Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.OS(O)(=O)=O.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A solution of 49.5 g (169 mmol) of 2-acetylamino-5-nitro-4-trifluoromethyl-benzoic acid in 600 ml of methanol and 100 ml of water is cooled to 0° C. and 71.1 ml (1.33 mol) of concentrated H2SO4 are added dropwise. Upon completion of the addition, the mixture is heated to reflux for 1 hour. The mixture is then cooled to 0° C., the pH is adjusted to 10 with a 30% aqueous NaOH-solution and it is stirred for 1 hour. The methanol is distilled off and the remaining aqueous solution is diluted with water and extracted with t-butyl methylether. The aqueous phase is acidified with concentrated HCl-solution and the resulting yellow suspension is filtered and washed with water. The solid is dried in vacuo at 100° C. to give 28.3 g (67%) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid, m.p. 237° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedures described for intermediates 3B, 3C, 1, 4B and for example 1, the title compound has been prepared by the following reaction sequence: i) 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester [Lawrence, L.; Rigby, A.; Sanganee, H.; Springthorpe, B. PCT Int. Appl. (2001), WO 2001077101 A1] was reacted with benzoyl chloride to give 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester; ii) 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid to give benzoic acid [1,4′]bipiperidinyl-4-yl ester; iii) 4-bromo-2,6-dimethyl-benzoic acid was converted into its acid chloride and reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester to give benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester; iv) benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester was saponified to give (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone; v) Suzuki reaction of (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone with 3-trifluoromethyl-phenyl boronic acid gave the title compound as light brown solid. MS: 461.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:43]([CH3:44])=[CH:42][N:41]=[C:40]([CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[C:43]([CH3:44])=[CH:42][N:41]=[C:40]([CH3:45])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)cn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)ncc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K17) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (250 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C-]#N.[Li+].[CH3:18][N:19](C=O)C>>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][C:18]#[N:19])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)C1(CCCCBr)CCCC1
Agent: [C-]#N
Agent: [Li+]
Product: COC(=O)C1(CCCCC#N)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-bromobutyl)cyclopentane carboxlic acid methyl ester was treated with a solution of 0.5 molar lithium cyanide in DMF (5 mmol, 10 mL) and stirred overnight at room temperature followed by heating at 75° C. for two hrs. The reaction mixture was evaporated to dryness, the residue was dissolved in ethyl acetate (30 mL) and washed with sat'd sodium bicarbonate (2×10 mL), and brine (5 mL) and dried over magnesium sulfate to give a yellow oil (860 mg). Silica gel chromtography eluting with 1:3 ethyl acetate:hexane yielded a pale oil (83%, 693 mg). LR MS (C12H19NO2): Obs mass, 227 (M+NH4), 248 (M+K).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[Br:13]N1C(=O)CCC1=O>C(Cl)Cl.C(OCC)(=O)C>[Br:13][CH2:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: C=C(O[Si](C)(C)C)c1ccc[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccc[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Crude 2-[1 -(trimethyl-silanyloxy)-vinyl]-1H-pyrrole was diluted with CH2Cl2 (10 ml), cooled to 0° C., and treated with N-bromosuccinimide (1.94 mmol, 0.35 g). The resulting mixture was put in a −20° C. freezer overnight. After warming to room temperature, the mixture was diluted with ethyl acetate (75 ml), washed with saturated aqueous sodium bicarbonate (2×20 ml), brine (2×20 ml), and the organics concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 0.29 g (80%) of 2-bromo-1-(1H-pyrrol-2-yl)-ethanone. 