Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:66]=[CH:65][C:51]([CH2:52][NH:53][CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=2)[OH:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:66]=[CH:65][C:51]([CH2:52][N:53]([CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=2)[OH:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(Cl)c(Cl)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.4 %

Procedure:
To a solution of 36 mg (0.22 mmol) of 1H-indole-7-carboxylic acid and 72 mg of TBTU (0.22 mmol) in 3 ml DMF, were added 0.19 ml (1.12 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 79 mg (0.22 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-amine was added. After stirring for 17 h at rt, the reaction mixture was diluted with 30 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 68 mg (59%) of an off-white solid. MS (ISP) 495.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([O:13][CH:14]=[CH:15][C:16]#[N:17])[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:16]([C:15]([C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[CH:14][O:13][CH2:11][CH3:12])#[N:17]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CCOC=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC=C(C#N)c1cc(F)ccc1C#N
Temperature: 100 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
Palladium acetate (II) (0.556 g, 2.5 mmol) is added to a degassed solution of 2-bromo-4-fluoro-benzonitrile (10 g, 50 mmol), 3-ethoxyacrylonitrile (10.3 mL, 100 mmol) and triethylamine (14 mL, 100 mmol) in toluene (75 mL). The reaction mixture is stirred in an oil bath at 100° C. for 1 day. The reaction mixture is cooled to RT, filtered through a pad of Celite, and the filter cake is rinsed with EtOAc. After evaporation of the solvent, the residue is purified using a Biotage column eluted with 0-50% EtOAc/hexanes (20 CV) to afford 8.77 g (94%) of 2-(1-cyano-2-ethoxy-vinyl)-4-fluoro-benzonitrile. LC/MS: RT=3.38 min, no ionization.
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>C1COCC1>[C:1]([C:3]1([NH:9][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2]
Reactant: C#CC1(N)CCCCC1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: C#CC1(NCCCS(=O)(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 1-ethynylcyclohexylamine (6 g, 48.7 mmol) and 1,3-propane sultone (6.55 g, 53.6 mmol) in THF (35 mL) was heated at reflux for 2 hours (thick paste). The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with THF (3×5 mL), air-dried 15 minutes (7.3 g). The solid was suspended in ethanol (30 mL) and the suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature and the solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 10 min, and further dried in a vacuum oven at 60° C. overnight (crop 1, 7.10 g). The combined mother liquors were stirred overnight at room temperature. There was a lot of solid. The solid was collected by filtration, rinsed with acetone (3×5 mL), air-dried for 30 minutes, and then suspended in ethanol (12 mL). The suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature and the solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 2 minutes, and further dried in a vacuum oven at 60° C. overnight (crop 2: 1.85 g). Compound DX was obtained as a fine white solid (two crops in total 8.95 g, 75% yield). 1H NMR (500 MHz, D2O) δ 0.95-1.05 (m, 1H), 1.38-1.54 (m, 5H), 1.60-1.64 (m, 2H), 1.94 (qt, J=7.8 Hz, 2H), 2.85 (t, J=7.3 Hz, 2H), 3.01 (s, 1H), 3.22 (t, J=7.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 21.8, 22.3, 24.2, 34.4, 40.9, 48.0, 59.2, 78.6, 79.3. ES-MS 243.0 (M−1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:33]=[N+:34]=[N-:35].[Na+].[NH4+].[Cl-]>CN(C=O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[NH:35][N:34]=[N:33][N:32]=5)[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)C(Cc2cccc(-c3nnn[nH]3)c2)CCC1
Temperature: 120 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 2-(4,5-diphenyloxazol-2-yl)-1-(3-cyanobenzyl)-2-cyclohexene (400 mg) in DMF (8 ml) were added NaN3 (100 mg) and NH4Cl (80 mg). After stirred for 12 hours at 120° C., the mixture was partitioned between ethyl acetate and water and the organic layer was washed with 1N-HCl and brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with a mixture of ether and n-hexane to afford 2-(4,5-diphenyloxazol-2-yl)-1-{3-(1H-tetrazol-5-yl)benzyl}-2-cyclohexene (0.36 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:14])[C:2]([F:1])([F:15])[F:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)C(F)(F)F)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(CCc1ccc(O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of 1,1,1-trifluoro-4-[4-methoxyphenyl]-2-butanone (43.5 g, 0.187 mol) in dichloromethane (500 ml) at −78° C. (dry ice-acetone) was added dropwise boron tribromide (53 ml, 0.561 mol). The mixture was then stirred at 0° C. (ice bath) for 3 h, and cautiously quenched by dropwise addition of ice-water (200 ml) over a period of 1 h. The aqueous phase was saturated with solid sodium chloride, extracted with dichloromethane (500 ml) followed by diethyl ether (500 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by bulb-to-bulb distilation (96-100° C., 0.2 mmHg) to afford the title compound (34.4 g, 84%) as a yellow liquid which solidified upon standing.
