Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([CH2:16][C:17]([OH:19])=O)[C:6]1=[O:20].Cl.[CH3:23][NH:24][CH3:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:23][N:24]([CH3:25])[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[C:6]1=[O:20]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)O)c2cc(C)cc(C)c21
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1c(=O)n(CC(=O)N(C)C)c2cc(C)cc(C)c21

Procedure:
A solution of [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (Intermediate 9) (305 mg, 1.04 mmol), N,N-dimethylamine hydrochloride (128 mg, 1.60 mmol), EDC (300 mg, 1.60 mmol), HOBT (240 mg, 1.60 mmol), and N, N-diisopropylethylamine (0.909 mL, 5.20 mmol) were stirred for 16 h at ambient temperature in DMF (3 mL). The mixture was partitioned between CH2Cl2 (10 mL) and saturated NaHCO3 (10 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated to give the compound. MS: m/z=320 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=1[I:14])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:16][O:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: COc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(I)c(N)cn1
Yield: 78.4 %

Procedure:
A solution of (6-methoxy-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (18 g, 51 mmol) in DCM (50 mL) and TFA (50 mL) was stirred at ambient temperature for 1 h and then evaporated in vacuo. The resultant residue was treated with saturated aqueous sodium hydrogen carbonate solution (25 mL), diluted with water (100 mL) and extracted into ethyl acetate (2×100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown foam (10 g, 60%).
Reaction SMILES: Cl.Cl[C:3](Cl)([CH:5]([CH3:7])[CH3:6])[CH3:4].[C:9]([Cl:12])([Cl:11])=[CH2:10]>>[Cl:11][C:9]([Cl:12])=[CH:10][C:5]([CH3:7])([CH3:6])[CH:3]=[CH2:4]
Reactant: CC(C)C(C)(Cl)Cl
Reactant: C=C(Cl)Cl
Agent: Cl
Product: C=CC(C)(C)C=C(Cl)Cl

Procedure:
The addition of hydrogen chloride to isoprene leads to dichloroisopentane, which adds to vinylidene chloride and undergoes an elimination reaction with bases to give 1,1-dichloro-3,3-dimethyl-1,4-pentadiene. Reaction with sodium phenolate and hydrolysis yields the chloromethyl ketone of the formula (III): ##STR10##
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26](=[O:35])[CH2:27][C:28]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[O:29])=[O:23])[C:11](=[O:20])[NH:12][O:13]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[C:45]1([CH3:55])[CH:50]=[CH:49][C:48]([S:51]([OH:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1>CO>[C:45]1([CH3:55])[CH:46]=[CH:47][C:48]([S:51]([OH:54])(=[O:52])=[O:53])=[CH:49][CH:50]=1.[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26](=[O:35])[CH2:27][C:28]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[O:29])=[O:23])[C:11](=[O:20])[NH:12][OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCC1CCCCC1)C(=O)NO
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.1 %

Procedure:
A solution of 0.205 g of 2(R)-(4-Cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-2′-isobutyl-4-methyl-2′-[2-(1-imidazoyl)acetyl]valerohydrazide in 5 ml of methanol was treated with 0.075 g of p-toluenesulphonic acid monohydrate. The mixture was stirred at room temperature for 6 hours and evaporated. The residue was purified by flash column chromatography on silica gel using methanol/dichloromethane (5:95) as the eluant to give 0.080 g of 2(R)-[4-cyclohexyl-1(S)-(hydroxycarbamoyl)butyl]-2′-isobutyl-4-methyl-2′-(2-(1-imidazoyl)acetyl]valerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:28])[C@@H:10]([NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=1[CH3:27])[C:11]1[O:12][C:13]([CH3:16])=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:26][C:20]1[C:19]([CH3:27])=[C:18]([NH:17][C@@H:10]([C:11]2[O:12][C:13]([CH3:16])=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: Cc1nnc([C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O[Si](C)(C)C(C)(C)C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nnc([C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O)o1
Temperature: 0 °C
Yield: 94.6 %

