Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([CH2:18][CH2:19][C:20](Cl)=[O:21])([O:16][CH3:17])=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:17][O:16][C:14](=[O:15])[CH2:18][CH2:19][C:20]([C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:13][CH:12]=1)=[O:21]
Reactant: Fc1ccccc1-c1ccccc1
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1

Procedure:
In a manner similar to Example 2, Step (a), 2-fluoro-biphenyl (6.284 g, 0.0365 mol) was allowed to react with 3-carbomethoxypropionyl chloride (4.95 mL, 0.0402 mol) in the presence of anhydrous aluminum chloride (10.7 g, 0.0802 mol) in dichloromethane to give, after chromatography on silica gel (456 g, 230-400 mesh), eluting with chloroform (15×450 mL), 7.36 g of 4-(2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 75.5-77.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([O:11]C)[C:4]=1[OH:13])#[N:2].B(Br)(Br)Br.O.Cl>ClCCl>[C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([OH:11])[C:4]=1[OH:13])#[N:2]
Reactant: COc1cc(C#N)cc(C#N)c1O
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(O)c(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution containing 2,4-dicyano-6-methoxyphenol in 20 ml of dichloromethane 20 ml of 1 molar solution of BBr3 in dichloromethane was added. The solution was stirred overnight at room temperature. Water and hydrochloric acid were added and the mixture was extracted with dichloromethane. The solvent was evaporated. Yield 0.8 g (50%), m.p. 300° C. (decomp.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]3[CH:24]=[CH:23][C:13]4[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=4[CH:11]=3)=[CH:6][CH:7]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: BrCC1CCC1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(OCC4CCC4)cc3)cc2o1
Yield: 70 %

Procedure:
Using N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (150 mg, 0.464 mmol) obtained in Example 165 and (bromomethyl)cyclobutane (0.155 mL, 1.39 mmol) and in the same manner as in Example 158, the title compound was obtained (127 mg, yield 70%) as a white solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:14]>C(O)(=O)C>[CH2:1]([CH:8]([CH2:12][Br:14])[CH2:9][C:10]([OH:11])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(Cc2ccccc2)CO1
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)CC(CBr)Cc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 4-benzyl-dihydrofuran-2-one (1.0 g, 5.6 mmol), acetic acid (1.7 mL), HBr (33% in acetic acid, 2.0 mL) is heated at 80° C. for 4 h. The mixture is cooled to room temperature, poured into ice-water (20 mL), and extracted with chloroform (2×30 mL). The combined organic extracts are washed with water and brine, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 3-benzyl-4-bromo-butyric acid, 1.5 g (99%), as a colorless liquid.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:34][C:31]3[S:32][CH:33]=[C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[N:30]=3)=[O:20])=[CH:16][CH:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (400 mg, 1.26 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (290 mg, 1.64 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off-white solid. Yield: 235 mg (39%). 1H-NMR: 8.63-8.60 (m, 1H), 8.21 (d, J=8.5 Hz, 2H), 8.00 (d, J=8.0 Hz, 7.93-7.88 (m, 2H), 7.76 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.24-7.19 (m, 1H), 7.14-7.08 (m, 2H), 3.84-3.79 (m, 2H), 2.93 (t, J=8.5 Hz, 2H). 2.45 (t, J=6.5 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]([OH:29])[CH2:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[OH:19])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([O:19][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)[CH2:17][CH2:16][CH:15]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(C(O)CCC(O)c2cccc([N+](=O)[O-])c2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1cccc([N+](=O)[O-])c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.3 mL, 3.87 mmol) was added dropwise to a cold (0° C.) solution of Example 55B (0.5089 g, 1.531 mmol) and triethylamine (0.65 mL, 4.66 mmol) in THF (10 mL). The reaction was removed from the ice bath and stirred at ambient temperature for 30 minutes. Solvent was removed under vacuum to provide the title compound as a solid that was used without purification.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCN(C)C1=O.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH2:22])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(C)=O)cc1
Solvent: CN1CCN(C)C1=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: C=C(OC(=O)c1ccc(C(C)(C)C)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 25 %