Reaction SMILES: BrC1N=C2C=CNC2=NC=1.COC1C=C(B(O)O)C=CC=1OC.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:34]2[N:35]=[C:36]3[C:42]([I:43])=[CH:41][NH:40][C:37]3=[N:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].[H-].[Na+].[S:46](Cl)([C:49]1[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=1)(=[O:48])=[O:47]>C1COCC1.CCOC(C)=O.O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:34]2[N:35]=[C:36]3[C:42]([I:43])=[CH:41][NH:40][C:37]3=[N:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:34]2[N:35]=[C:36]3[C:42]([I:43])=[CH:41][N:40]([S:46]([C:49]4[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=4)(=[O:48])=[O:47])[C:37]3=[N:38][CH:39]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Brc1cnc2[nH]ccc2n1
Agent: COc1ccc(-c2cnc3[nH]cc(I)c3n2)cc1OC
Agent: COc1ccc(B(O)O)cc1OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(-c2cnc3c(n2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 121 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-7-iodo-5H-pyrrolo[2,3-b]pyrazine was prepared starting from 2-bromo-5H-pyrrolo[2,3-b]pyrazine and 3,4-dimethoxyphenylboronic acid. To a 0° C. solution of 2-(3,4-dimethoxy-phenyl)-7-iodo-5H-pyrrolo[2,3-b]pyrazine (821 mg, 2.1 mmol) in THF (20 mL) was added NaH (55% dispersion in mineral oil, 168 mg, 3.85 mmol) portionwise and the resultant mixture was stirred for 15 min, treated with TsCl (736 mg, 3.85 mmol), stirred overnight at room temperature, and poured into water and EtOAc. A yellow solid precipitated and the heterogeneous biphasic mixture was filtered to afford 680 mg (39%) of 2-(3,4-dimethoxy-phenyl)-7-iodo-5-(toluene-4-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine as a yellow solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1.[Mg].O1CCCC1>C(OCC)C>[CH2:7]([O:6][C:1](=[O:5])[C:2]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)([OH:3])[CH3:4])[CH3:8]
Reactant: Clc1ccc(I)cc1
Reactant: CCOC(=O)C(C)=O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 11.5 g ethyl pyruvate in 20 ml diethylether is slowly added under cooling (0° C.), a freshly prepared Grignard solution (from 23.9 g 4-chloro-iodobenzene and 3 g magnesium turnings). Some tetrahydrofurane is added to prevent the formation of viscous suspension. After stirring for 2 hours at room temperature the reaction is quenched by pouring it onto a mixture of ice and 2N sulfuric acid. Extraction of the suspension with diethyl ether followed by washing with brine, drying over sodium sulfate and evaporation leads to a residue which is purified on silicagel (hexane-ethyl acetate) to obtain 2-(4-chlorophenyl)-2-hydroxy propionic acid ethyl ester as yellowish oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3cnc(Nc4ccc(CN5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1

Procedure:
Compound 338 was prepared as an off-white solid (TFA salt) from compound 4 and compound 339 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.68 (1 H, s), 9.35 (1 H, s), 8.68 (2 H, q, J=6.3 Hz), 8.43 (1 H, d, J=1.5 Hz), 8.26 (1 H, dd, J=8.9, 2.1 Hz), 7.88 (1 H, d, J=8.8 Hz), 5.48 (1 H, quin, J=8.7 Hz), 3.78 (2 H, s), 3.27-3.30 (4 H, m), 2.83 (4 H, br. s.), 2.48-2.59 (2 H, m), 2.15-2.31 (4 H, m), 1.83-1.97 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 429.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-])=O)[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>C(O)C.O>[NH2:38][C:34]1[CH:33]=[C:32]([C:25]2[N:26]=[C:27]3[N:31]([C:24]=2[C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:17][C@@H:13]4[CH2:14][CH2:15][CH2:16][N:11]([S:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)(=[O:10])=[O:9])[CH2:12]4)[N:23]=2)[CH:30]=[CH:29][S:28]3)[CH:37]=[CH:36][CH:35]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-nitrophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (1.05 g, 1.76 mmol) was dissolved in ethanol 95% (10 ml) and water (2.5 ml). The solution was treated with irn powder (1 g, 17.6 mmol) and concentrated HCl (200 uL). The reaction mixture was stirred at 100° C. for one hour. The mixture was cooled down and diluted with ethanol (100 ml). The heterogenous mixture was filtered over Celite and the volatiles were removed in vacuo. The residue was taken up in EtOAc (150 ml) and the organic phase was washed with a saturated aqueous NaHCO3 solution (2×100 ml), water (100 ml) and a saturated aqueous NaCl solution (100 ml). After drying over sodium sulfate and concentration, the solid was triturated in ether, giving the title compound as a yellow powder, 0.835 g (84%). M.p.