Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of 4-bromobenzylalcohol (2 g, 10.7 mmol) in DCM (30 mL) at 0° C. was added Et3N (2.2 mL, 16.0 mmol) followed by methanesulfonyl chloride (910 μL, 11.8 mmol). The reaction was allowed to warm to room temperature, stirred for 2 hours and then quenched with water. Saturated aqueous NaHCO3 was added, the product was extracted with DCM, the combined organic extracts were filtered through a phase separator cartridge and concentrated to give methanesulfonic acid 4-bromo-benzyl ester (2.67 g, 10 mmol, 94%). A solution of the crude product (2.67 g, 10 mmol) in DMSO (40 mL) was stirred at room temperature for 16 hours with potassium thioacetate (1.26 g, 11 mmol). The reaction was treated with water and extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give thioacetic acid S-(4-bromo-benzyl)ester (1.81 g, 7.39 mmol, 69%). 1H NMR (300 MHz, CDCl3): δ 7.41 (d, 2H), 7.16 (d, 2H), 4.05 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [C:1]1([CH2:17][CH2:18][CH2:19][CH2:20]O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31].[O:35]1CCCC1>>[C:29]([O:33][CH:17]([C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH3:20])(=[O:35])[C:30]([CH3:32])=[CH2:31]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCCCc1ccc2ccc3cccc4ccc1c2c34
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(CCC)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 ml of tetrahydrofuran, 5.0 g of 1-pyrenebutanol and 3.68 g of triethylamine were dissolved, and 1.90 g of methacryloyl chloride was added dropwise thereto at 0° C., followed by stirring at room temperature for 1 hour. A deposited material was filtered while being washed with ethyl acetate. The filtrate and the washing liquid were mixed. After the mixture was dried with magnesium sulfate, the solvent was removed by evaporation under a reduced pressure. A residue was purified by a column chromatograph (silica gel, hexane:ethyl acetate=10:1), and vacuum-dried to thus obtain 1-pyrenylbutyl methacrylate.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([C:12]2[CH2:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CI>C1COCC1>[CH3:1][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [Li]CCCC
Reactant: C1=C(c2ccccc2)Cc2ccccc21
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(c2ccccc2)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Butyllithium (2.5 M in hexanes, 3.0 mL, 7.6 mmol was added dropwise to a suspension of 2-phenylindene (1.382 g, 7.2 mmol) in THF (50 mL) at −78 C. Upon addition of n-butyllithium the reaction mixture turned a dark orange color and 2-phenylindene dissolved. When the addition of the reagents was complete the solution was allowed to warm to room temperature and stirred for 30 minutes. CH3I (1.3 mL, 22 mmol) was added to this solution dropwise and the light brown reaction mixture was heated to 40° C. and stirred for 24 hours. After that the solvents were removed in vacuo and the light brown solid was recrystallized from EtOH (25 mL) at room temperature affording white needles (1.075 g, 75% yield). 1H NMR (CDCl3, 20° C., 300 MHz): Λ 7.52-7.19 (overlapping signals from aromatic protons, 9H), 3.74 (s, 2H), 2.31 (s, 3H). 13C {1H} NMR (CDCl3, 20° C., 75 MHz): δ□1147.49 (C), 142.42 (C), 140.31 (C), 137.56 (C), 134.70 (C), 128.37 (CH), 128.24 (CH), 126.63 (CH), 126.40 (CH), 124.74 (CH), 123.32 (CH), 119.11 (CH), 40.96 (CH2), 11.94 (CH3).
