Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:31])[NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH2:30])=[CH:18][CH:17]=3)[CH2:12]2)=[CH:6][CH:5]=1.[OH-].[K+]>C1COCC1.O.CO>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:22]([C:19]1[CH:18]=[CH:17][C:16]([N:13]2[CH2:14][CH2:15][C@H:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=3)[CH2:12]2)=[CH:21][CH:20]=1)=[O:31]
Reactant: COC(=O)c1ccc(O[C@H]2CCN(c3ccc(C(=O)Nc4ccccc4N)cc3)C2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](Oc3ccc(C(=O)O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 20.8 %

Procedure:
A solution of 372 (100 mg, 0.23 mmol) and KOH (100 mg, 1.78 mmol) in 1:1:1 mixture of THF/water/MeOH (6 mL) was stirred at room temperature for 5 days. The reaction mixture was concentrated and partitioned between water (5 mL) and ether (5 mL). Organic phase was discarded and the aqueous phase was acidified to pH=6 using 1M HCl solution and extracted with EtOAc. The extract was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography, eluent MeOH-DCM (gradient of MeOH from 5 till 20% MeOH) to afford the title compound (20 mg, 21% yield). 1H NMR (DMSO) δ 9.34 (σ, 1H), 7.85 (m, 4H), 7.11 (d, 1H, J=7.8 Hz), 7.00 (d, J=8.4 Hz, 2H), 6.92 (d, 2H, J=7.7 Hz), 6.75 (d, J=8.0 Hz, 2H), 6.6 (m, 3H), 5.26 (br.s., 1H), 3.75 (m, 1H), [3.34 DMSO, 4H], 2.44 (m, 1H), 2.31 (m, 1H) m/z: 418.4 (MH+).
Reaction SMILES: [I-:1].[Na+].CNCCNC.Br[C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1.CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[I:1][C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCCCCCCCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(I)c1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
A Schlenk tube was charged with CuI, sodium iodide (fine powder, dried, 300 mg, 2.00 mmol), evacuated and backfilled with argon. N,N′-Dimethylethylenediamine, 5-bromo-m-xylene (136 μL, 1.00 mmol), and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 22 h. The resulting suspension was allowed to reach room temperature. Ethyl acetate (2 mL) and dodecane (internal GC standard, 230 μL) were added to the reaction mixture. A 50 μL, sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC. The results are tabulated below.
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.CS(C)=O.[NH2:28][C:29]1[CH:38]=[C:37](F)[C:36]([O:40][CH3:41])=[C:35]2[C:30]=1[C:31](=[O:49])[C:32]([C:46]([OH:48])=[O:47])=[CH:33][N:34]2[C@@H:42]1[CH2:44][C@@H:43]1[F:45]>C(Cl)(Cl)Cl>[NH2:28][C:29]1[CH:38]=[C:37]([N:14]2[CH2:15][CH2:16][C@@H:12]([C:9]3([NH2:8])[CH2:10][CH2:11]3)[CH2:13]2)[C:36]([O:40][CH3:41])=[C:35]2[C:30]=1[C:31](=[O:49])[C:32]([C:46]([OH:48])=[O:47])=[CH:33][N:34]2[C@@H:42]1[CH2:44][C@@H:43]1[F:45]
Reactant: COc1c(F)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(N2CC[C@@H](C3(N)CC3)C2)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 90 °C
Reaction time: 168 h
Yield: 5.1 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)amino]cyclopropyl]pyrrolidine (788 mg, 3.48 mmol) and triethylamine (2 ml) to dried dimethyl sulfoxide (1 ml, 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (621 mg, 2.00 mol) was added thereto and stirred at 90° C. for 168 hours while sealing in a sealed tube under a nitrogen atmosphere. After letting the reaction solution cool and then concentrating the reaction solution under a reduced pressure, the residue obtained was dissolved in chloroform (200 ml) and washed with a 10% aqueous citric acid solution (100 ml). The organic layer was then dried over anhydrous sodium sulfate, and after filtering, the filtrate was concentrated under a reduced pressure. After adding dropwise concentrated hydrochloric acid (10 ml) to the obtained residue while cooling with ice, it was stirred at the same temperature for 30 minutes. 1 mol/l Hydrochloric acid (20 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.8 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. The organic layers were then combined and dried over anhydrous sodium sulfate, and then the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by recrystallization from a mixed solvent of ethanol and diethyl ether, and then dried under a reduced pressure. 74 mg (9%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[NH:18][C:19]1[NH:23][C:22]2[C:24]3[CH2:25][C:26]([CH3:36])([CH3:35])[O:27][C:28]=3[C:29]([C:31](OC)=O)=[CH:30][C:21]=2[N:20]=1>C1COCC1.O>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[NH:18][C:19]1[NH:23][C:22]2[C:24]3[CH2:25][C:26]([CH3:36])([CH3:35])[O:27][C:28]=3[C:29]([C:31]3[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=3)=[CH:30][C:21]=2[N:20]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: CC(C)C(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1noc(-c2cc3nc(Nc4c(F)cccc4Cl)[nH]c3c3c2OC(C)(C)C3)n1
Yield: 17.7 %

