Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:6]([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH3:13][O:14][CH2:15][C:16]#[N:17]>>[CH3:12][N:10]([CH3:11])[CH:6]([N:7]([CH3:8])[CH3:9])[CH:15]([O:14][CH3:13])[C:16]#[N:17]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COCC#N
Product: COC(C#N)C(N(C)C)N(C)C
Yield: 33.2 %

Procedure:
360.4 g of 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (Bredereck's reagent) (2068 mmol, 1 eq.) and 150.0 g of methoxyacetonitrile (2068 mmol, 1 eq.) were stirred for 18 hours at 80° C. The reaction mixture was concentrated in vacuo. The residue was purified by vacuum distillation to yield 117 g (687 mmol, 33.0%) of the analytical pure target compound as a yellowish liquid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:14][C:15]1[C:22]([CH3:23])=[C:21](I)[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>O1CCOCC1.[Cu]I>[Cl:14][C:15]1[C:22]([CH3:23])=[C:21]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: Cc1c(I)ccc(C#N)c1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)c(Cl)c1C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a pressure reaction flask containing diethyl malonate (4.1 mL, 27 mmol) in 50 mL of anhydrous dioxane was added NaH (1.1 g, 27.5 mmol, ˜60% in mineral oil) in several portions at RT, and stirred for 30 min. Compound 1E (2.5 g, 9 mmol) and CuI (5.1 g, 26.8 mmol) were added, sealed and heated at 100° C. for 3 days. The reaction was cooled to RT and filtered through a pad of celite. The celite pad was washed with EtOAc. The organics were washed twice with water, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (silica gel, 110 g ISCO, 10% EtOAc in hexane) gave the title compound (2.3 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH2:3][C:2]1=O.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[N:9]=[CH:8][CH:7]=[C:6]2[CH:3]=[CH:2][O:1][C:5]=12
Reactant: O=C1Cc2ncccc2O1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ccoc12

Procedure:
For example, furan-3-acrylic acid is converted to the acid azide by first reacting the acid with ethoxycarbonyl chloride and triethylamine to form the acid chloride and then reacting the mixed anhydride with sodium azide in water. The furan-3-acrylic acid azide is then heated in diphenylmethane with tributylamine to a temperature of about 190° C. to about 210° C. to form the furopyridone represented by the formula ##STR12## The furopyridone is allowed to react with phosphorus oxychloride to form 7-chlorofuro[2,3-c]pyridine and the latter is reductively dechlorinated with zinc in acetic acid to provide furo[2,3-c]pyridine.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.088 mmol), β-alanine (624 mg, 7.0 mmol) and NaOMe solution (10.5 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 22 mg of the title compound as a light yellow solid. MS: (+) m/z 458.36 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[C:10](=[O:17])[N:11]([CH2:13][C:14](O)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:39](=[O:53])([O:41][CH2:42][CH:43]([NH2:52])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46](Cl)[C:45]=1Cl)[NH2:40].Cl>CN(C=O)C>[C:39](=[O:53])([O:41][CH2:42][CH:43]([NH:52][C:14](=[O:15])[CH2:13][N:11]1[CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[C:10]1=[O:17])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:20]([F:23])([F:22])[F:21])[CH:45]=1)[NH2:40]