Reaction SMILES: [NH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[NH2:2].[C:14](N1C2N(C(=O)C)C(=O)N(C(=O)C)C2N(C(=O)C)C1=O)(=[O:16])[CH3:15].C(O)(=O)C>C(#N)C.C(O)C>[C:14]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1)(=[O:16])[CH3:15]
Reactant: NNc1ccc(OCC(=O)O)cc1
Reactant: CC(=O)N1C(=O)N(C(C)=O)C2C1N(C(C)=O)C(=O)N2C(C)=O
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCO
Product: CC(=O)NNc1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Yield: 122.4 %

Procedure:
4-Hydrazinophenoxyacetic acid 0.1H2O (10.0 g) and 1,3,4,6-tetraacetyltetrahydroimidazo[4,5-d]imidazole-2,5-(1H,3H)-dione (7.8 g) were suspended in dry acetonitrile (200 ml) containing acetic acid (1 ml). The mixture was heated under reflux for 3 hours, cooled to room temperature, and filtered. The precipitate was washed well with acetonitrile; the washings were combined with the filtrate, and this solution was evaporated to give a dark oil. The residue was taken up in hot ethanol (25 ml) and the brownn powder which precipitated on chilling was filtered off and dried. Recrystallization from acetonitrile gave the product as chunky, tan crystals (6.9 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:25][C:26]1[S:30][CH:29]=[N:28][CH:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[S:30][C:26]([CH3:25])=[CH:27][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: Cc1cncs1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4cccnc4Cl)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12l and 5-methylthiazole
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:2]1([CH2:16][C@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Na]
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCN(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-propionic acid, sodium salt and 4-phenyl-piperazine were condensed to give the title compound as a beige solid, mp=192-193° C.
Reaction SMILES: COP([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][N:31]=1>C1COCC1.O>[C:18]([O:17][C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:22])[CH:7]=[CH:36][C:33]1[CH:32]=[N:31][C:30]([CH3:29])=[N:35][CH:34]=1)([CH3:19])([CH3:20])[CH3:21]
Reactant: Cc1ncc(C=O)cn1
Reactant: COP(=O)(CC(=O)CCCCCNC(=O)OC(C)(C)C)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(C=CC(=O)CCCCCNC(=O)OC(C)(C)C)cn1
Yield: 58.9 %

Procedure:
A solution of 24-2 (3.13 g, 9.28 mmol), potassium carbonate (1.75 g, 12.6 mmol), and 2-methyl-pyrimidine-5-carbaldehyde (1.04 g, 8.51 mmol) in THF (20 mL) was warmed to 40 ° C. for 5 h. The mixture was diluted with water and extracted four times with ether. The combined organics were washed with brine and dried (Na2SO4). Purification via silica chromatography (hexane/ethyl acetate) afforded the title compound 24-3 (1.67 g).
Reaction SMILES: [CH2:1]([S:7][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:9]([O:11]C)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[OH-].[Li+]>O1CCCC1.O.CO>[CH2:1]([S:7][CH:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSC(C(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCSC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a stirred solution of methyl α-hexylthio-3,4-dichloro-phenylacetate (0.197 g) in tetrahydrofuran (10 ml) were added a solution of lithium hydroxide monohydrate (0.123 g) in water (10 ml) and methanol (10 ml), and the mixture was continued to stir for 2 hours at room temperature. At the end of the stirring it was evaporated to remove the organic solvents and the residue was partitioned between methylene chloride and 1N HCl. The organic layer was separated, washed with brine, dried (sodium sulfate) and evaporated to give an oily residue of α-hexylthio-3,4-dichloro-phenylacetic acid (0.179 g).
Reaction SMILES: [NH2:1][CH2:2][S:3]([OH:6])(=[O:5])=[O:4].C([O-])(=O)C.[K+:11].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C(O)(=O)C>[K+:11].[C:12]1(=[O:17])[N:1]([CH2:2][S:3]([O-:6])(=[O:5])=[O:4])[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: NCS(=O)(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CS(=O)(=O)[O-]

Procedure:
A suspension of 15.1 g. (0.136 mol.) of aminomethanesulfonic acid and 14.2 g. (0.145 mol.) of anhydrous potassium acetate in 48 ml. of acetic acid is refluxed for ten minutes. Phthalic anhydride (21.4 g., 0.145 mol.) is then added and the resulting mixture is refluxed for 2.5 hours. The product is collected by filtration and washed with acetic acid and ethanol to give phthalimidomethanesulfonic acid potassium salt.