Procedure:
Under nitrogen atmosphere, to a solution of N′-hydroxyisobutyrimidamide (0.028 g, 0.268 mmol) in THF was added sodium hydride (0.021 g, 0.51 mmol). The reaction mass was refluxed for 15-20 minutes. Then added methyl 2-((2-chloro-6-fluorophenyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Step-1 of Intermediate-15, 0.100 g, 0.255 mmol) and continued reflux for 4-5 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified column chromatography to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.28 (d, 6H), 1.48 (s, 6H), 3.09 (m, 3H), 7.24 (m, 1H), 7.39 (m, 1H), 7.54 (d, J=7.2 Hz, 1H), 9-10 (s, 1H), 10.5 (s, 1H); MS [M]+: 458.14.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.501 g (5.0 mmol) of 1-hexanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.77 g (87.7%, yellow oily substance) of the desired product.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:26][N:27]=2)=[CH:19][CH:18]=1.[C:33](O)(=[O:39])/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH3:38]>CN(C)C1C=CN=CC=1.ClCCl>[C:33]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:26][N:27]=2)=[CH:21][CH:22]=1)(=[O:39])/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH3:38]
Reactant: CCC/C=C/C(=O)O
Reactant: CCCCCc1nnc(-c2ccc(O)cc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1ccc(-c2nnc(CCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dicyclohexylcarbodiimide (0.2 g) is added to a solution of 2-(4-hydroxyphenyl)-5-pentyl-1,3,4-thiadiazole [Mol. Cryst. Liq. Cryst., (1990) Vol., 191, pp 223] (0.25 g), (E)-hex-2-enoic acid, (0.1 g) 4-(dimethylamino)pyridine (0.05 g) and dichloromethane (20 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down. The residue is purified by column chromatography on silica gel using hexanelethyl acetate (9/1 v/v) as eluent and recrystallisation from hexane to yield 0.17 g of 2-(4-[(E)-hex-2-enoyloxy]phenyl)-5-pentyl-1,3,4-thiadiazole.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH3:31])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=1)=[O:9].[CH2:41]1COCC1.[N+](=C)=[N-]>C(OCC)C>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:34]=1)[CH2:6][N:7]([CH3:31])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:41])=[O:29])=[CH:24][CH:23]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(C(=O)O)cc2)c2cccnc2c(=O)n1C
Reactant: C1CCOC1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(C)c(=O)c3ncccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of the compound obtained in Example 74 (50 mg) and THF (15 ml) was added a solution of diazomethane (excess) in ethyl ether. After the mixture was stirred for 30 minutes at room temperature, the solvent was evaporated to give the titled compound as colorless crystals (25 mg).
Reaction SMILES: N1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[CH2:6][CH2:5][C:4]=2C=N1.FC(F)(F)C(OCC)=[O:17].C[O-].[Na+]>CO>[C:9]1(=[O:17])[C:8]2[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: c1ccc2c(c1)CCc1cn[nH]c1-2
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCCc2ccccc21