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Reactant: NC(=O)OCC(N)c1cccc(Cl)c1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)OCC(NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A quantity of 58 mg (0.11 mmol) of [4-(4-chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]acetic acid from Example 184A was dissolved in 2 ml of DMF, and the solution was admixed with 28 mg (0.15 mmol) of EDC and with 20 mg (0.15 mmol) of HOBt and subsequently stirred at room temperature for 20 minutes. Then 42 mg (0.12 mmol) of the compound from Example 183A were added and the mixture was left with stirring at room temperature for 16 h. For work-up, 100 μl of 1N hydrochloric acid were added and the crude product was purified directly by preparative HPLC [Method 19]. This gave 13 mg (18% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:12].[CH3:13][O:14][C:15](=[O:27])[CH2:16][CH:17]1[C:21]2[CH:22]=[CH:23][C:24](O)=[CH:25][C:20]=2[O:19][CH2:18]1.C(P(CCCC)CCCC)CCC.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:27])[CH2:16][CH:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:12][CH:6]3[C:7]4[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][C:8]=4[F:11])[CH2:4][CH2:5]3)=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: COC(=O)CC1COc2cc(O)ccc21
Reactant: OC1CCc2c(Br)ccc(F)c21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)CC1COc2cc(OC3CCc4c(Br)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Reaction under argon atmosphere: to a solution of 15.3 g (66.3 mmol) of 4-bromo-7-fluoroindan-1-ol (product of step 1) and 11.0 g (53.0 mmol) of (6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester in 60.0 ml DCM are added 29.7 ml (116 mmol) of tributylphosphine. 24.4 ml (116 mmol) of diisopropylazodicarboxylate are added dropwise and under cooling in an ice/EtOH bath at 5° C.-15° C. over 20 min. It is stirred at r.t. for 1 h. The solvent is evaporated and the residue is chromatographed on silica gel (PE/EtOAc=100/0→95/5) to give the title compound. Yield: 16.9 g; LC (method 4): tR=4.84 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:16]=[C:9]2[N:10]=[CH:11][C:12]([Br:15])=[C:13]([CH3:14])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Br:15][C:12]1[CH:11]=[N:10][C:9]2=[N:16][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=[C:8]2[C:13]=1[CH3:14]
Reactant: Cc1c(Br)cnc2nn(CC(C)(N)C#N)nc12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1c(Br)cnc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-bromo-7-methyl-2H-[1,2,3]triazolo[4,5-b]pyridin-2-yl)-2-methylpropionitrile (90 mg, described in Example 178) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (65 mg, 43%). Rf=0.4 (1:1 EA/heptane). MS (ES): M/Z [M−H]=497. 1H NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 2.56 (s, 3H), 5.40 (d, 1H), 5.54 (d, 1H), 7.82-7.94 (m, 4H), 8.86 (s, 1H) and 8.93 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:12])[CH2:10]Cl)[CH:5]=[CH:6][CH:7]=1.[N-:13]=[N+:14]=[N-:15].[Na+].[Na+].[I-]>CN(C=O)C.CCOCC>[N:13]([CH2:10][CH:9]([OH:12])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:14]=[N-:15]
Reactant: OC(CCl)Cc1cccc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=NCC(O)Cc1cccc(Br)c1
Temperature: 75 °C