Procedure:
4-tert-butylbenzoyl chloride (1.78 g, 9 mmol), 0.47 g of cuprous chloride and 4 mL of 1,3-dimethyl-2-imidazolidinone were added to crude 4-methoxyacetophenone trimethylsilylenol (4.3 mmol). After stirring the solution for 21 hours at room temperature, 1 mL of triethylamine and 10 mL of chloroform were added. Then the solution was chromatographied through flash silica column (hexane/ethyl acetate 10:1). The first collected fraction was purified by flash chromatography (hexane/dichloromethane 3:2) giving 0.34 g of 1-(4-methoxyphenyl)-vinyl 4-tert-butylbenzoate. Yield 25%.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[F:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][O:21][C:22]2[N:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=2[CH3:31])=[CH:18][CH:17]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:25]3[CH:26]=[N:27][C:22]([O:21][CH2:20][C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:33][CH:32]=4)=[C:23]([CH3:31])[CH:24]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OCc1ccc(F)cc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCc1ccc(F)cc1
Yield: 92 %

Procedure:
The title compound is prepared in 92% yield (683 mg, colorless amorphous) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.80 mmol, Step-1 of Intermediate-1) and 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanamine (240 mg, 0.86 mmol, Amine-71, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.[N:16]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[F-].[Na+].O>C(Cl)Cl>[OH:4][CH:2]([CH3:3])[CH2:1][N:19]1[CH2:20][CH2:21][N:16]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17][CH2:18]1
Reactant: CC1CO1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: C[Al](C)C
Agent: [F-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(O)CN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a solution of propylene oxide (4.0 mL, 57 mmol) in DCM (160 mL) was added 2.0 M of trimethylaluminum in toluene (27 mL, 54 mmol) at −78° C. under N2. After being stirred at that temperature for 10 min, a solution of benzyl piperazine-1-carboxylate (from Aldrich, 9 mL, 40 mmol) in DCM (60 mL) was added. The resulting reaction mixture was stirred at −78° C. for 30 min. The reaction was then allowed to warm up to 0° C., stirring for another 30 min. To the reaction mixture was added sodium fluoride (8.2 g, 200 mmol) in one portion, followed by water (5.2 mL, 290 mmol) slowly and periodically at 0° C. The resulting suspension was rapidly stirred for 1 h at 0° C. and filtered through a short column of Celite and the column was subsequently washed with DCM (120 mL). The combined filtrates were dried over Na2SO4, concentrated and purified on silica gel (eluting with 0-10% MeOH in DCM) to provide the desired product (9.6 g, 76%). LCMS calculated for C15H23N2O3(M+H)+: m/z=279.2; Found: 279.3. 1H NMR (500 MHz, DMSO-d6): δ 7.39˜7.31 (5H, m), 8.07 (2H, s), 4.29 (1H, J=4.0 Hz), 3.75 (1H, m), 3.38 (4H, br s), 2.38 (4H, m), 2.24 (1H, dd, J=12.5 and 7.0 Hz), 2.17 (1H, dd, J=12.5 and 7.0 Hz), 1.04 (3H, d, J=6.0 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19](SC)[N:20]([CH2:23][CH3:24])[C:21](=[O:22])[C:16]=4[C:15]([CH3:27])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>COCCOC.C(O)C.[Ni]>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:29]=[CH:28][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[CH:19][N:20]([CH2:23][CH3:24])[C:21](=[O:22])[C:16]=4[C:15]([CH3:27])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCn1c(SC)nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCn1cnc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 40 °C
Yield: 82.4 %