=226-228° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.73 (br. s, 1H), 8.10 (d, J=5.6 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.36 (d, J=4.4 Hz, 1H), 7.09 (t, J=7.7 Hz, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.81 (s, 1H), 6.69 (d, J=7.6 Hz, 1H), 6.65 (d, J=7.9 Hz, 1H), 6.49 (d, J=5.3 Hz, 1H), 5.01 (br. s, 2H), 4.02-3.88 (m, 1H), 3.73 (dd, J=11.1, 3.5 Hz, 1H), 3.47 (d, J=11.7 Hz, 1H), 2.60-2.46 (m, 1H), 2.39 (t, J=10.2 Hz, 1H), 1.98-1.80 (m, 2H), 1.68-1.51 (m, 1H), 1.47-1.32 (m, 1H). LCMS: 566 [M+H]. Calc. for C26H24N7O2S2Cl: C, 55.16; H, 4.27; N, 17.32. Found C, 54.98; H, 3.85; N, 17.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][C:29]([CH3:34])([CH3:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>C1COCC1.C([O-])(O)=O.[Na+]>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)=[O:11])[C:29]([CH3:34])([CH3:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1cccc(C(=O)O)n1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 410 mg (2.28 mmol) 6-methoxy-2-pyridinecarboxylic acid and 400 μL (3.02 mmol) 1-chloro-N,N,2-trimethylpropenylamine in 10 mL THF was stirred at RT. After 1.5 h, 600 mg (2.66 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 1.00 mL (5.81 mmol) DIPEA was added and the reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=1/1).
Reaction SMILES: [C:1]([N:4]([C:8]1[C:12]2[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Fe].C(OCC)(=O)C>[C:1]([N:4]([C:8]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1nsc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C(C)=O)c1nsc2ccc(N)cc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
To a suspension of N-acetyl-N-(5-nitro-benzo[d]isothiazol-3-yl)-acetamide (1.133 g, 4.06 mmol) in a 1:1 acetic acid:ethyl acetate solution (70 mL) at 50° C. was added iron powder (680 mg, 12.2 mmol). The resulting mixture was stirred at 50° C. for 5 h, then cooled, poured into saturated sodium bicarbonate and extracted into ethyl acetate. The organic layers were combined, washed with water and then brine, dried (MgSO4), filtered, and evaporated. The residue was purified using flash chromatography on silica to afford the desired amine as an orange solid (383 mg, 38%), single spot at Rf 0.30 (1:1 dichloromethane:ethyl acetate). mp 213.0-214.2° C. 1H NMR (CDCl3): δ 8.56 (1H, d, J=9.2 Hz), 7.48 (d, J=2.7 Hz), 7.14 (1H, dd, J=9.2, 2.7 Hz), 2.62 (3H, s), 2.56 (3H, s).
Reaction SMILES: [N:1]([C:4]1[C:5]([F:19])=[C:6]([CH:11]2[CH2:15][N:14]([CH2:16]O)[C:13](=[O:18])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[F:10])=[N+:2]=[N-:3].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(Cl)Cl>[N:1]([C:4]1[C:5]([F:19])=[C:6]([CH:11]2[CH2:15][N:14]([CH2:16][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[C:13](=[O:18])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[F:10])=[N+:2]=[N-:3]
Reactant: c1c[nH]cn1
Reactant: [N-]=[N+]=Nc1c(F)ccc(C2CC(=O)N(CO)C2)c1F
Solvent: ClCCl
Product: [N-]=[N+]=Nc1c(F)ccc(C2CC(=O)N(Cn3ccnc3)C2)c1F
Temperature: 28 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
In a 100 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, distilled tetramethyl-chloro-enamine (1.1 ml, 8.5 mmol) is added to a solution of 4-(3-azido-2,4-difluoro-phenyl)-1-hydroxymethyl-pyrrolidin-2-one a15 (1.9 g, 7.08 mmol) in CH2Cl2 (45 ml) at 0° C. After 3.5 h, the mixture is transferred via a canula into a second three necked flask fitted with a magnetic stirrer, under inert atmosphere, containing a solution of imidazole (2.4 g, 35.4 mmol) in CH2Cl2 (45 ml) at room temperature. The temperature raised up to 28° C. and a precipitate appears. After 1 h, the reaction mixture is filtered, evaporated in vacuo, diluted with CH2Cl2 and the organic layer is washed with water, dried over MgSO4, filtered and evaporated in vacuo. The residue is purified by chromatography on silicagel (CH2Cl2/EtOH/NH4OH: 93.5/06/0.5 (v/v)) to afford 4-(3-azido-2,4-difluoro-phenyl)-1-imidazol-1-ylmethyl-pyrrolidin-2-one 5 (1.66 g, 75%). The racemate is resolved by preparative chiral chromatography (Chiralpak AD, benzine/EtOH) and the enantiomers are recrystallized successively in toluene and AcOEt to afford the two enantiomers 6 (first eluted) and 7 (second eluted) as white solids (0.5 g and 0.45 g).
