Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([S:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:1]1([CH2:7][C:8]([C:14]2[CH:15]=[CH:16][C:11]([S:17][CH3:18])=[CH:12][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)Cc2ccccc2)cc1
Reaction time: 3.5 h
Yield: 898.2 %

Procedure:
To a solution of 46.8 g (0.030 mole) of phenylacetyl chloride in dry methylene chloride (330 ml) was added 37.6 g (0.030 mole) of thioanisole. The solution was cooled to 5° in an ice-acetone bath, and anhydrous aluminum chloride (40.9 g, 0.031 mole) was added portionwise over 30 minutes at a rate to maintain the temperature constant at 5°. The reaction mixture was stirred at 5° for 3.5 hours, after which time the mixture was carefully poured into 1300 ml of aqueous 1N HCl and was stirred overnight. The layers were separated and the aqueous layer was extracted with methylene chloride (2×1l). The organic fractions were combined and washed with 1N hydrochloric acid (2×500 ml), 5% aqueous sodium hydroxide (2×500 ml) and brine (2×500 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The crystalline product was collected by filtration and washed with cold ethanol to afford 65.3 g (89%) of 2-phenyl-1-(4-methylthiophenyl)ethanone as a white solid, m.p. 98°-100°.
Reaction SMILES: C(OC([NH:7][C@@:8]1([C:18]([OH:20])=[O:19])[C@@H:13]([F:14])[CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([OH:17])=[O:16])=O)C=C.Br[CH2:22][C:23]1[O:24][C:25](=[O:29])[O:26][C:27]=1[CH3:28]>>[NH2:7][C@@:8]1([C:18]([O:20][CH2:22][C:23]2[O:24][C:25](=[O:29])[O:26][C:27]=2[CH3:28])=[O:19])[C@@H:13]([F:14])[CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][CH2:22][C:23]1[O:24][C:25](=[O:29])[O:26][C:27]=1[CH3:28])=[O:16]
Reactant: Cc1oc(=O)oc1CBr
Reactant: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Product: Cc1oc(=O)oc1COC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)OCc3oc(=O)oc3C)[C@@H]21
Yield: 29.3 %

Procedure:
(1S,2S,3S,5R,6S)-2-(((Allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (A-1-1, 660 mg) and 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (639 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (C-2, 207 mg) as a pale yellow oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.[CH2:33]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:49]([CH:46]2[CH2:47][CH2:48][N:43]([C:41]([O:40][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:42])[CH2:44][CH2:45]2)=[O:50])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCc1nccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) in DCM (27.0 mL) was treated with and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.2 g, 0.017 mol), (1.5 g, 0.011 mol) and 1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol). The mixture was stirred at rt overnight then diluted with DCM (30 mL), washed with sat. NaHCO3 (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude material thus obtained was chromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding 3.38 g of the title compound. 1H NMR (400 MHz, CDCl3); δ 1.68-1.78 (m, 2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m, 2H), 4.70 (d, J=4.8 Hz, 2H), 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m, 5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z 389.17 [MH+].
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:39])[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:39])[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.C1(N)CCCCC1>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: CC(C)O
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 46 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-chloro-2'-nitro-4-biphenylyl)-4-oxo-butyric acid. Yield: 46% of theory. Melting point of the cyclohexylamine salt: 171°-172° C. (from isopropanol).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[CH3:15][NH:16][C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)=[S:18]
Reactant: CN=C=S
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CCO
Product: CNC(=S)NCCSCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution was prepared containing 0.80 g. of 2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethylamine and 0.29 g. of methylisothiocyanate in 10 ml. of ethanol. The solution was stirred at room temperature for about 17 hours after which time the solvent was removed by evaporation in vacuo. The residual gum, comprising N-methyl-N'-2-([2-(dimethylaminomethyl)-4-thiazolyl]methylthio)ethylthiourea formed in the above reaction, was purified by chromatography over silica using a gradient elution technique with ethyl acetate containing increasing quantities of methanol as the eluant. Fractions containing the above compound were combined and the solvent evaporated therefrom in vacuo, leaving as a residue 0.83 g. of a glassy solid.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[CH3:32][S-:33].[Na+]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[S:33][CH3:32])=[CH:13][CH:14]=1
Reactant: C[S-]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: [Na+]
Product: CSc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (0.15 g, 0.35 mmol, intermediate 14) was dissolved in sodium thiomethoxide (5 mL). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 1.875 min; LCMS MH+-THP 395.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: Clc1ncccn1
Reactant: C1CNCCN1
Product: c1cnc(C2CNCCN2)nc1
Reaction time: 21 h

