Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:37]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[N:37]1([C:42]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][C:10]([C:13]4[CH:18]=[N:17][N:16]5[C:19]([C:22]6[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[O:30])[CH:25]=[CH:26][CH:27]=6)=[CH:20][N:21]=[C:15]5[CH:14]=4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCNCC5)nc4)cnn23)c1
Reactant: O=C(Cl)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCN(C(=O)N6CCCC6)CC5)nc4)cnn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-{3-[7-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.5 mg, 0.0413 mmol) HCl salt, 1-pyrrolidinecarbonyl chloride (6.84 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol) in DMSO (0.5 mL) was stirred at r.t. for 1 h. The mixture was diluted with DMSO, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=594.2.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C(#N)C.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (40 mg, 0.076 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0 ml), treated with potassium carbonate (16 mg, 0.12 mmol) and pyrrolidine (7 μl, 0.084 mmol), and stirred 18 hours at room temperature. The reaction was quenched in water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to an oil which was purified by reverse phase HPLC to yield 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)ethoxy)benzamide. MS (Q1) 514 (M)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]=1[C:16]([O:18]CC)=[O:17])[CH3:3].[OH-].[Na+]>CO>[CH3:3][CH:2]([C:4]1[S:8][C:7]([CH2:9][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[N:6][C:5]=1[C:16]([OH:18])=[O:17])[CH3:1]
Reactant: CCOC(=O)c1nc(CN2CCOCC2)sc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1sc(CN2CCOCC2)nc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
A solution of ethyl 5-(1-methylethyl)-2-(4-morpholinylmethyl)-1,3-thiazole-4-carboxylate (77 mg) in methanol (5 ml) was treated with 2M sodium hydroxide solution (5 ml) and the mixture stirred at 20° C. for 18 h. The mixture was concentrated in vacuo and the residue taken up in water (3 ml). The pH was adjusted to pH 5-6 using 2M hydrochloric acid solution and extracted with DCM (10 ml), separated by hydrophobic frit and evaporated to give the title compound as a pale yellow gum (33 mg).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]2[OH:12])#[N:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N#Cc1ccccc1N
Product: CCOC(=O)c1cnc2c(C#N)cccc2c1O
Temperature: 60 °C

Procedure:
Anthranilonitrile (8.23 g) and diethyl ethoxymethylenemalonate (14 mL) are heated at 130° C. for 1 hour. The reaction is cooled to 60° C., poured into 50 mL hexanes, and the resulting enamine intermediate filtered and dried. The enamine is added to 60 mL diphenyl ether and heated to 250° C. for 1 hour with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the orange-brown solid filtered, washed thoroughly with hexanes, and dried to give ethyl 8-cyano-4-hydroxyquinoline-3-carboxylate (5.69 g). A mixture of this ester (1.00 g) is added to 60 mL 1:1 THF:MeOH. Lithium hydroxide (1.0 M solution, 16 mL) is added dropwise and the reaction mixture heated at 40° C. overnight. The reaction is poured into 20 mL acetic acid. The volume is reduced by half on the rotary evaporator after which a solid precipitated. The solid is filtered, washed with water, and dried. An additional crop of the desired acid is obtained by further reducing the volume of the filtrate. The crops are combined to yield 0.72 g of 8-cyano-4-hydroxyquinoline-3-carboxylic acid. The acid (0.24 g) and carbonyldiimidazole (0.20 g) are added to 10 mL freshly distilled tetrahydrofuran and heated at reflux overnight. The reaction is cooled to room temperature and 4-chlorobenzylamine (0.13 mL) is added dropwise. The reaction is stirred at room temperature for 24 hours, then at reflux for 6 hours. The reaction is cooled and a white solid filtered and dried to give the desired product (0.17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[S:12][C:11](SC)=[N:10][C@H:9]2[CH3:15])=[CH:4][CH:3]=1.[N+:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[S:12][C:11](=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N+:16]([O-:18])=[O:17])[NH:10][C@H:9]2[CH3:15])=[CH:4][CH:3]=1
Reactant: CSC1=N[C@@H](C)[C@H](c2ccc(Cl)cc2)S1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=C1N[C@@H](C)[C@H](c2ccc(Cl)cc2)S1)[N+](=O)[O-]
Reaction time: 5 h
Yield: 63.5 %

