7-Methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[d]azepin-1-one (8.0 g/23 mmol; prepared in 4 steps as described by Kanao et al. Chem. Pharm. Bull., 1982, 30, 180-188) was dissolved in trifluoroacetic acid (10 mL) and cooled to 0° C. Triethylsilane (ca. 20 mL/230 mmol) was then added via syringe (mild exotherm) and the reaction allowed to warm to room temperature overnight. The reaction was concentrated and the residue partitioned between diethyl ether and 1 M aqueous sodium hydroxide (100 mL). The organic layer was washed with brine (100 mL), dried (magnesium sulfate), filtered and concentrated onto silica gel. Chromatography on silica gel (eluting with 0→30% ethyl acetate/hexanes) afforded 7-Methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid (4.0 g/55%). 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 6.98 (d, J=9.1 Hz, 1H), 6.68 (m, 2H), 3.78 (s, 3H), 3.28 (m, 4H), 2.94 (m, 4H), 2.39 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][C:24](=[O:26])[NH:23][C:22]([CH3:27])=[C:21]2[C:28](O)=[O:29])=[CH:16][C:15]=1[O:31][CH3:32].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][C:24](=[O:26])[NH:23][C:22]([CH3:27])=[C:21]2[C:28]([NH:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][N:4]=[C:3]3[CH2:1][CH3:2])=[O:29])=[CH:16][C:15]=1[O:31][CH3:32]
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)O)ccc1Cl
Reactant: CCc1n[nH]c2ccc(N)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc(Cl)c(OC)c3)cc12
Temperature: 30 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
3-Ethyl-1H-indazol-5-amine (218 mg, 1.35 mmol, 1.00 equiv) was combined with the product from Example 93, Step 4 (0.400 g, 1.35 mmol, 1.00 equiv), EDC (0.310 g, 1.62 mmol, 1.2 equiv) and Et3N (226 μL, 1.62 mmol, 1.20 equiv) in DMF (4 mL) and stirred at 30° C. for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. Solid precipitated out of the organic phase and was filtered and triturated with ether to provide 295 mg (50%) of the title compound as a white solid. MS (ES+) m/e 439 [M+H]+
Reaction SMILES: C1(=O)N([N:6]([C:11](=[O:22])[CH2:12][S:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][C:8]([O-:10])=O)C(=O)CC1.[NH2:25][C@@H:26]([C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[CH2:27][OH:28].CO>C(O)C.O>[C:14]([S:13][CH2:12][C:11]([NH:6][CH2:7][C:8]([NH:25][C@@H:26]([C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[CH2:27][OH:28])=[O:10])=[O:22])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@H](CO)C(=O)NCC(=O)O
Reactant: O=C([O-])CN(C(=O)CSC(=O)c1ccccc1)N1C(=O)CCC1=O
Solvent: CCO
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)[C@@H](CO)NC(=O)CNC(=O)CSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6.4 succinimidyl-N-(S-benzoylmercaptoacetyl)glycinate in 40 ml of ethanol at 70° C. is added in one portion a solution of 1.008 g of the above D-serylglycine in 10 ml of water at 70° C. The reaction mixture is refluxed for 1 hour and then stirred at room temperature overnight. After evaporation of the solvents the residue is agitated with 25 ml of acetone. The precipitate is removed by filtration. Diethylether is added to the filtrate until precipitation is complete. The precipitate is collected by filtration and washed with diethylether. After drying 1.56 g of a yellowish powder is obtained. To 600 mg of this is added 15 ml of chilled methanol. After agitation during 5 min. the white precipitate is filtered off, washed with cold methanol and dried to obtain 400 mg of S-benzoylmercaptoacetylglycyl-D-serylglycine as a white powder, m.p. 149° C. N.M.R. (DMSO-d6): δ 3.61 (2H, d, CH2 --OH), 3.77 (2H, d, α--CH2 --N), 3.84 (2H, d, δ--CH2 --N), 3.88 (2H, s, S--CH2), 4.38 (1H, dt, CH), 8.03 (1H, d, β--NH), 8.17 (1H, t, α--NH), 8.44 (1H, t, γ--NH).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[F:14][C:15]([F:43])([F:42])[C:16]1[CH:17]=[C:18]([C@H:26]2[O:30][C:29](=[O:31])[N:28]([CH2:32][C:33]3[C:38]([Br:39])=[CH:37][CH:36]=[C:35](Cl)[N:34]=3)[C@H:27]2[CH3:41])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.O1CCOCC1>C(OCC)(=O)C>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[C:18]([C@H:26]2[O:30][C:29](=[O:31])[N:28]([CH2:32][C:33]3[C:38]([Br:39])=[CH:37][CH:36]=[C:35]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:34]=3)[C@H:27]2[CH3:41])[CH:17]=[C:16]([C:15]([F:14])([F:42])[F:43])[CH:21]=1
Reactant: C1COCCN1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CCOCC2)ccc1Br
Temperature: 140 °C
Yield: 82.1 %