Reaction SMILES: Cl.CC1C2COC(=O)C=2C=CC=1CCN1CCNCC1.C(OC([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:45]=[CH:44][C:39]3[C:40](=[O:43])[O:41][CH2:42][C:38]=3[C:37]=2[CH2:46][CH3:47])[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH2:46]([C:37]1[C:38]2[CH2:42][O:41][C:40](=[O:43])[C:39]=2[CH:44]=[CH:45][C:36]=1[CH2:35][CH2:34][N:31]1[CH2:30][CH2:29][NH:28][CH2:33][CH2:32]1)[CH3:47]
Reactant: CCc1c(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Agent: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: CCc1c(CCN2CCNCC2)ccc2c1COC2=O

Procedure:
4-Ethyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride above starting from tert-butyl-4-[2-(4-ethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate. LC-MS (IE, m/z): 275 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:7]([O:9]CC)=[O:8].[OH-].[K+].Cl>CO>[CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1ccc(OC)c(C(OC)OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1C(OC)OC
Temperature: 50 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
Ethyl 3-dimethoxymethyl-4-methoxybenzoate (3.67 g) obtained in step A was dissolved in 20 mL of methanol, 12 mL of a 20% aqueous solution of potassium hydroxide was added to the solution, and the mixture was stirred for 3 hours at 50° C. The reaction mixture was cooled to 0° C., and 1M hydrochloric acid was added little by little until the mixture became nearly pH 7, whereafter the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with purified water and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was dried under reduced pressure to obtain 1.82 g (55%) of 3-dimethoxymethyl-4-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C1(C)C=CC=CC=1.CC([O-])(C)C.[Na+]>CCOC(C)=O.O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[N:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: N#Cc1ccc(Br)cn1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(C#N)nc2)CC1
Temperature: 75 °C
Yield: 31 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (3.70 g, 23.5 mmol) and 5-bromo-pyridine-2-carbonitrile (3.66 g, 20 mmol) in toluene (50 mol) was added NaOtBu (2.31 g, 24.0 mol), BINAP (374 mg, 0.60 mmol) and tris(dibenilideneacetone)dipalladium(0) (366 mg, 0.40 mmol). The reaction mixture was heated at 75° C. for 1 hours, cooled down to RT, and diluted with AcOEt (500 mL) and H2O (50 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 1.61 g (31%) of 6′-cyano-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 260.3 (M+H+)
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([S:19]([N:1]2[C:9]3[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=3[CH:3]=[CH:2]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CCCc2[nH]ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A stirred solution of 1,5,6,7-tetrahydro-4H-indol-4-one (5.0 g, 37.0 mmol) in THF is treated portionwise with NaH (60% dispersion in mineral oil, 1.5 g, 37.0 mmol) under N2 at room temperature, stirred for 0.5 hr, treated with benzene sulfonyl chloride (4.7 ml, 37.0 mmol), stirred for 24 hr, quenched with water and diluted with EtOAc. The phases are separated. The organic phase is washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexanes, 1/1 as eluent) to afford the title product as an off-white solid, 8.72 g (85% yield), mp 108-110° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1](=[C:4]([OH:10])[C@H:5]([OH:9])[CH2:6][CH2:7]O)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O.CCCCCC>C(Cl)Cl>[Br:30][CH2:7][CH2:6][C@@H:5]([OH:9])[C:4](=[C:1]([CH3:3])[CH3:2])[OH:10]
Reactant: CC(C)=C(O)[C@H](O)CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)=C(O)[C@H](O)CCBr
Temperature: 0 °C
Yield: 46.8 %

Procedure:
(R)-Isopropylidenebutane-1,2,4-triol (0.3 g, 2.05 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) were dissolved in methylene chloride (5 ml) and cooled to 0° C. and N-bromosuccinimide (0.38 g, 2.16 mmol) was added in small portions with stirring. After additional 1 h of stirring at 0° C. hexane (15 ml) was added and the resulting precipitate was removed by filtration and washed twice with hexane (2×5 ml). The combined hexane solution was passed through a short column of silica gel (5 g). Elution with hexane (15 ml) gave after evaporation and distillation the title compound as a colourless oil (0.2 g, 0.96 mmol, 47%): b.p. 74°-76° C. at 2.7 kPa (20 mm Hg), nD20 =1.4630. {α}D20 =+27.7° (c=20, CHCl3).