Reaction SMILES: Br[CH2:2][CH3:3].[NH:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:18](N(CCOCCOC)CCOCCOC)[CH2:19]OCCOC>ClCCl.O>[CH2:18]([N:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[C:6]([O:8][CH2:2][CH3:3])=[O:7])[CH3:19]
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Reactant: CCBr
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN1CC
Reaction time: 43 h
Yield: 420.5 %

Procedure:
Bromoethane (27.2 g, 0.25 mol) was added during 1 h to a stirred suspension of L-proline (11.5 g, 0.1 mol), potassium carbonate (27.6 g, 0.2 mol), and tris (3,6-dioxaheptyl)amine (TDA-1) (6.5 g, 0.02 mol) in dichloromethane (90 ml) at 25°. The reaction mixture was stirred for another 43 h at 26°-27° C. Water (100 ml ) was added and after stirring for a short while at room temperature, the two homogeneous phases were separated. The waterphase was extracted with another portion of dichloromethane (150 ml). The combined organic phases were dried (MgSO4), filtered, and evaporated affording 14.4 g of a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.Br>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1Br
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1Br
Yield: 22 %

Procedure:
A mixture of 32 (5.7 g, 0.017 mole), glacial HOAc (30 ml), and 48% HBr (85 ml) was stirred and heated at reflux for 12 hours. The hydrobromide salt that precipitated on cooling was collected and shown to consist of a mixture of 32 and 33. The mixture was resuspended in glacial HOAc (30 ml)-48% HBr (85 ml) and again heated at reflux for 12 hours. The precipitated hydrobromide was collected, washed with HOAc and Et2O and then stirred with saturated NaHCO3 (100 ml) for 2 days. The solid was collected, chromatographed on silica gel and the product eluted with 70 toluene--30 EtOAc to yield 1.2 g (22%) of 33, m.p. 125°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(Cl)ccc4N3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and 4-methyl-benzenesulfonyl chloride (103 mg, 0.63 mmol) were dissolved in pyridine (5 ml). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/Ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-methyl-benzenesulfonamide (133 mg, yield: 46%) as yellow solid. MS (ESI+APCI) M+1=441.1.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C:35]1[CH:53]=[CH:52][C:38]([C:39]([NH:41][CH2:42][C:43]([CH3:51])([CH3:50])[CH2:44][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:40])=[CH:37][C:36]=1[O:54][CH3:55].CC(C)CC(O)C>CO>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:34][C:35]4[CH:53]=[CH:52][C:38]([C:39]([NH:41][CH2:42][C:43]([CH3:50])([CH3:51])[CH2:44][N:45]5[CH2:49][CH2:48][CH2:47][CH2:46]5)=[O:40])=[CH:37][C:36]=4[O:54][CH3:55])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)NCC(C)(C)CN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 120 °C
Yield: 17.9 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 101 mg, 0.33 mmol), p-toluenesulphonic acid monohydrate (155 mg, 0.81 mmol) and 4-amino-N-(2,2-dimethyl-3-pyrrolidin-1-yl-propyl)-3-methoxy-benzamide (Intermediate 206; 100 mg, 0.33 mmol) were added to 4-methyl-2-pentanol (7 mL). The reaction was heated at 120° C. over the weekend. The sample was transferred to an SCX cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (34 mg, 18%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[Cl:17].[CH3:18][C:19]1[N:24]=[C:23]([SH:25])[N:22]=[C:21]([OH:26])[CH:20]=1.C(N(CC)CC)C>C(O)C>[Cl:17][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)[CH:7]=[CH:8][C:3]=1[CH2:2][S:25][C:23]1[N:22]=[C:21]([OH:26])[CH:20]=[C:19]([CH3:18])[N:24]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCN1CCN(c2ccc(CBr)c(Cl)c2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCN(c2ccc(CSc3nc(C)cc(O)n3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[4-(bromomethyl)-3-chlorophenyl]-4-ethylpiperazine, 6-methyl-2-sulfanylpyrimidin-4-ol (1.42 g, 10 mmol) and triethylamine (2.8 mL, 20 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide crude product, which was further purified by CombiFlash to yield a white solid (400 mg, 5% overall yield); 1H NMR (400 MHz, DMSO-d6): δ 1.16 (t, 3H), 2.20 (s, 3H), 2.48 (q, 4H), 3.06 (q, 4H), 4.35 (s, 2H), 5.98 (br, 1H), 6.88 (d, 1H), 7.00 (s, 1H), 7.42 (d, 1H); M+ 379.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:18])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2>>[Br:5][C:6]1[CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[C:13]([NH:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:18])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: CCOC(=O)C(=O)Nc1ccc(Br)c2cccnc12
Reactant: O=[N+]([O-])O
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