Procedure:
Triethylamine (3.23 mL, 23.18 mmol), morpholine (1.683 mL, 19.32 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 24, 2 g, 3.86 mmol) and 1,4-dioxane (10.0 mL) were mixed in a 20 mL microwave vial, capped and heated at 140° C. for 6 hours in microwave with monitoring by TLC and LCMS. Once the reaction was determined to be complete, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, water and brine. The organic phase was dried with Na2SO4, filtered and the filtrate concentrated. The crude was purified by silica gel chromatography in 30% ethyl acetate/hexanes to give the titled compound (1.8 g, 3.17 mmol, 82% yield) as white solid. LCMS (M+H)+: 569.9. 1H NMR (CDCl3, 500 MHz): δ 7.93 (s, 1H), 7.80 (s, 2H), 7.63 (dd, 1H), 6.52 (d, 1H), 5.75 (d, 1H), 4.91 (d, 1H), 4.32 (d, 1H), 4.28 (t, 1H), 3.87-3.84 (t, 4H), 3.57-3.48 (m, 4H), 0.83 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Br)[N:21]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Br:19])[N:21]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Reactant: BrCc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
8.75 g (40.3 mmol) of 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester was dissolved/suspended in 100 mL DMF followed by the addition of 1.93 g (48.3 mmol) of 60% sodium hydride. After the bubbling has ceased 12.1 g (48.3 mmol) of 2-bromo-6-bromomethyl-pyridine was added and the solution was stirred at r.t. overnight. The reaction was quenched using 900 mL of water, filtered and washed with 200 mL of water. The solid was further washed with 100 mL DCM. The DCM washes were evaporated and chromatographed on silica using 0-30% methanol in DCM. The purified compound was combined with the washed solid to give 14.9 g of the product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([O:17]C)=[O:16])=[C:7]([CH3:9])[N:8]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=2)[C:15]([OH:17])=[O:16])=[C:7]([CH3:9])[N:8]=1
Reactant: COCc1nc(C)c(-c2cc(C(=O)OC)c(C)cc2C)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1nc(C)c(-c2cc(C(=O)O)c(C)cc2C)[nH]1
Temperature: 40 °C
Reaction time: 15 h
Yield: 98.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 2.1, 150 mg, 0.52 mmol) in methanol (15 mL) and H2O (5 mL). Sodium hydroxide (280 mg, 7.00 mmol) was added and the resulting solution was stirred at 40° C. for 15 h. After cooled to room temperature, the solution was adjusted to pH 5 with aqueous HCl (2 M) and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and the solids were filtered off. The filtrate was concentrated under reduced pressure to yield the title compound as a light yellow solid (140 mg, crude), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[C:22]C3N(C)C=NC=3)[CH:20]=2)[CH:4]=1.[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38]C#C)[CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:22]#[C:21][C:19]2[CH:20]=[C:15]([C:5]3[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH:6]=3)[CH:16]=[N:17][CH:18]=2)[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: CNc1cc(-c2cncc(C#Cc3cncn3C)c2)cc(-c2ccccn2)n1
Reactant: C#CCN1CCN(C(C)C)CC1
Product: CNc1cc(-c2cncc(C#CCN3CCN(C(C)C)CC3)c2)cc(-c2ccccn2)n1

