Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.CC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(Cl)cc2)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a mixture of 5-hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg), 1-bromomethyl-4-chlorobenzene (209 mg), CH3CN (8 ml) and DMF (1 ml) was added potassium carbonate (282 mg), and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo and diluted with water. The mixture was extracted with EtOAc, and extract was washed successively with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with n-hexane to give the title compound (210 mg) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C[Si](C)(C)Cl.C(N(CC)CC)C.CC(OC[C:32]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)C(COC(C)=O)=[C:38]2[C:33]=1[CH:34]=[CH:35][CH:36]=[CH:37]2)=O.C1C[O:54][CH2:53]C1>O>[CH:53]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([O:12][CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:45]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12)=[O:54]
Reactant: C1CCOC1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC=O)[C@H]2SC1
Reaction time: 2 h

Procedure:
To a suspension of 7-amino-3-methylceph-3-em-4-carboxylic acid (7.76 g., 0.036 mole) in anhydrous THF at 0°, cooled in an ice-bath, was added trimethylchlorosilane (7.8 g., 9.07 ml., 2 equivalents) and triethylamine (7.3 g., 10 ml., 2 equivalents). After 10 minutes the ice-bath was removed and the mixture left at ambient temperature for 2 hours. To the mixture was added two equivalents of acetic formic mixed anhydride and the mixture was allowed to stand at ambient temperature for a further 1.5 hours. Water (5 ml.) was added, the precipitated triethylamine hydrochloride was filtered off and the filtrate evaporated on a rotatory evaporator. THF (50 ml.) was added to the residual oil and the solution was esterified with diphenyldiazomethane. The product was purified by chromatography on silica using CH2Cl2 /ether 1:1 v/v as eluant to give diphenylmethyl 7-formylamino-3-methylceph-3-em-4-carboxylate.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[CH:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:8]1([CH2:7][C:6]([OH:17])=[O:5])[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)Cn1ccc2cnccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1ccc2cnccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 150.2 %

Procedure:
To a solution of pyrrolo[3,2-c]pyridin-1-yl-acetic acid tert-butyl ester (0.44 g, 1.89 mmol) in CH2Cl2 (10 mL) at 0° C. is added trifluoroacetic acid (1 mL). After 15 minutes, the solution is allowed to warm to room temperature and stirred for 18 hours. The reaction mixture is concentrated in vacuo and then azeotroped with toluene to give 0.5 g of the title compound as a residue (wet with excess TFA) which is used as is in the subsequent step
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][N:36]1[CH:40]=[C:39]([S:41](Cl)(=[O:43])=[O:42])[N:38]=[C:37]1[CH3:45]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:35][N:36]1[CH:40]=[C:39]([S:41]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:43])=[O:42])[N:38]=[C:37]1[CH3:45]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol) in DMF (3 mL) was added diisopropylethylamine (100 uL, 0.56 mmol), DMAP (20 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.168 mmol). The reaction mixture was stirred at room temperature overnight. The solution was filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (25 mg, 37%)
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[NH:27])[NH:25][OH:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:28](Cl)(=O)[CH2:29][CH2:30][CH3:31]>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:27]=[C:28]([CH2:29][CH2:30][CH3:31])[O:26][N:25]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCC(=O)Cl
Reactant: N=C(NO)N1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: CCCc1nc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)no1

Procedure:
The title compound is prepared from N-cyclopropyl-N-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide and butyryl chloride following a procedure analogous to that described in Example 47. LC (method 8): tR=1.33 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+:10].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[S:20].[CH3:21][CH2:22][OH:23]>C1COCC1.C(#N)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22](=[O:23])[CH:21]=[CH:17][C:12]([C:13]#[N:18])=[C:19]1[S-:20].[Na+:10]
Reactant: CCO
Reactant: S=C=Nc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: N#Cc1ccc(=O)n(-c2ccccc2Cl)c1[S-]
Temperature: 25 °C
Yield: 88 %