10 ml 100% nitric acid was cooled to 0° C. and 1.0 g (3.1 mmol) 5-Bromo-8-ethoxalylaminoquinoline was added gradually. The reaction mixture was stirred at 25° C. for 1/2 h and then poured into 150 ml ice-water. The precipitate was filtered off, washed with water and ethanol to give 1.0 g (88%) of 5-Bromo-8-ethoxalylamino-7-nitroquinoline. M.p. 213°-215° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16]>O.C(O)(=O)C>[NH:5]1[C:6]2[C:7](=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)[CH:16]=[N:1]1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)c(C)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
A solution of sodium nitrite (836 mg, 59.1 mmol) in water (2 ml) was added to a solution of methyl 4-amino-3-methylbenzoate (2.00 g, 12.1 mmol) in acetic acid (80 ml) at room temperature and stirred at room temperature for 5 hours. The reaction solution was concentrated and the resulting residue was diluted with chloroform and washed with a 5% aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain methyl 1H-indazole-5-carboxylate (645 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Cl)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1COc2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-amino-5-chloro-phenol (27) (2.0 g, 14 mmol, 1 equiv) in 30 ml of THF, chloroacetyl chloride (1.26 ml, 16.8 mmol, 1.2 equiv), and saturated aqueous NaHCO3 50 mL was stirred at RT for 2 hrs and then heated at 80° C. overnight. The reaction mixture was diluted with EtOAc, and washed with water. Purification of the crude product by flash chromatography provided 7-chloro-4H-benzo[1,4]oxazin-3-one (28): LCMS Retention time: 1.48 min.; LCMS observed (M+H)+: 184.
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([O:30][CH3:31])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:32].C(N(CCOC1C=CC(CCC(O)=O)=CC=1)C)CCCCCCCCCCC>>[ClH:32].[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([O:30][CH3:31])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(OC)c1
Agent: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)cc1
Agent: Cl
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)c(OC)c1
Yield: 62 %

Procedure:
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]propanoic Acid, Methyl Ester (468 mg, 1.07 mmol) was saponified as described in the preparation of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, hydrochloride and afforded the title compound (280 mg, 62%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.CC#N.[OH2:25]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([OH:25])=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccncc2)cc1
Reactant: O
Solvent: CC#N
Solvent: ClCCl
Product: Oc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
To a round bottom flask was added 3,6-dichloro-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazine (1.5 gm, 4.464 mmol), CH3CN (5 ml), water (1 ml) and LiOH monohydrate (0.938 gm, 22.32 mmol). The reaction was heated to 80° C. and stirred at this temperature for 4 hrs. After this time, the reaction was colled to rt and concentrated under reduced pressure. The residue was diluted with water (30 ml). The pH of the aqueous solution was adjusted to 7 with 1N HCl. The resulting solution was poured into a separatory funnel and extract with EtOAc (4×20 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give a white solid residue. The residue was stirred in CH2Cl2 (10 ml) for 15 min. The solution was then filter and the solid was collected to give product 6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-ol as white solid (0.70 gm, 48% yield). HPLC retention time (method A) 1.332 min.
Reaction SMILES: [SH:1][CH2:2][C:3](O)=O.[OH-:6].[K+].[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1)=[CH2:9].Cl>CO>[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][CH2:3][C:2]([OH:6])=[S:1])=[CH:12][CH:11]=1)=[CH2:9]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: O=C(O)CS
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: C=Cc1ccc(CCC(O)=S)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Mercaptoacetic acid (9.2 g, 0.1M) was added over 5 minutes to a stirred solution of potassium hydroxide (12.3 g, 0.22M) in methanol (40 ml). 4-Vinylbenzyl chloride (15.25 g, 0.1M) was then added over 5 minutes during which an exothermic reaction ensued and the mixture turned yellow. The mixture was stirred at room temperature for 5 minutes, then it was heated under reflux on a steam-bath for 1 hour. After being allowed to cool, the mixture was concentrated under reduced pressure to leave a yellow solid. 3M Hydrochloric acid (100 ml) was added to the solid and this mixture was stirred at room temperature for 2 hours. The resulting cream solid was filtered off, washed with water and dried, 20.0 g. The solid was stirred with 60-80 petroleum-ether (60 ml) for 2 hours then the resulting white solid was filtered off, washed with 60-80 petroleum-ether and dried to give 4-vinylbenzylthioacetic acid, 17.8 g (85%). The negative ion mass spectrum was consistent with the structure of the required product as was the 1H nmr spectrum, which also indicated high purity. LCMS showed a single component of the requisite molecular weight.