Procedure:
To a solution of 1-(3-bromophenyl)-3-chloropropan-2-ol (8.49 g, 34.0 mmol) in anhydrous DMF (100 mL) under N2 was added NaN3 (11.05 g, 170.0 mmol) and NaI (cat., 0.75 g, 5.0 mmol). The mixture was heated at 75° C. overnight. After cooling to room temperature, the mixture was diluted with ether and washed with water and brine. The solution was dried over Na2SO4 and concentrated under reduced pressure. The product was dried in a vacuum oven at 40° C. for 2 h to give 1-azido-3-(3-bromophenyl)propan-2-ol as a yellow oil which was used without purification. Yield (8.6 g, 98% crude).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)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: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 49.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.035 g (49%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>[Cl-].[Zn+2].[Cl-]>[CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:24]([CH:20]3[C:21]([CH3:23])([CH3:22])[C:19]3([CH3:27])[CH3:18])=[O:25])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: CS(=O)(=O)c1ccc2cc[nH]c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1(C)C(C(=O)c2c[nH]c3cc(S(C)(=O)=O)ccc23)C1(C)C
Yield: 12.9 %

Procedure:
The 6-(methylsulfonyl)-1H-indole (Apollo Scientific, 1.0 g, 5.1 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.1 mL, 6.1 mmol), zinc chloride (1.0 M solution in Et2O, 6.1 mL, 6.1 mmol) and the product of Example 1A (7.7 mmol) were processed as described in Example 1B to provide the title compound (0.21 g, 0.66 mmol, 13% yield). MS (DCI/NH3) m/z 378 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)[N:20]=[N:21][C:16]3=[CH:15][CH:14]=2)[CH:10]=[CH:9][C:3]=1[C:4]([NH:6]CC)=[O:5].ClC1C=CC=C(C(OO)=[O:41])C=1>ClCCl.O>[C:4]([C:3]1[CH:9]=[CH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N+:29]([O-:41])=[CH:28][CH:27]=[CH:26]5)[N:20]=[N:21][C:16]3=[CH:15][CH:14]=2)=[CH:12][C:2]=1[Cl:1])(=[O:5])[NH2:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5c(ccc[n+]5[O-])c4)c3n2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of example 119 (0.060 g, 0.135 mmol) in dichloromethane (1 ml), 3-chloroperbenzoic acid (0.46 g, 0.270 mmol) was added and stirred at RT for 12 h. The mixture was diluted with water, extracted with dichloromethane, the organic layer dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane as the eluent to afford the title compound as a grey solid. (0.016 g, 26%). M.P.: 212-215° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.71 (d, J=8.8 Hz, 1H), 8.68 (d, J=9.1 Hz, 1H), 8.56 (m, 2H), 8.30 (d, J=1.5 Hz, 1H), 8.24 (m, 2H), 8.12 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.86 (dd, J=9.1, 1.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.48 (dd, J=8.4, 6.0 Hz, 1H), 6.20 (s, 2H), 3.28 (m, 2H), 1.14 (t, J=7.3 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH:12]([OH:22])[CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:9].[CH3:23][S:24][CH2:25][C:26](Cl)=[O:27]>CN(C)C=O>[CH3:23][S:24][CH2:25][C:26](=[O:27])[NH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH:12]([OH:22])[CH2:11][O:10][CH2:8][CH3:9])=[CH:21][CH:20]=1
Reactant: CSCC(=O)Cl
Reactant: CCOCC(O)COc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCC(O)COc1ccc(NC(=O)CSC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
Dissolved in 4 ml of dimethylformamide were 2.00 g of triethylamine and 2.11 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline. To the solution was added 1.25 g of methylmercaptoacetyl chloride with ice-cooling and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The chloroform layer was washed with water and concentrated. The resulting residue was purified by silica gel column chromatography using a 1:5 ethanol-chloroform mixture, giving 2.85 g of 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethyl methyl sulfide in 95.3% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13].CCN(CC)CC.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:21](=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CNCc1cc2ccccc2n1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cc2ccccc2n1C

Procedure:
To a stirred solution of 1-methyl-2-(methylaminomethyl)-1H-indole (13 g, 8.6 mmole) and Et3N (1.35 mL, 9.6 mmole) in CH2Cl2 (75 mL) at 0° C. was added dropwise acryloyl chloride (0.77 mL, 93 mmole) over 5 minutes. After 2 h the reaction was washed with cold H2O, brine, dried (MgSO4) and concentrated under vacuum. The residue was used without further purification.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C@H:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>C(Cl)Cl>[Br:23][C:24]1[S:28][C:27]([S:29]([N:14]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:9][CH:6]3[CH2:5][CH2:4][O:3][CH2:8][CH2:7]3)[CH2:15]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: C1CN[C@@H](CC2CCOCC2)CN1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)s1)N1CCN[C@@H](CC2CCOCC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
The (S)-2-((tetrahydro-2H-pyran-4-yl)methyl)piperazine dihydrochloride (390 mg, 1.516 mmol, Intermediate C) was dissolved in CH2Cl2 and the solution was chilled to 0° C. To this solution was added triethylamine (634 μL, 4.55 mmol) followed by 5-bromothiophene-2-sulfonyl chloride (497 mg, 1.90 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to slowly warm to room temperature and stirring was continued for 2 h. The mixture was concentrated and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give (3S)-1-((5-bromo-2-thiophenyl)sulfonyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)piperazine (520 mg).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[C:1]([NH:3][C:4]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: COCCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Product: COCCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (4.05 g) was dissolved in 2-methoxyethylamine (15 ml) and heated under reflux for 6 hours. Evaporation of the solvent and chromatographic purification of the residue on a column of silica gel with elution by chloroform and then with chloroform/methanol (20:1) yielded the title compound as a pale yellow oil (2.7 g). (Found: C, 47.8; H, 7.0; N, 28.0; S, 11.2%. C12H20N6OS requires: C, 48.6; H, 6.8; N, 28.4; S, 10.8%). n.m.r. analysis in DMSO-d6 at 100 mHz:
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH3:20])[C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:7]=2[CH:8]=[O:9])[CH2:3][CH2:2]1.[CH3:21][Mg]Br>C(OCC)C>[CH:1]1([CH2:4][N:5]([CH2:18][CH2:19][CH3:20])[C:6]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:7]=2[CH:8]([OH:9])[CH3:21])[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)O
Reaction time: 0.5 h