Procedure:
Synthetic Scheme III shows the procedure for preparation of 4,5-dihydrobenz[g]indazole compounds embraced by Formula I. In step 1, ethyl trifluoroacetate is reacted with base, such as 25% sodium methoxide in a protic solvent, such as methanol, and a 1-tetralone derivative (9) to give the intermediate diketone (10). In step 2, the diketone (10) in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the free base or hydrochloride salt of a phenylhydrazine at reflux for 24 hours to afford a mixture of pyrazoles (11) and (12). Recrystallization gives the 4,5-dihydro benz[g]indazolyl-benzenesulfonamide (11). ##STR12##
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([Br:25])[CH:9]=1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([NH:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([Br:25])[CH:9]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 95.3 %

Procedure:
Pyridine (4.0 ml) was added dropwise to a stirred solution of 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (5.0 g), acetyl chloride (3.0 g) and dry chloroform (30 ml), causing an exothermic reaction (maximum temperature 60° C.). The reaction mixture was stirred at laboratory temperature for 2h and evaporated to dryness. The residue was dissolved in ethanol (25 ml), ammonia solution (d. 0.880; 25 ml) was added, and the solution was boiled under reflux for 1 h. The cooled reaction mixture was evaporated to dryness, dissolved in dichloromethane (100 ml), washed with dilute hydrochloric acid (3×50 ml) and water (50 ml), dried over anhydrous magnesium sulphate, filtered, and evaporated to give 5-acetamido-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (5.3 g), m.p. 180-187° C., in the form of a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]1)[CH:5]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH2:31])[C:26]([NH2:30])=[CH:27][C:28]=1[CH3:29]>>[Cl:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26]2[NH:30][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)=[N:31][C:25]=2[CH:24]=1
Reactant: Cc1cc(N)c(N)cc1Cl
Reactant: CN1CCCN(CCCOc2ccc(C=O)cc2Cl)CC1
Product: Cc1cc2[nH]c(-c3ccc(OCCCN4CCCN(C)CC4)c(Cl)c3)nc2cc1Cl
Yield: 7.9 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (61 mg, 0.20 mmol, 1.0 equiv), 4-chloro-5-methyl-benzene-1,2-diamine (31 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (48 mg, 0.25 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 7.1 mg (8%) of the title compound. MS (electrospray): mass calculated for C23H28Cl2N4O, 446.16; m/z found, 447.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.96 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8.6, 2.2 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.08 (t, J=6.0 Hz, 2H), 2.76-2.64 (m, 10H), 2.36 (s, 3H), 2.30 (s, 3H), 1.96-1.88 (m, 2H), 1.80-1.73 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)#[N:2].[C:8]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=CC=C[CH:9]=1.C(O)C#C.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH2:13]([N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1]#[N:2])[C:8]#[CH:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc[nH]1
Agent: C#CCO
Agent: CCOC(=O)N=NC(=O)[O-]
Solvent: C1CCOC1
Product: C#CCn1cccc1C#N
Yield: 46.7 %

Procedure:
51.57 g of 2-cyano-pyrrol[prepared by the process of Can. J. Chem. Vol. 59, p. 2763 (1981)], 146.9 g of triphenylphosphine, and 43.95 g of propargyl alcohol were mixed together and 420 ml of tetrahydrofuran were added. The mixture was cooled at +5° C., and over half an hour at 0° to 5° C., 97.5 g of ethyl azodicarboxylate were introduced. The temperature was allowed to return to ambient, and stirring was maintained for 18 hours. The solvent was evaporated under reduced pressure, and the crystallized residue was taken up in ethyl ether and filtered. After concentrating the filtrate, an oil was obtained which was chromatographed over silica. Elution with a hexane-ethyl acetate (7-3) mixture yielded 34 g of 1-(2-propynyl)-1H-pyrrole-2-carbonitrile.
Reaction SMILES: Cl[CH2:2][C:3]([C@H:5]1[CH2:7][C@@H:6]1[C:8]1[CH:13]=[C:12]([N:14]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[N:15]2)[N:11]=[C:10]([CH3:21])[N:9]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:20][C:16]1[N:17]=[C:18]([CH3:19])[N:14]([C:12]2[N:11]=[C:10]([CH3:21])[N:9]=[C:8]([C@H:6]3[CH2:7][C@@H:5]3[C:3]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]4[CH:2]=3)[CH:13]=2)[N:15]=1
Reactant: Nc1ccccn1
Reactant: Cc1nc([C@H]2C[C@@H]2C(=O)CCl)cc(-n2nc(C)nc2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc([C@H]2C[C@@H]2c2cn3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 80 °C