Procedure:
A mixture of 2-chloropyrimidine (10.0 g) and piperazine (16 g) in alcohol (120 ml) is stirred for 21 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried with sodium sulfate and concentrated to give 2-pyrimidinyl piperazine. The 2-pyrimidinyl piperazine (4.64 g) is stirred at 70° in acetonitrile (200 ml) with 21-bromo-17 α-hydroxypregna-4,9(11)-diene-3,20-dione (11.52 g) and potassium carbonate (3.75 g) for 1.5 hr and at 20°-25° for 2 days. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate, the phases are separated and the organic phase is dried with sodium sulfate and concentrated. The concentrate is chromatographed on silica gel eluting with 4 to 6% methanol/methylene chloride. The appropriate fractions are pooled and concentrated to give the title compound which is crystallized from ethyl acetate.
Reaction SMILES: C([O-])(=O)C.[Na+].C([CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[C:12]1[C:22]([OH:24])=O)(O)=O>C(OC(=O)C)(=O)C>[C:16]1([C:14]2[CH:13]=[C:12]3[N:11]([CH2:10][CH2:9][C:22]3=[O:24])[CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CCn1cc(-c2ccccc2)cc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCn2cc(-c3ccccc3)cc21
Yield: 26 %

Procedure:
Anhydrous sodium acetate (200 mg, 2.5 mmol) was added to a stirred solution of 1-(2-carboxyethyl)-4-phenyl-pyrrole-2-carboxylic acid (1.0 g, 3.90 mmol) in acetic anhydride (10 mL) and heated at reflux for 16 h. Excess acetic anhydride was evaporated in vacuo and water was added. The mixture was extracted with ethyl acetate and the separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude product. Purification by column chromatography over neutral alumina using 25% ethyl acetate in petroleum ether as eluent afforded 6-phenyl-2,3-dihydropyrrolizin-1-one (200 mg, 27%) as a brown solid.
Reaction SMILES: [H][H].[F:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3.CO.[OH-].[K+]>C(O)C.[Pd]>[F:3][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5]1=[O:23])[C@:18]1([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: [H][H]
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](F)C[C@@H]12
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: C[C@]12CCCC[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](F)C[C@@H]12

Procedure:
250 mg of 16β fluoro-5-α-androsten-17-one in 50 ml of ethanol was treated with 50 mg of 5% palladium on carbon and hydrogen gas for 21/2hours. The reaction mixture, as indicated by the IR, is compatible with 16β-fluoro-5α-androstan-17-one. This crude product was treated with 5 ml methanol and 5 ml of 1N methanolic KOH for one hour. The mixturewas partitioned between methylene chloride and water and subjected to HPLC as indicated above. Crystallization of the less mobile component from methanol gave 30 mg of 16β-fluoro-5β-androstan-17-one as prismatic needles, melting point 148°-150° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C@H:10]([C:12]([OH:14])=O)[CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH3:27])([CH3:26])[O:18][C:17]1=[O:28]>>[CH:1]1([CH2:6][C:7]([NH:9][C@H:10]([C:12]([NH:15][CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH3:26])([CH3:27])[O:18][C:17]2=[O:28])=[O:14])[CH3:11])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](NC(=O)CC1CCCC1)C(=O)O
Reactant: CC1(C)OC(=O)C(N)c2ccccc21
Product: C[C@H](NC(=O)CC1CCCC1)C(=O)NC1C(=O)OC(C)(C)c2ccccc21