Procedure:
NaHMDS (13.2 mL, 1.0M in THF, 13.2 mmol) was added slowly to a solution of 2-chlorophenyl isothiocyanate (1.02 g, 6.0 mmol) in THF (50 mL) and acetonitrile (5 mL) at −78° C. The mixture was warmed to r.t. over 1 h. N,N-Dimethyluracil (841 mg, 6.0 mmol) and EtOH (75 mL) were added and the mixture heated at reflux for 4 h. Volatiles were removed in vacuo and the residue was dissolved in hot EtOH (10 mL). Et2O (˜100 mL) was added slowly to precipitate out the product. The solid was filtered off, washed with Et2O (2×30 mL) and dried to give the title compound (1.5 g, 88%) (v. hygroscopic). δH (DMSO-d6) 7.35-7.32 (1H, m), 7.25-7.20 (2H, m), 7.15 (1H, d, J 9.1 Hz), 7.05-7.01 (1H, m), 5.85 (1H, br s), 5.58 (1H, d, J 9.1 Hz). LCMS (ES+) RT 3.06 minutes, 285 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][CH:11]=[C:10]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[CH:22][CH:21]=1.C(=O)([O-])[OH:39].[Na+]>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][CH:11]=[C:10]2[O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([N+:1]([O-:4])=[O:2])=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:39])=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(OCCSc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Reactant: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc(S(=O)CCOc4ccc([N+](=O)[O-])c(OC)c4)cc3)c2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Nitric acid (0.5 ml) was added to 6,7-dimethoxy-4-(4-{[2-(3-methoxyphenoxy)ethyl]sulfanyl}phenoxy)quinoline (20 mg), and the mixture was stirred at 0° C. for 30 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (14 mg, yield 60%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)C(O)=O.CN(C)C=O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.8 %

Procedure:
Oxalyl chloride (0.053 mL, 0.6 mmol) was added to a stirred solution of 3-chloro-4-[(cyclopropylmethyl)oxy]benzoic acid (WO 2005058848; 68 mg, 0.3 mmol) in dichloromethane (DCM) (2 ml) containing N,N-dimethylformamide (DMF) (0.02 ml) at 0° under nitrogen, and the mixture was allowed to warm to room temperature with stirring overnight. The solvent was evaporated to give the title compound as a yellow oil (ca 80 mg) which was used crude in the subsequent reaction (D46).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[CH2:17][C:16]4[C:12]([CH:13]=[CH:14][N:15]=4)=[CH:11][C:10]=3[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1.C(N1C2C(=CC(O)=C(Br)C=2)CC1)(=O)C>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH:13]=[CH:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[O:27][C:28]([CH3:31])=[N:29][N:30]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CC1)COC1=C2CC2=NC=CC2=C1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Agent: CC(=O)N1CCc2cc(O)c(Br)cc21
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)n4ccc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 2,3-dihydro-1'-methylspiro[furo[2,3-f]indole-3,4'-piperidine] (D7) and 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11) using a similar procedure to Example 8 (22%). This was converted to its oxalate salt, which crystallised from acetone/methanol as a white solid mp 234-237° C.
Reaction SMILES: [K].C([O:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:26])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:11]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)C1C=CC=CC=1>CCO.O.[Pd]>[OH:9][C:10]1[CH:15]=[C:14]([CH2:16][CH:17]([CH3:26])[C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:12][C:11]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1
Reactant: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: [K]
Solvent: O
Solvent: CCO
Product: CC(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)c1ccccc1