Procedure:
9 g of trans-5-(4-chlorophenyl)-4-methyl-2-methylthio-2-thiazoline, 4.7 g of ethyl nitroacetate, and 0.06 g of zinc chloride were added into a 100 ml capacity of four neck flask, and the mixture was heated under nitrogen flow at the temperature ranging from 110˜130° C. for about five hours. After the completion of the reaction, the product mixture was dissolved with chloroform, washed with water, dried with magnesium sulfate, and then condensed under reduced pressure. The oily product obtained was purified by column chromatography to give 7.6 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)CCO2
Reactant: O=C(Cl)c1ccccc1Cl
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3ccccc3Cl)nc1)CCO2
Yield: 59.8 %

Procedure:
Similarly, (2-chlorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (164) (13.1 mg, yield: 59.8%, purity>95%) was prepared from 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (161) (13 mg, 0.06 mmol) and 2-chlorobenzoyl chloride (23 μl).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][O:19][C:20]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[NH2:22][C:21]1[CH:23]=[CH:24][C:25]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:26][C:20]=1[O:19][CH3:18]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Product: COc1cc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)ccc1N
Yield: 60.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.30 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (150 mg, 0.50 mmol) to afford the desired product (64 mg, 60%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 7.61 (d, J=5.3 Hz, 1H), 7.58-7.53 (m, 2H), 7.41 (d, J=5.3 Hz, 1H), 7.16 (s, 1H), 7.01 (d, J=5.3 Hz, 1H), 6.09 (d, J=5.1 Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br>C1COCC1.CCOC(C)=O>[CH3:32][O:33][C:34](=[O:37])[CH2:35][N:12]([CH2:11][C:7]1[N:6]([CH2:5][C:4]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:2]([Cl:1])[CH:3]=2)[CH:10]=[CH:9][N:8]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: Fc1cccc(CNCc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Reactant: COC(=O)CBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To a solution of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amine (200 mg, 0.55 mmol) and triethylamine (0.18 mL, 1.37 mmol) in THF (2 mL) was added methylbromoacetate (78 uL, 0.82 mmol). The reaction was stirred at ambient temperature for 18 h before diluting with EtOAc (50 mL). The solution was washed with water (20 mL) and brine then dried over Na2SO4. The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, 5% MeOH in CH2Cl2). The purified product was treated with excess 2N HCl in Et2O solution to afford the hydrochloride salt of the desired product 7e (74 mg, 26%): ESI MS m/z 436 [C21H20Cl2FN3O+H]+.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:28](O)CC.S(=O)(=O)(O)O>O>[CH3:1][N:2]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH2:24][CH3:28])=[O:21])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CCCO
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCOC(=O)C(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of ethyl 2-{4-[N-methyl-N-(7-chloro-1,2,4-benzotriazin-3-yl)amino]phenoxy}propionate (80 g, compound No. 21, Example 7), n-propanol (800 ml) and concentrated sulfuric acid (3 ml) was heated under reflux for a period of 6 hours. A small volume of water was added and the mixture was concentrated. Dichloromethane was added and the mixture was washed first with dilute aqueous potassium carbonate solution and then with water. The organic phase was dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give the title compound (80 g) as a red oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].[N-:34]=[N+:35]=[N-:36].[Na+]>CS(C)=O>[N:34]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)OC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 23.0 g (45.3 mmol) of (methylethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (40a) dissolved in 210 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 5.9 g (93.6 mmol) of sodium azide (NaN3). After work-up, the crude title compound (40b) was obtained and used in the next step without further purification. Rf=0.29 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.24-1.35 (m, 6H), 1.57 (d, J=5.2 Hz, 3H), 2.03-2.10 (m, 2H), 3.10-3.16 (m, 2H), 3.44-3.48 (m, 2H), 3.84-3.85 (2s, 1H), 3.94-3.96 (2d, J=8.8, 9.2 Hz, 1H), 4.18-4.22 (2d, J=9.2, 9.6 Hz, 1H), 4.33-4.38 (2d, J=11.2, 11.2 Hz, 1H), 4.64 (t, J=11.2 Hz, 1H), 4.78-4.97 (m, 1H), 6.82-6.87 (m, 1H), 7.32-7.37 (m, 5H) ppm. MS (ESI) m/z 538.07 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[S:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[N:19][C:18]=3[CH3:32])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:33])C.[Li+].[OH-]>>[CH3:33][C:7]1[N:6]([CH2:5][C:4]([OH:34])=[O:3])[C:14]2[C:9]([CH:8]=1)=[CH:10][C:11]([O:15][CH2:16][C:17]1[S:21][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)=[N:19][C:18]=1[CH3:32])=[CH:12][CH:13]=2
Reactant: CCOC(=O)Cn1c(C)cc2cc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(c1)cc(C)n2CC(=O)O