Procedure:
Following General Procedure A above using N-(cyclopentylacetyl)-L-alanine and 4-amino-1,1-dimethyl-3-isochromanone, the title compound could be prepared.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:35]#[N:36])=[C:30](B(O)O)[CH:31]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:35]#[N:36])=[C:28]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:27]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Product: N#Cc1ccc(Cl)cc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 12.4 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 5-chloro-2-cyanophenylboronic acid (available from Combi-Blocks Inc.; 73 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5′-chloro-2′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (12 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.31-8.37 (m, 2H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.65-7.73 (m, 2H), 7.59 (d, J=8.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36]C)[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.CC(O)=O.Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([OH:36])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A flask was charged with 4-(4-chlorophenyl)-N-(4-(6-methoxyquinolin-4-ylthio)phenyl)phthalazin-1-amine (0.325 g, 0.624 mmol), AcOH (5.71 ml, 99.8 mmol) and HBr (5.42 ml, 99.8 mmol). The mixture was stirred at 85° C. for 2 h, then cooled to RT and quenched with saturated aqueous NaHCO3 to precipitate a solid. The solid was filtered, washed with water and dried to give 4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol as a light yellow solid. MS: m/z=[M+H]+. 508.0 Calc'd for C29H19ClN4OS: 507.0.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[N:3]=[CH:2]1>Cl.O1CCOCC1>[S:1]1[CH:5]=[C:4]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cscn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1nc(C2CCNCC2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
The title compound from Step C above (280 mg, 1.04 mmol) was dissolved in 4 M HCl in dioxane (4.0 mL) and stirred at RT for 1 h. The product was concentrated under reduced pressure and dried under high vacuum to give the title compound (i-30) (237 mg, 94%). ESI-MS calculated for C8H12N2S: Exact Mass: 168.07. Found 169.07.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>C(O)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C:2]([N:1]=[CH:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[N:3]2)=[CH:8][C:9]=1[C:14]([F:17])([F:15])[F:16]
Reactant: COc1ccc(C=O)cc1
Reactant: NC1=NN(c2ccc(Br)c(C(F)(F)F)c2)CC1
Solvent: CC(=O)O
Product: COc1ccc(C=NC2=NN(c3ccc(Br)c(C(F)(F)F)c3)CC2)cc1
Yield: 90.4 %

Procedure:
3-Amino-1-(4-bromo-3-trifluoromethylphenyl)-2-pyrazoline (prepared in Example 39 of our European patent specification No. 22-578) (240 mg) in S.V.M. (5 ml) together with 4-methoxybenzaldehyde (160 mg) and 1 drop of glacial acetic acid were heated to reflux for 1 hour. A yellow product separated which was collected, washed with methanol and dried in vacuo to yield 300 mg 1-(4-bromo-3-trifluoromethylphenyl)-3-(4-methoxybenzylideneamino)-2-pyrazoline, m.p. 175°-176° (decomp).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1)=O)(C)(C)C>ClCCl>[NH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)c1ccc(CNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
Trifluoroacetic acid (6 mL) was added to a solution of ethyl 2-(4-((tert-butoxycarbonylamino)methyl)phenyl)propanoate (6.0 g, 19.54 mmol) in dichloromethane (30 mL) at 0° C. and stirred for 4 h at room temperature. The volatiles were evaporated under reduced pressure, basified with saturated NaHCO3 and extracted with ethyl acetate (3×50 mL). Combined organic layers washed with water (100 mL), brine solution (50 mL), dried over sodium sulfate and concentrated to give ethyl 2-(4-(aminomethyl)phenyl)propanoate (3.5 g, 86%) as colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:23](=[O:24])[NH:22][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C=Nc1ccccc1Cl
Reactant: CN1CCCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2cc(OC(=O)Nc3ccccc3Cl)ccc21
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.326 g., 2 mmol) in dry dimethylformamide (5 ml) was added to a stirred suspension of sodium hydride (0.048 g., 2 mmol) in dry dimethylformamide (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 30 min. Then 2-chloro-phenyl isocyanate (0.329 g., 2 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (35° C.). The reaction mixture was quenched with water (0.2 ml), diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20:80) as eluant to give 2o; yield: 0.50 g. (78.9%), m p. 120° C., C17H17ClN2O2; 1H NMR δ ppm (CDCl3); 1.95-2.01 (m, 2H), 2.77 (t, 2H), 2.88 (s, 3H), 3.21 (t, 2H), 6.54-6.58 (m, 1H), 6.81-7.05 (m, 31), 7.23-7.44 (m, 2H), 8.18-8.22 (m, 1H); IR vmax (KBr) (cm−1); 563, 670, 758, 1017, 1201, 1305, 1432, 1507, 1596, 1746, 2375, 2940, 3020, 3282, 3413, 3686, 3763.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH2:11]Br)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]([CH2:11][P:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:21])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(CBr)CC(C)C
Reactant: CCOP(OCC)OCC
Product: CCOC(=O)CC(CC(C)C)CP(=O)(OCC)OCC
Temperature: 190 °C
Yield: 47.8 %