Procedure:
This compound is prepared analogously to Methyl-[5″-(3-methyl-3H-imidazol-4-ylethynyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.182) by replacing 1-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole with 1-isopropyl-4-(prop-2-ynyl)piperazine (Intermediate D1)
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.CN([C:32]([O:36][N:37]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.CON>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([NH:37][O:36][CH3:32])=[O:28])[CH:3]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CONC(=O)c1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.4 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.20 g, 0.49 mmol), HATU (0.37 g, 0.98 mmol), N-methyl morpholine (0.10 mL, 1.5 mmol) and methoxyamine hydrochloride (0.12 g, 1.5 mmol) in THF (10 mL) and DMF (2.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (Hexanes/EtOAc, 1:2) to give (1R,10R,11S,16S)-5-hydroxy-N-methoxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxamide (95) (0.035 g, 16%) as a white solid. 1H NMR (CD3OD): δ 7.27 (d, 1H), 6.87 (d, 1H), 3.83 (s, 3H), 3.47 (m, 2H), 2.70 (m, 1H), 2.11 (d, 1H), 1.87-1.38 (m, 10H), 1.30-1.15 (m, 1H), 1.04-0.94 (m, 5H), 0.90 (s, 3H), 0.86 (s, 3H). MS m/z 434 (C23H33NO5S−H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]([CH3:19])[C:16]([C:14]1[S:13][C:12]2[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:27][C:7]=3[O:8][CH2:9][CH2:10][C:11]=2[CH:15]=1)=[O:17]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Reactant: CN(C)CCN
Product: CN(C)CCNCc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
8-(Bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was reacted with N1,N1-dimethylethane-1,2-diamine using the procedure of Example 153 to give 197.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([SH:11])=[N:9][N:10]=2)[N:7]=1.[CH3:12][NH2:13].Cl>>[CH3:12][NH:13][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([SH:11])=[N:9][N:10]=2)[N:7]=1
Reactant: CN
Reactant: Sc1nnc2ccc(Cl)nn12
Agent: Cl
Product: CNc1ccc2nnc(S)n2n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (330 mg, 1.77 mmol) was treated with a 40% v/v aqueous solution of methylamine. The reaction mixture was stirred at 100° C. for 17 h, then it was cooled to room temperature and acidified to pH 1-2 with 1 N aqueous HCl. The resulting precipitate was filtered, washed with water, and dried in vacuo to give 185 mg of 6-methylamino-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol as a yellow powder (58% yield): 1H NMR (DMSO-d6): δ 2.83 (d, 3H), 6.85 (d, 1H), 7.44 (broad q, 1H), 7.74 (d, 1H), 14.2 (s, 1H); MS (m/z) 182 [M+H+]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N+:11]([O-])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:29][C@H:28]4[N:24]([CH2:25][CH2:26][CH2:27]4)[C:23]4[N:30]=[C:31]([NH:34][CH2:35][CH3:36])[N:32]=[CH:33][C:22]=4[C:21]3=[O:37])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([N:20]3[CH2:29][C@H:28]4[N:24]([CH2:25][CH2:26][CH2:27]4)[C:23]4[N:30]=[C:31]([NH:34][CH2:35][CH3:36])[N:32]=[CH:33][C:22]=4[C:21]3=[O:37])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc([N+]3([O-])CCN(C(=O)OC(C)(C)C)CC3)c1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c1)C2=O
Yield: 71.8 %

Procedure:
(S)-4-Tert-butoxycarbonyl-1-[3-(9-ethylamino-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]piperazine-1-oxide (0.338 g, 0.645 mmol) obtained in Step 2 was dissolved in ethanol (10 mL), and the mixture was stirred for 1.5 hours under a stream of hydrogen gas after adding 10% palladium-on-carbon (137 mg, 0.0646 mmol). The mixture was filtered through sellite, and the filtrate was concentrated to give (S)-5-[3-(4-tert-butoxycarbonylpiperazine-1-yl)phenyl]-9-ethylamino-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (0.235 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>O1CCCC1>[Cl:19][CH2:20][CH2:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)=[O:24]
Reactant: Nc1cccc2cccnc12
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCl)Nc1cccc2cccnc12
Yield: 53 %

Procedure:
A solution of 8-aminoquinoline (10 L g, 0.069 mole) and triethylamine (10 ml, 0.072 mole) in dry tetrahydrofuran (40 ml) was treated dropwise at room temperature with 4-chlorobutyryl chloride (about 0.07 mole) until the green reaction mixture turned yellow in colour. The reaction was filtered and the solids (triethylamine hydrochloride) were washed with tetrahydrofuran. The combined filtrates were concentrated by vacuum distillation, (≃15 mm Hg), filtered over alumina in methylene chloride, concentrated and recyrstallized from ether/petroleum ether affording 4-chloro-N-(8-quinolyl)butyramide. An analytical sample was prepared by recrystallization (m.p. 62°-63°), yield 53%.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:14])[C:12](=[O:15])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C.Cl>O>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:11][CH2:10]3)[C:12](=[O:15])[N:13]([CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 43 %

Procedure:
A mixture of 0.406 g (0.00133 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53), 0.237 g (0.00142 mole) of 4-amino-3-methoxylbenzoic acid, 7 mL of ethanol, 28 mL of water and 1.2 mL of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.250 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methoxybenzoic acid (I-53) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.[Pt]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=C(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: [Pt]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
The product of Example 2 (0.5 g.) was hydrogenated in ethanol (10 ml.) at room temperature and atmospheric pressure using a platinum catalyst (5 mg.). After 41/2 hours the mixture was filtered and the filtrate concentrated. The product was recrystallised from a mixture of ether and light petroleum (b.p. 40°-60° C.) to give 2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 112°-113° C.