Procedure:
A solution of 5-[2-benzyloxy-4-(2-methyl-3-oxo-3-phenylpropyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (15 mg) in 4 mL of EtOH/water (1:1) is hydrogenated over Degussa Pd/C (5 mg) at 1 atm for 15 min. The catalyst is filtered and the solvent is removed under reduced pressure. The residue is purified by reverse phase HPLC followed by lyophilization to give the title compound. (M−1)−=373. HPLC retention time=1.13 min (Method A).
Reaction SMILES: [Al].ClC(Cl)=[CH:4][C@@H:5]1[C@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].O.[Br:15][CH2:16][Br:17]>>[Br:15][C:16]([Br:17])=[CH:4][C@@H:5]1[C@H:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: BrCBr
Agent: [Al]
Solvent: O
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under a dry nitrogen atmosphere, approximately 3 g of aluminum shot was added to 225 ml of dibromomethane. The temperature was raised to 35°-40° C., and hydrogen bromide gas was bubbled into the mixture. After 1 hour a reaction began to occur, and, with the temperature being maintained at 35°-40° C., a second and third portion of aluminum shot (total of 9.67 g, 0.358 mole) was added to the mixture. After complete addition, the reaction mixture was heated at 55° C. for 1 hour. The hydrogen bromide gas flow was stopped, and the reaction mixture was cooled to approximately 6° C. Cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid (50.0 g, 0.239 mole) in 150 ml of dibromomethane was added to the cooled reaction mixture during 1 hour. After complete addition, the reaction mixture was stirred for 30 minutes. A nitrogen inlet was placed in the reaction mixture, and nitrogen was pulled through the mixture for 90 minutes by applying a slight vacuum to the reaction pot. Distilled water was added dropwise, and the resulting mixture was allowed to stand at room temperature for approximately 18 hours. The organic phase was separated, and the aqueous phase was extracted with 600 ml and 200 ml portions of diethyl ether. The ether washes were combined with the organic phase, and the whole was washed once with a 1 N hydrochloric acid solution and once with a saturated aqueous solution of sodium chloride. The organic phase was dried with magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a solid. The solid was dried under a vacuum for 18 hours, then was recrystallized twice from n-heptane and sublimed to give (±)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylic acid, m.p. 109°-111° C.
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[CH:11]=[C:12]([CH3:14])[CH3:13])=[O:5].S(=O)(=O)(O)O>>[CH3:13][C:12]([CH3:14])=[CH:11][C@H:7]1[C:8]([CH3:9])([CH3:10])[C@@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Agent: O=S(=O)(O)O
Product: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Yield: 80.5 %

Procedure:
The water layer was made acidic with sulfuric acid and extracted with toluene (80 g) two times. The toluene layer was washed and evaporated, and the residue was distilled under reduced pressure to give trans-chrysanthemic acid (47.1 g; trans-isomer, 80.5 %). B.P. 110° to 114°C/2 mmHg.
Reaction SMILES: CC1(C)CCC(C)(C)C2C=C(O)C(C(O)=O)=CC1=2.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[C:25]([Br:32])=[C:24]([OH:33])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2.[CH3:38][O:39][CH2:40]Cl>>[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:30])([CH3:31])[C:26]2[C:25]([Br:32])=[C:24]([O:33][CH2:38][O:39][CH3:40])[C:23]([C:34]([OH:36])=[O:35])=[CH:22][C:21]1=2
Reactant: COCCl
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Agent: CC1(C)CCC(C)(C)c2cc(C(=O)O)c(O)cc21
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene (Compound H, available in accordance with the publication Krause Synthesis 1972 140), is the starting material in the example shown in Reaction Scheme 2. Compound H is brominated to provide the corresponding 3-bromo compound (Compound I) which is thereafter protected in the hydroxyl function by treatment with methoxymethyl chloride (MOMCl) to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (Compound J). Compound J is reacted with t-butyllithium and carbon dioxide to provide the corresponding carboxylic acid (Compound K) from which the methoxymethyl protecting group is removed by acid to give 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-hydroxynaphthalene-3-carboxylic acid (Compound L). Compound L is brominated to yield 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-hydroxynaphthalene-3-carboxylic acid (Compound M). Compound L and Compound M serve as reagents in accordance with Formula 2. The hydroxy group of Compound M is protected for further transformations with methoxymethyl chloride (MOMCl) in the presence of base, yielding 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1-bromo-2-methoxymethoxynaphthalene-3-carboxylic acid (Compound N). ##STR6##
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=O>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:18]1[NH:17][C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1cc3ccccc3[nH]1)C(=O)N2