Procedure:
2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (6.0 g) is dissolved in diethylether (50 ml) and thereto is added a 2M methyl magnesium bromide in diethylether (7.35 ml) under nitrogen flow at −70° C. The mixture is stirred at the same temperature for 30 minutes, and the reaction solution is quenched with a saturated aqueous ammonium chloride solution and the mixture is extracted with diethylether. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to give 1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethanol (5.43 g). MS (m/z): 302 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.CC(=O)OCC>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].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>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)Cn1cc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnn(CC(=O)O)c2)CC1
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of 2-(4-bromo-1H-pyrazol-1-yl)acetic acid (867 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.2 g) and Pd(PPh3)4 (232 mg) in dioxane (15 mL) and sat. K2CO3 (7.5 mL) was heated at 100° C. overnight. After cooling down, EA was added and the mixture was washed with water and brine. The combined aq. layers were acidified to pH=2 with NaHSO4 and extracted with EA. The org. layers from the second extraction were dried (MgSO4), filtered off and evaporated in vacuo to afford 1.05 g of brown resin that was used without purification. LC-MS (B): tR=0.72 min; [M+H]+: 308.26.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-bromo-benzenesulfonyl chloride (3.914 mmol, 1.0 equiv) and 1-methyl-piperazine (7.83 mmol, 2.0 equiv) were dissolved in 15 mL DCM. Et3N (15.66 mmol, 4.0 equiv) was added via syringe to the reaction and stirred at room temperature for 2 h. The reaction was diluted with DCM, the organic phase was extracted with saturated NaHCO3 and brine and dried (Na2SO4). The organics were removed under reduced pressure to give 1-(3-bromo-benzenesulfonyl)-4-methyl-piperazine, as a white solid (1.1 g. 88% yield). 1H NMR (DMSO-d6): δ 2.14 (s, 3H), 2.35 (m, 4H), 2.92 (m, 4H), 7.62 (t, J=7.9 Hz, 2H0, 7.55 (dd, J=7.9 Hz, J=0.8 Hz, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.95 (dd, J=9.1 Hz, J=0.9 Hz, 1H) MS (ES+) m/z=321 LC retention time 1.74 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:21])[C:17](=O)[O:16]C(C)(C)[O:14]2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[NH3:24]>>[F:1][C:2]([F:23])([F:22])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:14])([CH3:21])[C:17]([NH2:24])=[O:16])=[CH:9][CH:8]=1)(=[O:5])=[O:4]
Reactant: CC1(C)OC(=O)C(C)(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)O1
Reactant: N
Product: CC(O)(C(N)=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 4-(2,2,4-trimethyl-5-oxo-1,3-dioxolan-4-yl)phenyl trifluoromethanesulfonate (15.5 g, 0.044 mol) in ammonia solution (30 mL, 7N in methanol) was left under stirring overnight at room temperature. After solvent evaporation under vacuum a crude was obtained that, after purification by flash chromatography (CH2Cl2/MeOH 98:2) afforded pure 2-[4-(trifluoromethanesulfonyloxy)phenyl]-2-hydroxy propanamide (9.7 g, 0.031 mol) as a white solid. Yield 70%. mp 105-107° C. 1H-NMR (CDCl3) δ 7.80 (d, 2H, J=7 Hz), 7.35 (d, 2H, J=7 Hz), 6.50 (bs, 1H, CONH), 5.42 (bs, 1H, CONH), 3.05 (bs, 1H, OH), 1.94 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[ClH:11].O=[C:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19](O)=[O:20]>>[ClH:11].[CH3:2][CH:1]([C:4]1[CH:9]=[CH:8][C:7]2[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[C:19](=[O:20])[O:10][C:6]=2[CH:5]=1)[CH3:3]
Reactant: CC(C)c1cccc(O)c1
Reactant: O=C(O)C1CNCCC1=O
Agent: Cl
Product: CC(C)c1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 28.2 %

Procedure:
Prepared by the method described in Example 1 from 3-isopropylphenol (150 g, 0.66 moles) and 4-oxo-3-piperidinecarboxylate hydrochloride (114 g, 0.59 moles). Recrystallization from dilute aqueous hydrochloric acid yielded the product (46.6 g) as the hydrochloride, mp 257°-261° C.