1H NMR (CDCl3) δ7.12 (1H, dt, J=2.7, 1.3), 7.02 (1H, ddd, J=3.8, 2.4, 1.3), 6.36-6.31 (1H, m), 4.27 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:9]2=[O:14])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1NCCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To the product from Example 23B (0.43 g, 1.50 mmol) as a solution in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran) (1.80 mL, 1.80 mmol) via syringe under nitrogen followed by the addition of ethyl 2-bromoacetate (0.18 mL, 1.65 mmol). The reaction mixture heated at 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:4) gave the title compound. MS (DCI) m/z 374 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][C@@H:39]([CH3:43])[CH2:38]1)(=[O:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:32][C:29]2[CH:30]=[N:31][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:9]=[CH:8][C:7]([S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:6])=[O:5])=[CH:12][CH:11]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:22][CH:23]=3)=[CH:27][CH:28]=2)[C@@H:39]([CH3:43])[CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCN[C@@H](C)C1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (3 mL) was added (3S)-1-acetyl-3-methylpiperazine (140 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (273 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (184 mg, yield 72%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 591 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].CC(C)=O>CC(C)=O.O>[C:23]([NH:27][S:12]([C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:14])=[O:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)NC(C)(C)C
Reaction time: 5 h

Procedure:
A solution of 5.0 g (19.9 mmol) of 2-methoxy-4-nitro-benzenesulfonyl chloride in acetone/water (60 ml/15 ml) is mixed at room temperature with 2.9 ml of triethylamine and 2.2 ml of tert.-butylamine. After 5 hours, the acetone is drawn off, and the residue is extracted from ethyl acetate. The combined organic phases are washed with dilute HCl solution and saturated NaCl solution and then filtered through a Whatman filter and concentrated by evaporation. The crude product that is obtained is recrystallized from ethyl acetate. 4.2 g (14.6 mmol, corresponding to 73% of theory) of the product is obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:14][C@H:13]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=[O:11]
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@@H](C=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dimethylsulfoxide (1.01 g, 918 μL, 12.9 mmol) was added dropwise to a stirred solution of oxalyl chloride (790 mg, 543 μL, 6.23 mmol) in dry CH2Cl2 (12.6 mL) at −78° C. under N2 and the reaction was stirred for 15 min. A solution of benzyl [(1S)-2-hydroxy-1-methylethyl]carbamate (965 mg, 4.61 mmol) in dry CH2Cl2 (12.6 mL) was added dropwise by cannula and the mixture was stirred at −78° C. for 30 min. Triethylamine (1.34 g, 1.85 mL, 13.2 mmol) was added and the reaction was allowed to warm to room temperature and was stirred for 2 h. Water (15 mL) was added and the aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with saturated NaHCO3 and brine, then dried (MgSO4) and concentrated in vacuo to afford benzyl [(1S)-1-methyl-2-oxoethyl]carbamate as a colorless oil. Rf=0.75 (50% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.39-7.35 (m, 5H), 5.39 (br s, 1H), 5.15 (s, 2H), 4.33 (m, 1H), 1.40 (d, J=7.1 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][N:11]2[C:12](=[O:20])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=O)(C)(C)C.Cl>>[ClH:19].[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:20])[N:11]1[CH2:21][CH2:22][NH:8][CH2:9][CH:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(Cl)cccc3C2C1
Agent: Cl
Product: O=C1c2c(Cl)cccc2C2CNCCN12
Reaction time: 0.25 h
Yield: 185.2 %

Procedure:
To (±)-N-(t-butoxycarbonyl)-1,3,4,10b-tetrahydro-7-chloropyrazino[2,1-a]isoindol-6(2H)-one (15 mg, 0.05 mmol) was added concentrated hydrochloric acid (1 mL). After 15 min, the resulting solution was concentrated, diluted with water, and lyopholized to give (±)-1,3,4,10b-tetrahydro-7-chloro-pyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt as an off-white solid (12 mg, 100%). MS (ESI) 223.2, 225.2 (M−Cl).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][N:12](CC2C=CC=CC=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>C(O)C.[Pd]>[CH3:1][N:2]([C@@H:10]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: C[C@@H]1C[C@@H](N(C)C(=O)OC(C)(C)C)CN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CNC[C@H](N(C)C(=O)OC(C)(C)C)C1
Yield: 87 %

Procedure:
Into a Parr shaker jar was added Pd/C Deguessa type (0.922 g, 0.433 mmol) followed by a solution of 1,1-dimethylethyl methyl[(3R,5R)-5-methyl-1-(phenylmethyl)-3-piperidinyl]carbamate (1.38 g, 4.33 mmol) in Ethanol (20 mL). The Parr shaker jar was then placed on to the Parr Shaker machine and flushed the jar with N2 then pressurized the jar with hydrogen to 30 psi. The reaction was let shake at room temperature overnight. The reaction was filtered and concentrated to isolate 860 mg of crude product as a clear oil, which was used without purification. LC-MS (ES) m/z=229 [M+H]+.