Procedure:
In a mixture of DME (65 ml) and ethanol (6 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3-ethyl-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (500 mg) followed by addition of acetic acid (336 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (370 mg).
Reaction SMILES: [Si]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C:14]2[CH:15]=[C:16]([C:21]3([O:32][CH3:33])[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@H:24]([OH:29])[C@@H:23]([CH2:30][OH:31])[O:22]3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([C:21]2([O:32][CH3:33])[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@H:24]([OH:29])[C@@H:23]([CH2:30][OH:31])[O:22]2)=[CH:15][C:14]=1[CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:35][CH:34]=1
Reactant: COC1(c2ccc(Cl)c(Cc3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC1(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
The crude (3R,4S,5S,6R)-2-(3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (9.0 g) was dissolved in tetrahydrofuran (70 mL). To the resulting solution was added tetrabutyl ammonium fluoride trihydrate (22.1 g, 70 mmol). The resulting mixture was stirred at room temperature for 2 hr, and concentrated under a reduced pressure. To the mixture were added ethyl acetate (400 mL) and water (200 mL). The resulting mixture was separated into an aqueous phase and an organic phase. The organic phase was successively washed with water (200 mL×3) and a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure to produce 6.5 g of a crude product, which was directly used in the next reaction without purification.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].C(N(CC)CC)C.CO>ClCCl.CN(C)C=O>[CH3:1][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[N:16][C:8]=1[Cl:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80428.5 %

Procedure:
Oxalyl chloride (13.28 ml, 0.15 mmol) was added dropwise to a solution of 2-chloronicotinic acid (24 g, 0.153 mmol) in dichloromethane (250 ml) containing dimethylformamide (10 drops) under nitrogen at room temperature. The reaction was stirred at room temperature for 1.5 h and was then cooled to 0° C. Triethylamine (63.7 ml, 0.457 mmol) was added slowly followed by methanol (60 ml). After stirring at 0° C. for 30 min, the solvent was removed under reduced pressure and the residue was dissolved in sat. sodium bicarbonate solution (200 ml). This was extracted with diethylether (5×100 ml) and the combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with diethylether to give 2-chloronicotinic acid methyl ester (20.7 g) as a pale yellow oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].N1C=CC=CC=1.[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=O.O>ClCCl>[CH3:5][CH:4]([C:3]1[N:7]=[C:16]([C:15]([Cl:20])([Cl:19])[Cl:14])[O:1][N:2]=1)[CH3:6]
Reactant: CC(C)C(=N)NO
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)c1noc(C(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 42 h
Yield: 76.3 %

Procedure:
A stirred solution of N-hydroxy-2-methylpropanimidamide (16.33 g, 160 mmol) in pyridine (16.81 mL, 208 mmol) and dichloromethane (165 mL) at −15° C. was treated with trichloroacetyl chloride (19.63 mL, 176 mmol) over 40 min. The reaction was allowed to warm to ambient temperature and stirred for 42 h. Water (100 mL) was added and the reaction was stirred for 30 min. The dichloromethane was removed and the residue was diluted with water (50 mL) and extracted with ether (300 mL). The ether layer was washed with water, dried over MgSO4 and concentrated to afford 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (28.0 g, 76% yield) as an orange liquid. 1H NMR (400 MHz, CDCl3): δ 3.13 (septet, 1H, J=7.0 Hz), 1.36 (d, 6H, J=7.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[C:17]4=[N:18][S:19](=[O:23])(=[O:22])[CH2:20][CH2:21][N:16]4[CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.C1COCC1.[C].[Pd].[C].[Rh].[Ru].[Pt](=O)=O>[C:1]1([C:7]2[S:11][C:10]([CH:12]3[C:17]4=[N:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21][N:16]4[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)s3)C2=N1
Agent: O=[Pt]=O
Agent: [Pd]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CCO
Product: O=S1(=O)CCN2CCCC(c3ccc(-c4ccccc4)s3)C2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.8 %