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH:25]=[O:26])=[N:8]2)=[CH:4][CH:3]=1.[CH3:29][Mg]Br.C(OCCCC)CCC.Cl>COCCOC.ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([O:23][CH3:24])=[C:15]4[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]4[C:10]=3[C:9]([CH:25]([OH:26])[CH3:29])=[N:8]2)=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: COc1c2n(c3c(C=O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Agent: Cl
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCCCOCCCC
Product: COc1c2n(c3c(C(C)O)nn(Cc4ccc(F)cc4)c(=O)c13)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-8-methyl-10-methoxy-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carboxaldehyde (42 mg, 0.11 mmol) in anhydrous DME (10 mL), a solution of methyl magnesium bromide in butyl ether (0.26 mL, 0.26 mmol; 1 M) was added. After stirring at room temperature for 5 minutes, the reaction mixture was treated with dilute hydrochloric acid, and diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound as yellow solid. ES MS M+1=401
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N:12]([O-])=O.[Na+]>Cl.O.C([O-])(=O)C.[Na+]>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:11])[CH:10]=[N:12][NH:1]2)=[CH:4][CH:5]=1
Reactant: CC(=O)c1ccc(C)cc1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(=O)cn[nH]c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-amino-4-methylphenylethanone (5.0 g, 33.6 mmol) in concentrated HCl (100 mL) is treated, in portions, with a solution of sodium nitrite (5.7 g, 82.6 mmol) in water (˜10 mL). The resulting solution is stirred at 60° C. for 2 hr, cooled to ambient temperature and diluted with a saturated solution of sodium acetate (˜200 mL). Solid sodium acetate is added portionwise until the solution tested basic to pH paper. Upon stirring, the title compound precipitated as a white solid which is collected and air dried (2.3 g, 14.3 mmol). MS m/z: [M+H]+=161; 1H NMR (CDCl3, 300 MHz) δ8.1 (d, 1H), 7.85 (s, 1H), 7.45 (s, 1H) 7.3 (d, 1H), 2.55 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21]([OH:23])=O)=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]=2[Cl:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:38](CC)CC)C.N>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:23])[NH2:38])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]=2[Cl:27])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc([N+](=O)[O-])cc2C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc([N+](=O)[O-])cc2C(N)=O)CC1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-carboxy-3-chloronitrobenzene (2.6 g) in dichloromethane (80 ml) were added isobutyl chloroformate (1.0 ml) and triethylamine (1.1 ml) in an ice bath and the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 28% aqueous ammonia (0.5 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol 19/1 as an eluant to give the desired compound (2.2 g, yield 84%) as a pale yellow amorphous solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CN(C)C=O.O[C:13]1[CH:18]=C[N:16]=[CH:15][CH:14]=1.I[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>[Cu](I)I.O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([N:16]2[CH:15]=[CH:14][CH:13]=[CH:18][C:1]2=[O:4])=[CH:21][CH:22]=1
Reactant: Oc1ccncc1
Reactant: COc1ccc(I)cc1
Reactant: O=C([O-])[O-]
Agent: I[Cu]I
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-n2ccccc2=O)cc1
Temperature: 150 °C
Reaction time: 21 h
Yield: 51.4 %

Procedure:
Potassium carbonate (1.16 g, 8.41 mmol) and copper iodide (16 mg, 0.084 mmol) were added to a dimethylformamide (12 mL) solution of 4-hydroxypyridine (800 mg, 8.41 mmol) and 4-iodo-1-methoxybenzene (3.94 g, 16.8 mmol), and stirred at 150° C. for 21 hours. The reaction mixture was cooled to room temperature, then water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane/ethyl acetate=1/1) to obtain the entitled compound (870 mg, 51%).