Procedure:
In analogy to the procedure described in example 2 c], {2-methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {2-methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid as off-white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH2:19][CH2:20][C:21]#[N:22])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25]>>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:55][CH2:54][N:53]3[C:46](=[CH:47][C:48]4[CH2:49][C:50]([CH3:57])([CH3:56])[CH2:51][C:52]=43)[C:45]2=[O:58])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:23]=[C:14]3[CH2:15][N:16]([CH2:19][CH2:20][C:21]#[N:22])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(CCC#N)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(CCC#N)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Yield: 51.3 %

Procedure:
Following the procedure of Example 309d, and starting with 338c (150 mg, 0.45 mmol) and {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (358 mg, 0.90 mmol) afforded 338d as a yellow solid (150 mg, 52%). MS-ESI: [M+H]+ 650.3
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCI
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Temperature: 25 °C

Procedure:
To 500 ml of toluene in a one liter round bottom flask, fitted with a condenser and magnetic stirrer, are added 7.6 g (0.03M) of the potassium salt of 4-hydroxy-4'-nitrobiphenyl, 4.9 g (0.035M) of 6-iodo-1-hexanol, and 0.5 g of 18-crown-6ether. The mixture is refluxed for about 20 hours until all of the potassium salt has dissolved and reacted as evidenced by the absence of the blue crystalline solid. The solution is filtered hot, and then cooled to room temperature. After solvent removal, the solid residue is recrystallized from ethanol to yield a purified product, m.p. 117°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16](=O)[NH:17][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[Cl-:20].[Cl-].[Cl-].[P+3]=O>>[Cl:20][C:16]1[N:17]=[N:18][C:13]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][CH:15]=1
Reactant: [Cl-]
Reactant: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Agent: O=[P+3]
Product: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC

Procedure:
29.9 g of 6-(3-methoxy-4-n-propoxyphenyl)-3[2H]pyridazinone are introduced in portions into 65 ml of phosphorus oxide-trichloride, with stirring, and the mixture is then stirred at 100° for 1 hour. The reaction mixture is concentrated to half in vacuo and poured onto ice, with thorough stirring. The crystals which deposit are filtered off with suction, washed with water and dried in vacuo. 31.6 g of 3-chloro-6-(3-methoxy-4-n-propoxyphenyl)pyridazine are obtained.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13]C)=[C:9]2[C:4]=1[N:5]=[CH:6][CH:7]=[N:8]2.[Cl-:15].[Ce+3].[Cl-].[Cl-]>>[Cl:15][C:12]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[NH:5][C:12]1[C:3](=[O:2])[C:4]2[N:5]=[CH:6][CH:7]=[N:8][C:9]=2[C:10](=[O:13])[CH:11]=1
Reactant: [Cl-]
Reactant: COc1ccc(OC)c2nccnc12
Agent: [Ce+3]
Product: O=C1C=C(Nc2cccc(Cl)c2)C(=O)c2nccnc21

Procedure:
Following the procedure of Example 5,3-chloroaniline was reacted with the aqueous solution of 5,8-dimethoxyquinoxaline in the presence of cerium chloride to give the title compound. Mass spectrum gave M+ of 285 and 287.
Reaction SMILES: C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[C:15]([O:19][C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=O)=[O:21])([CH3:18])([CH3:17])[CH3:16].[NH2:30][C:31]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>O.C1COCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:31]([NH:30][C:24]([C@@H:23]2[CH2:27][CH2:28][CH2:29][N:22]2[C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])=[O:26])=[C:32]([C:33]([O:35][CH3:36])=[O:34])[CH:37]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)ccc1NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
Under ice-cooling, 1.73 mL (12.4 mmol) of triethylamine and 0.88 mL (7.23 mmol) of 2,2-dimethyl propanoyl chloride were added to a THF (10 mL) solution comprising 1.50 g (6.97 mmol) of 1-(tert-butoxycarbonyl)-L-proline, and the mixture was stirred under ice-cooling for 30 minutes. Subsequently, 269 mg (4.65 mmol) of methyl 2-amino-5-chlorobenzoate was added thereto under ice-cooling, and the mixture was heated under reflux for 19 hours. After condensation and addition of water, the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1% hydrochloric acid, water, saturated sodium bicarbonate water, and saturated saline, followed by drying over magnesium sulfate. After condensation, the resultant was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1→4/1), thereby giving 1.65 g of tert-butyl (2S)-2-{[4-chloro-2-(methoxycarbonyl)phenyl]carbamoyl}pyrrolidine-1-carboxylate (yield: 93%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:24][CH2:25][N:26](CC)CC.Cl.C(=N)(OCC)C>CO>[NH:26]=[C:25]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)[CH3:24]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: CCN(CC)CC
Agent: CCOC(C)=N
Agent: Cl
Solvent: CO
Product: CC(=N)N1CCC(N(Cc2ncccc2C)Cc2ncccc2C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.1 %