Procedure:
3-Bromomethyl-3-isobutyl-propionic acid ethyl ester (4.6 g, 18.3 mmol) is warmed in a 170° C. oil bath under Ar. Triethyl phosphite (3.6 g, 22 mmol) is added dropwise over 2 hours. When addition is complete, the oil bath temperature is raised to 190° C. for 4 hours. The reaction mixture is cooled to room temperature, and the product is purified by MPLC in EtOAc to give 2.7 g (48% yield) of 3-(diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester. NMR (H1, 400 MHz, CDCl3) δ 0.8 (6H, d); δ 1.2 (5H, m); δ 1.3 (6H, m); δ 1.6 (1H, m); δ 1.7 (1H, d); δ 1.8 (1H, d); δ 2.3 (2H, m); δ 2.5 (1H, dd); δ 4.1 (6H, m).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)[CH3:4].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCc1ccc(S)cc1
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1ccc(Sc2ccc(C=O)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.5 %

Procedure:
A 2.5 mol/L sodium hydroxide aqueous solution (2.0 mL, 4.9 mmol), and tetrabutylammonium bromide (0.019 g, 0.58 mmol) were added to 4-ethylbenzenethiol (0.20 g, 1.2 mmol), followed by stirring at 25° C. for 5 minutes. A toluene solution (2.0 mL) of 4-fluoro-3-nitrobenzaldehyde (0.20 g, 1.2 mmol) was added to the reaction liquid, followed by stirring at 25° C. for 12 hours. After the conventional post-reaction treatment, the product was purified by silica gel column chromatography (eluted by chloroform) to give 4-[(4-ethylphenyl)thio]-3-nitrobenzaldehyde (0.25 g, 75%).
Reaction SMILES: [B-](F)(F)(F)F.N#[O+].[NH2:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=2)[N:12]=[C:11]([C:23]([O:25][CH3:26])=[O:24])[C:10]=1[CH:27]=[CH2:28].[Br-:29].[K+].C1OCCOCCOCCOCCOCCOC1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C(Cl)Cl.CCOCC.[Cu](Br)Br.[Cu]Br.CC#N>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:29])=[CH:18][CH:17]=2)[N:12]=[C:11]([C:23]([O:25][CH3:26])=[O:24])[C:10]=1[CH:27]=[CH2:28]
Reactant: C=Cc1c(C(=O)OC)nc(-c2ccc(N)cc2)c(F)c1N
Reactant: [Br-]
Agent: Br[Cu]Br
Agent: [Cu]Br
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCl
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(Br)cc2)c(F)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
To a 0° C. suspension of nitrosyl tetrafluoroborate (0.122 g, 1.044 mmol) in CH2Cl2 (2 mL) was added a solution of methyl 4-amino-6-(4-aminophenyl)-5-fluoro-3-vinylpicolinate (0.3 g, 1.044 mmol) in a 1:1 mixture of CH2Cl2 and CH3CN (10 mL). The reaction mixture was stirred at 0° C. for 30 min, then was added dropwise to a suspension of potassium bromide (0.497 g, 4.18 mmol), 18-crown-6 (0.028 g, 0.104 mmol), copper(II) bromide (0.023 g, 0.104 mmol), copper(I) bromide (0.015 g, 0.104 mmol), and 1,10-phenanthroline (0.019 g, 0.104 mmol). The mixture was stirred at 20° C. for 1 h. Additional copper (I) bromide (0.749 g, 5 equiv) was added and the reaction was stirred at 20° C. for an additional 1 h. The reaction mixture was diluted with Et2O and filtered on a short pad of Celite™. The supernatant was concentrated and purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) followed by preparative reverse phase HPLC (water/acetonitrile gradient) to afford the title compound as a light brown solid (130 mg, 0.370 mmol, 35.5%).