Procedure:
To a solution of 1-5 (30 mg, 0.10 mmol) and 2-aminopyridine (10 mg, 0.11 mmol) in ethanol (1 mL) was added sodium bicarbonate (16 mg, 0.20 mmol) in a single portion and the reaction was heated at 80° C. After 2 h the mixture cooled to room temperature, diluted with ethyl acetate (5 mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (50-100% EtOAc/hexanes) to give Example 1 as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.03 (dt, J=6.7, 1.2 Hz, 1H), 7.57 (s, 1H), 7.52 (br d, J=9.1 Hz, 1H), 7.45 (s, 1H), 7.13 (ddd, J=9.0, 6.8, 1.2 Hz, 1H), 6.74 (td, J=6.8, 1.1 Hz, 1H), 2.88 (s, 3H), 2.81-2.76 (m, 1H), 2.68-2.62 (m, 1H), 2.65 (s, 3H), 2.39 (s, 3H), 1.93-1.83 (m, 2H); MS: m/z=346.5 (M+H).
Reaction SMILES: [C:1]([CH:3]([C:9]1([CH3:19])[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24].O>CS(C)=O>[C:1]([C:3]([C:9]1([CH3:19])[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)([CH2:24][CH:23]=[CH2:22])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C(C#N)C1(C)CC(C)(C)CC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC(C#N)(C(=O)OCC)C1(C)CC(C)(C)CC(C)(C)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of cyanoacetate 47 (1.25 g, 4.71 mmol) in anhydrous DMSO (10 ml) was added sodium hydride (0.284 g, 7.09 mmol; 60% mineral oil dispersion). The mixture was stirred for 30 min at 50° C., and cooled to 20° C. To this was added allylbromide (0.86 g, 7.1 mmol) and the mixture was stirred for 3 h at room temperature, then for 30 min at 50° C. The mixture was cooled, treated with water and extracted with diethyl ether. The extract was washed with water and with brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 20:1) to give 48 (0.92 g, 63.7%) as a colorless oil. 1H NMR (CDCl3, TMS): 0.98 (6H, s, 3′,5′-CH3eq); 1.11 (6H, s, 3′,5′-CH3ax); 1.00-1.85 (6H, m, ring CH); 1.31 (3H, t, 7 Hz, CH3-ethyl); 1.33 (3H, s, 1′-CH3); 2.42 and 2.86 (total 2H, both dd, 13 and 7 Hz, 3-CH2); 4.02 (2H, q, 7 Hz, OCH2); 5.05-5.37 (2H, m, ═CH2) and 5.55-6.05 ppm (1H, m, ═CH).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[H-].[Na+]>>[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:15][CH2:14][C:2]2([CH3:1])[O:7][C:6]3=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]3[CH2:4][CH2:3]2)=[CH:19][CH:18]=1
Reactant: CC1(CO)CCn2cc([N+](=O)[O-])nc2O1
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: CC1(COCc2ccc(I)cc2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 54 %