Procedure:
To a pre-cooled (−45° C.) solution of 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (2.90 g, 6.89 mmol) in THF (28 mL) was added TBAF (8.27 mL, 1 M solution in THF) over 1 minute. Upon complete addition, the reaction mixture was allowed to warm to 0° C. and concentrated under reduced pressure. The resulting orange residue was taken up in EtOAc (100 mL) and washed with H2O (400 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow/orange oil, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes) to provide the title compound as a yellow solid (2.0 g, 95%): mp: 181-183° C.; 1H NMR (400 MHz, DMSO-d6, δ in ppm) 7.48 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.75 (d, J=8.8 Hz, 1H), 4.92 (dd, J=6.0, 8.8 Hz, 1H), 4.42 (m, 1H), 2.44 (s, 3H), 2.33 (s, 3H), 1.33 (d, J=6.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a white solid (275 mg).
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[C:13](=[O:14])[C@@H:12]2[C@H:8]1[C@H:9]([CH2:22][C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH2:10][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(OCC)(=O)C>[O:14]=[C:13]1[C@@H:12]2[C@@H:8]([C@H:9]([CH2:22][C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH2:10][N:11]2[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[NH:7]1
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@H](CC(=O)COCC[Si](C)(C)C)CN3C(=O)OC(C)(C)C)cc1OC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](CC(=O)COCC[Si](C)(C)C)[C@H]2NC(=O)[C@H]21

Procedure:
This compound was prepared in analogy to Example 1g) starting from t-butyl (1S,4R, 5R)-6-(3,4-dimethoxybenzyl)-7-oxo-4-[2-oxo-3-(2-trimethylsilanyl-ethoxy)-propyl]-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate (25.7 g; 48 mmol). Yield: 12.7 g (69%) as a colourless solid. M.p. 89°-91° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](C)[C:5]2(O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.N[OH:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:23])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 83 %

Procedure:
A stirred mixture of 86.6 g (0.3 mole) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone and 62.5 g (0.9 mole) of hydroxylamine hydrochloride in 1500 ml ethanol was refluxed for 187 hr, and then cooled. The solid portion of the reaction mixture was collected on a filter, washed with ethanol, and dried in air to give 67.9 g (83%) of 6-chloro-4-phenyl-2(1H)-quinazolinone 3-oxide as yellow crystals: mp 267°-269°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:27]Br.O.[Cl-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:27][C:16]1[CH:15]=[CH:14][C:13]2[N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2C)cc1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A stirred suspension of 5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.73 g, 2.0 mmol) was heated to 50° C. in glacial acetic acid 20 mL) and treated drop-wise over seven hours with excess bromine (1.92 g, 12 mmol). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and the precipitate filtered. The organic phase filtrate was washed sequentially with a saturated, aqueous sodium thiosulfate solution, a 1 N hydrochloric acid solution, and water. The organic phase was further washed sequentially with a 2.5 N aqueous sodium hydroxide solution until a basic extract was obtained, water, and a saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and the solvent removed in vacuo to afford a crude yellow solid (0.75 g, 1.7 mmol, 85%). The crude solid was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a mixture of methyl tert-butyl ether-hexane (15:85) at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a solid. Crystallization of the solid from a mixture of diethyl ether-hexane yielded the title compound (0.43 g, 0.97 mmol, 48%) as a homogeneous, colorless, crystalline solid, m.p. 192-194° C.;
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[Cl:34])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42].O>ClCCl>[C:41]([NH:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][Si:17]([C:30]([CH3:31])([CH3:33])[CH3:32])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:9]=2[Cl:34])[CH:5]=[CH:6][CH:7]=1)(=[O:43])[CH3:42]
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2CN)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1cccn1-c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a mixture of 2-aminomethyl-1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)pyrrole (87 mg) and pyridine (20.3 mg) in dichloromethane (1 ml) was added acetic anhydride (20.9 mg) under ice-cooling, and the mixture was stirred for 3 hours at ambient temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 2-acetamidomethyl-1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)pyrrole (94 mg) as amorphous powder.
Reaction SMILES: BrC1C=CC(CC[C:10]([NH:12]C)=O)=CC=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=1.CN>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:12][CH3:10])=[O:24])=[CH:17][CH:16]=1
Reactant: CNC(=O)CCc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CN
Product: CNC(=O)Cc1ccc(Br)cc1
Yield: 75 %