Procedure:
A mixture of 10% palladium-carbon (50% wet, 12 mg) and 9-(5-phenylthiophen-2-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (120 mg) in ethanol (10 mL) and dehydrated THF (60 mL) was stirred under a hydrogen atmosphere at room temperature for 4 hr. To the reaction mixture was added 5% rhodium-carbon (50% wet, 12 mg) and the mixture was stirred under a hydrogen atmosphere at room temperature overnight, and under a hydrogen atmosphere (4 atm) for 6 hr. To the reaction mixture was added 5% ruthenium-alumina (12 mg) and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. To the reaction mixture was added platinum dioxide (12 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica-bound silica gel column chromatography (ethyl acetate/methanol) to give the title compound (42.3 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([C:18]1[C:17]([CH3:24])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[CH:7]=[CH:8][CH:9]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OC1CCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclopentyloxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a yellow solid (40%). MS 315 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25][CH2:26][O:27][CH3:28])([OH:3])=O.C[N:30]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>COCCOC>[NH2:30][C:1]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25][CH2:26][O:27][CH3:28])=[O:3]
Reactant: CN1CCOCC1
Reactant: COCOC1=C(C(=O)O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: COCOC1=C(C(N)=O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A mixture of 2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene (0.26 g, 0.67 mmol), N-methyl morpholine (0.09 ml, 0.8 mmol) and isobutyl chloroformate (0.1 mL, 0.77 mmol) in dry 1,2-dimethoxyethane (7 mL) was stirred under an argon atmosphere at room temperature for 10 min. Ammonium hydroxide (0.07 mL, 1.0 mmol) was added and stirring was continued for 0.5 h. The mixture was partitioned between methylene chloride and 5% aqueous sodium carbonate, was extracted three times, the organic layer was dried (potassium carbonate) and the solvent was removed in vacuo to provide a white solid (0.22 g, 85%): m.p. 120°-122° C.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH:14]([Br:18])[C:15](Br)=[O:16]>CC(C)=O>[CH3:1][S:2][C:3](=[NH:4])[NH:5][C:15](=[O:16])[CH:14]([C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[Cl:6])[Br:18]
Reactant: CSC(=N)N
Reactant: O=C(Br)C(Br)c1c(Cl)cccc1Cl
Solvent: CC(C)=O
Product: CSC(=N)NC(=O)C(Br)c1c(Cl)cccc1Cl
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To 7 g S-methylisothiourea in 50 ml of acetone at 10 degrees C., there are added in drops 12 g of 2-(2,6-dichlorophenyl)-2-bromo-acetyl bromide in 30 ml acetone. The mixture is stirred for 30 minutes at 10 degrees C., and the precipitate is suction-filtered. After concentration of the mother liquor, a second fraction of S-methyl-N-[2-(2,6-dichlorophenyl)-2-bromo acetyl] isothiourea is obtained. The decomposition point is 177 degrees.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:11](=[O:13])[C:10]3[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: O=C(O)c1ccccc1NCc1ccncc1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc2[nH]ncc2c1)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
228 mg of N-(4-pyridylmethyl)-anthranilic acid is introduced into 10 ml of dimethylformamide under argon and in a moisture-free environment. 266 mg of 5-aminoindazole, 0.27 ml of methylmorpholine and 456 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. The mixture is then stirred for 4 hours at room temperature. It is then mixed with dilute sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried, filtered and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with ethyl acetate as an eluant.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C@H:24]1[CH2:29][N:28]([CH3:30])[CH2:27][CH2:26][N:25]1[C:31]1[C:36]([F:37])=[C:35]([NH:38][NH2:39])[N:34]=[C:33]([CH3:40])[N:32]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:39][NH:38][C:35]2[C:36]([F:37])=[C:31]([N:25]3[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29][C@@H:24]3[CH3:23])[N:32]=[C:33]([CH3:40])[N:34]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NN)c(F)c(N2CCN(C)C[C@@H]2C)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)C[C@@H]2C)n1
Reaction time: 8 h
Yield: 48.4 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.139 g, 0.45 mmol), 4-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (0.118 g, 0.46 mmol), NMM (0.15 mL, 1.38 mmol), HOAt (0.063 g, 0.46 mmol), and EDC (0.088 g, 0.46 mmol) were dissolved in DMF (2 mL). The reaction was stirred overnight. Purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide as a white solid (0.118 g, 47%). LCMS: (M+H)+=542.7.