Procedure:
Alkylation of oxazine alcohol 149 (see Example 2OO) with 4-iodobenzyl bromide (1.7 equiv.) and NaH (1.9 equiv.) as in Example 2UU above for 3 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 1% EtOAc/CH2Cl2, gave 7-{[(4-iodobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (156) (54%) as a cream solid: mp (CH2Cl2/pentane) 130-132° C.; 1H NMR (CDCl3) δ 7.67 (dt, J=8.3, 2.0 Hz, 2H), 7.39 (s, 1H), 6.99 (br d, J=8.3 Hz, 2H), 4.49 (s, 2H), 4.09 (ddd, J=12.5, 7.0, 5.9 Hz, 1H), 4.01 (ddd, J=12.5, 7.1, 5.9 Hz, 1H), 3.62 (d, J=10.2 Hz, 1H), 3.58 (d, J=10.2 Hz, 1H), 2.37 (ddd, J=14.4, 7.0, 6.0 Hz, 1H), 2.10 (ddd, J=14.4, 6.9, 6.0 Hz, 1H), 1.46 (s, 3H). Anal. (C15H16IN3O4) C, H, N.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([N:20]2[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[N:21]2)[CH:10]=[C:11]([F:19])[C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[F:6][C:7]1[CH:8]=[C:9]([N:20]2[CH:24]=[C:23]([CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])[N:22]=[N:21]2)[CH:10]=[C:11]([F:19])[C:12]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cn(-c2cc(F)c(N3CCOCC3)c(F)c2)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cn(-c2cc(F)c(N3CCOCC3)c(F)c2)nn1
Reaction time: 0.75 h

Procedure:
Methanesulfonyl chloride (0.1 mL, 2.23 mmol) was added dropwise to a solution of [1-(3,5-difluoro-4-morpholin-4-yl-phenyl)-1H-[1,2,3]triazol-4-yl]-methanol (0.6 g, 2.02 mmol), obtained in Example 1, and Et3N (0.6 mL, 4.4 mmol) in CH2Cl2 (30 mL) at 0° C. After stirring for 45 min the reaction mixture was washed successively with water, aqueous NaHCO3 and brine and dried over sodium sulfate. Evaporation of volatiles left the title compound as oily liquid (0.7 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nc(Cl)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-chloro-2-methylpyridazin-3(2H)-one following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.179 min, m/z=422.1; 1H NMR (CDCl3) 1.08 (d, 6H), 1.49 (d, 3H), 2.10 (s, 3H), 2.18 (m, 1H), 2.32-2.41 (m, 1H), 2.83 (m, 1H), 3.79 (s, 3H), 5.63 (m, 1H), 6.90-7.03 (m, 5H), 7.23 (m, 2H), 7.46-7.59 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[O-:16][C:17]#[N:18].[K+].C(O)(=O)C>O1CCOCC1.O>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:17]([NH2:18])=[O:16])=[CH:15][CH:14]=1)#[N:13]
Reactant: N#Cc1ccc(OCCNCCO)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(OCCN(CCO)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(2-hydroxyethylamino)ethoxy]benzonitrile (5 g, 0.0242 mol; see Preparation C(ii) above) in dioxane (65 mL) and water (65 mL) was added, at rt, potassium cyanate (4.92 g, 0.0606 mol), followed by acetic acid (4.36 g, 0.0726 mol). The reaction mixture was then stirred at rt overnight, before being concentrated under reduced pressure. The resulting residue was partitioned between water and dichloromethane. The organic layer was separated, washed with water and brine, dried over sodium sulfate and then concentrated. The crude product was further purified by column chromatography. Yield: 3.5 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH3:14])=[C:6]([CH3:15])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(Cl)=[S:24]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[C:23]2=[S:24])=[C:6]([CH3:15])[CH:5]=[CH:4][CH:3]=1
Reactant: CCNCCCNc1c(C)cccc1Cl
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCCN(c2c(C)cccc2Cl)C1=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.5 %

Procedure:
To an ice-cold solution of the diamine of Step A (3.4 g) and triethylamine (4.0 mL) in dry chloroform (50 mL) was added thiophosgene (1.7 mL). After 20 minutes at ambient temperature, the reaction was quenched with water and extracted with dichloromethane. The extracts were combined, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided an orange solid which was triturated with diethyl ether to give the title product (2.4 g, 59.5%) as a white solid, m.p. 88-90° C.