Procedure:
Using a procedure analogous to that used to prepare 22A, 2-(4-bromophenyl)acetic acid (1.6 g, 7.0 mmol) was coupled to methylamine to yield 23A (2.0 g, 75%) as a white solid. MS (ESI) m/z 228.20/230.20 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl.O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a mixture of 2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (preparation 4; 0.2 g, 0.58 mmol), 2-aminothiazole (0.070 g, 0.70 mmol), HOBt (0.095 g), and EDCl (0.134 g, 0.70 mmol) in methylene chloride (6 mL), was added N-methyl morpholine (0.08 mL, 0.70 mmol). The resulting mixture was stirred at room temperature overnight followed by dilution with methylene chloride. The reaction mixture was poured into water; organic layer was washed with water, brine, dried over sodium sulfate, and the organic solvent evaporated to get a residue which was purified by preparative TLC to obtain a title compound (0.118 g)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH:12]=[C:11]2[NH2:25])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([C:13]2[CH:12]=[C:11]([NH2:25])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([NH2:7])[CH:9]=3)[N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(-c3cccc(Cl)c3)cc(N)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2nc(-c3cccc(Cl)c3)cc(N)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
The BOC protecting group was removed by the following procedure. Into a 200 mL round bottom flask equipped with a magnetic stir bar and nitrogen inlet was placed 1.0 g (2.71 mmoles, 1 equiv) of [4-amino-2-(3-chlorophenyl)-quinolin-6-yl]-carbamic acid tert-butyl ester and 60 mL of a 1:2 mixture of trifluoroacetic acid and methylene chloride. The mixture was stirred at room temperature for 3 hrs., then concentrated. The residue was made basic with dilute NaOH solution then extracted with ethyl acetate. The organic layer was washed with NaHO solution, dried over Na2SO4, filtered and concentrated. The residue was crystallized from methylene chloride and hexanes to give 700 mg (95%) of the title compound.
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:14]=[C:15]([CH:18]=O)[S:16][CH:17]=2)[CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:14]=[C:15]([CH:18]=[CH2:2])[S:16][CH:17]=2)[CH:8]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cc(-c2cc(Cl)ccn2)cs1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(-c2cc(Cl)ccn2)cs1
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (180 mg, 0.5 mmol) in THF (3 mL) was added n-BuLi (1.6 M, 0.34 mL) at 0° C. After the mixture was stirred for 30 minutes, a solution of 4-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (100 mg, 0.45 mmol) in THF (2 mL) was added. The resulting mixture was stirred at room temperature for 5 hours. Water was added and THF was removed. The water solution was extracted with EtOAc and organic layer was concentrated. The resulting residue was purified by silica gel column to yield 4-chloro-2-(5-vinyl-thiophen-3-yl)-pyridine.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[NH4+].[SH:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21].ClC(Cl)(Cl)C(O)=O>CN(C)C=O>[NH4+:6].[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[N:6]([S:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21])[CH2:7][CH2:1][CH2:2][O:3]1
Reactant: O=S(=O)([O-])CCS
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=P1(N(CCCl)CCCl)OCCCN1SCCS(=O)(=O)[O-]
Reaction time: 20 h

Procedure:
2.8 g (10 mmol), of 4-hydroxycyclophosphamide and 1.6 g (10 mmol) of ammonium-2-mercaptoethanesulphonate were dissolved with a cataytic quantity of trichloroacetic acid in 10 ml of dimethylformamide and were stored in a refrigerator at -25° C. for 20 hours. After a further 5 hours at 0° C., the mixture was mixed with ehter until clouding commenced and was triturbated. The crystrallised material was filtered with suction after 1 day at 0° C., washed dried and recrystallised from n-propanol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(F)nc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(F)nc(-c2ccc(F)cc2)c1
Yield: 36.1 %