Procedure:
To a solution of COMPOUND 249 (0.1054 g, 0.34 mmol) in MeOH (4 mL) was added Et3N (0.1 mL, 0.68 mmol) and ethyl acetimidate hydrochloride (0.0549 g, 0.41 mmol), and stirred at room temperature for 24 hours then concentrated. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (2×40 mL). Purification of the crude material by column chromatography on silica gel (15:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (50:3:2 CH2Cl2-MeOH—NH4OH) provided 0.0408 g (34%) of COMPOUND 338 as a white solid. 1H NMR (CDCl3) δ 1.60-1.72 (m, 2H), 1.90-1.95 (m, 2H), 2.09 (s, 6H), 2.12 (s, 3H), 2.47-2.68 (m, 4H), 3.82 (s, 4H), 4.17 (d, 2H, J=12.3 Hz), 7.06-7.10 (m, 2H), 7.37 (d, 2H, J=7.2 Hz), 8.34 (d, 2H, J=4.5 Hz). 13C NMR (CDCl3) δ 18.39, 23.92, 27.33, 45.64, 55.06, 57.89, 122.77, 133.81, 138.40, 146.29, 157.63, 164.64. ES-MS m/z 352.5 (M+H).
Reaction SMILES: OO.[OH-].[Li+].[CH:5]([C@@H:8]1[CH2:12][C@@H:11]([C@@H:13]([N:34]=[N+:35]=[N-:36])[CH2:14][C@H:15]([C:19](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:20])[CH:16]([CH3:18])[CH3:17])[O:10][C:9]1=[O:37])([CH3:7])[CH3:6].S([O-])([O-])=[O:39].[Na+].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C1(C)C=CC=CC=1.O>[CH:5]([C@@H:8]1[CH2:12][C@@H:11]([C@@H:13]([N:34]=[N+:35]=[N-:36])[CH2:14][C@H:15]([C:19]([OH:20])=[O:39])[CH:16]([CH3:17])[CH3:18])[O:10][C:9]1=[O:37])([CH3:6])[CH3:7]
Reactant: O=S([O-])[O-]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](C[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C(C)C)N=[N+]=[N-])OC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@H](C[C@H](N=[N+]=[N-])[C@@H]1C[C@@H](C(C)C)C(=O)O1)C(=O)O
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
175 ml of water, 74 ml of 30% hydrogen peroxide solution and 5.9 g of lithium hydroxide are slowly added in succession to a solution, stirred at -5° C., of 55.3 g of 3(S)-isopropyl-5(S)-{1(S)-azido-4-methyl-3(S)-[(4(S)-benzyl-oxazolidin-2-on-3-yl)-carbonyl]-pentyl}-tetrahydrofuran-2-one in 500 ml of tetrahydrofuran. The reaction mixture is stirred for one hour at 5° C. and for 150 minutes at room temperature, and then 750 ml of aqueous 1M sodium sulfite solution are added at 3° C. over a period of 30 minutes and the mixture is stirred for a further 30 minutes at room temperature. The reaction mixture is then freed of tetrahydrofuran by concentration, and the aqueous solution is washed three times with 1200 ml of ethyl acetate, the organic phases being back-extracted three times with 100 ml of 0.1N sodium hydroxide. The combined aqueous phases are adjusted to pH 1-2 with approximately 200 ml of 4N hydrochloric acid and are extracted with 3×1200 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, yielding the crude product which, for the purpose of cyclisation of the opened lactone, is dissolved in 500 ml of toluene and stirred for 2 hours at 50° C. with approximately 1 g of molecular sieve and approximately 1 g of p-toluenesulfonic acid. Filtration, concentration by evaporation and purification of the residue by means of FC (hexane/ethyl acetate/glacial acetic acid=30:60:1) yield the title compound, which crystallises spontaneously: m.p.=56°-58° C.; Rf (hexane/ethyl acetate/glacial acetic acid=30:60:1)=0.62; HPLC Rt =14.46 minutes; FAB-MS (M+H)+ =298.