Procedure:
A mixture of 2-bromo-6-fluoro-4-methylpyridine (9.5 g, 50 mmol), 4-fluorobenzeneboronic acid (7.8 g, 56 mmol), sodium bicarbonate (12.6 g, 150 mmol), water (200 mL) and catalytic amounts of tetrakis(triphenylphosphine)palladium(0) in DME under nitrogen is heated to reflux overnight. After filtration of the reaction mixture the solvents are removed under reduced pressure. The residue is partitioned between water and ethyl acetate. The layers are separated and the aqueous layer is washed with ethyl acetate. After drying of the combined organic layers with anhydrous magnesium sulphate, the solvent is removed in vacuo. The crude product is purified by flash column chromatography (silica gel, pentane/ethyl acetate 9/1) yielding colorless crystals of 2-fluoro-6-(4'-fluorophenyl)-4-methylpyridine (3.7 g, 36.1% of th.) with mp 49° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:16]=[C:15]([C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[O:27])[C:14]=2[CH3:42])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:16]=[C:15]([C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:31][CH2:30]3)=[O:27])[C:14]=2[CH3:42])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NC2CCN(S(C)(=O)=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Methanesulfonyl chloride (2 eq., 0.01 mL, 0.15 mmol) was added to tert-Butyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (1 eq., 35 mg, 0.076 mmol) and triethyamine (3 eq., 0.03 mL, 0.227 mmol) in tetrahydrofuran (2 mL). The reaction was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-methanesulfonyl-piperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide (36 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.53-1.78 (m, 2H) 2.06-2.22 (m, 2H) 2.37 (s, 3H) 2.67-3.00 (m, 5H) 3.82 (d, J=12.24 Hz, 2H) 4.01-4.17 (m, 1H) 6.88 (d, J=8.01 Hz, 1H) 7.07 (s, 2H) 7.19-7.36 (m, 4H) 7.43 (d, J=1.70 Hz, 1H).
Reaction SMILES: C(N1C(C2C=CC=CC=2)CC(C)(C)[N:10]2[N:22]=CC(C(=O)CC3C=CC(C)=CC=3)=C12)C1C=CC=CC=1.C(O[CH:38]=[C:39]([S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:44])=[O:43])[C:40]#[N:41])C.O.NN>C(O)C>[C:49]1([CH3:52])[CH:50]=[CH:51][C:46]([CH2:45][S:42]([C:39]2[CH:38]=[N:22][NH:10][C:40]=2[NH2:41])(=[O:44])=[O:43])=[CH:47][CH:48]=1
Reactant: CCOC=C(C#N)S(=O)(=O)Cc1ccc(C)cc1
Reactant: Cc1ccc(CC(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(CS(=O)(=O)c2cn[nH]c2N)cc1

Procedure:
7,7-Dimethyl-3-(4-methylbenzyl)sulfonyl)-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine (4): A slurry of 1.9 g (7.2 mmol) of 3 in 25 mL of ethanol was treated with 0.38 mL (7.9 mmol) of hydrazine monohydrate and heated to reflux for 3 h. The reaction was concentrated in vacuo to give crude 4-p-tolylmethanesulfonyl-2H-pyrazol-3-ylamine as a tan solid. The crude pyrazole, 1.3 g (7.9 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 2.8 mL (36 mmol) of trifluoroacetic acid was dissolved in 25 mL of 2-methoxyethanol and heated to reflux for 3 days. The reaction was then cooled to room temperature, concentrated in vacuo and dissolved in AcOEt. This solution was washed successively with saturated sodium bicarbonate, water and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude material was purified by flash chromatography eluting with a 75 to 33% hexanes/AcOEt gradient to give 1.25 g (44%) of the title compound as a powder. 1H NMR (CDCl3) δ 1.67 (s, 6H), 2.13 (s, 3H), 4.26 (s, 2H), 4.81 (d, J=2.0 Hz, 1H), 6.39 (s, 1H), 7.05 (dd, J=8.0, 18.5 Hz, 4H), 7.20 (dd, J=3.7, 7.4 Hz, 2H), 7.36-7.39 (m, 3H), 7.52 (s, 1H). MS Calcd.: 393. Found: 394 (M+H).