Reaction SMILES: [B-](F)(F)(F)[CH:2]=[CH2:3].[K+].Br[C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.ClCCl.[Pd](Cl)Cl>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:2]=[CH2:3])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(Br)cc2)c(C)c1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Temperature: 140 °C

Procedure:
A suspension of potassium trifluoro(vinyl)borate (241 mg, 1.800 mmol), 4-bromo-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (595 mg, 1.5 mmol), cesium carbonate (1466 mg, 4.50 mmol), palladium(II) chloride (5.32 mg, 0.030 mmol) and triphenylphosphine (23.61 mg, 0.090 mmol) was prepared in tetrahydrofuran (THF) (2 mL) and Water (0.2 mL). The mixture was heated to 140° C. by microwaves for 30 min, to yield a black suspension. Additional ½ eq of potassium trifluoro(vinyl)borate (121 mg, 0.9 mmol) was added, along with extra water (0.2 mL) and THF (2 mL) and reaction heated for a further 1 hour at 140° C. The reaction mixture was diluted with dichloromethane (15 mL) and water (5 mL), then filtered through a plug of celite to remove palladium catalyst. The resulting yellow solution was dried using a hydrophobic frit, concentrated, then purified by flash (Si) using 0-25% ethyl acetate/cyclohexane over 40 minutes. Fractions were combined to give a clear oil, 385.3 mg, and the product taken directly to the next step, without further purification. LCMS (M+1) 344, RT 1.48 mins.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][CH:10]=1)=[O:4].[BH4-].[Na+].[OH-].[Na+].CCCCC>C1COCC1>[CH3:17][C:12]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:2][O:4]3)=[CH:6][N:7]=2)[C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(C)n1-c1ccc(C2CO2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To the ketone from example 39 (1.34 g, 5.4 mmol) dissolved in dry THF (20 ml), cooled to 0° C., was added sodium borohydride (308 mg, 8.1 mmol) portionwise. The reaction mixture was stirred for 2 hours then 3M NaOH (aq) (10 ml) was added and stirring continued for a further 16 hours. The reaction mixture was extracted with ethyl acetate (2×29 ml) and the combined organic extracts washed with brine (5 ml), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate; pentane (1:5) to give the title compound as a colourless oil (900 mg, 4.2 mmol, 78%). 1H NMR (CDCl3, 400 MHz) δ: 2.13 (s, 6H), 2.91 (dd, 1H), 3.25 (t, 1H), 3.98 (t, 1H), 5.90 (s, 2H), 7.20 (d, 1H), 7.62 (dd, 1H), 8.58 (s, 1H). LRMS: m/z 215 (M-H+).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[C:18](/[N+:20]([O-:22])=[O:21])\[CH3:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(OCC)(=O)C>C(O)C.C1COCC1>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([CH2:17][CH:18]([N+:20]([O-:22])=[O:21])[CH3:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(/C=C(\C)[N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CC(C)[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
To a suspension of sodium borohydride (1.52 g, 40 mmol) in ethanol (20 ml) at 0° C. was added a solution of 208 (6 g, 20 mmol) in THF (40 ml). The addition was over 20 min, the reaction mixture was stirred for 1 h at 0° C. and at rt for 30 min. 2M HCl (20 ml) was added (care—vigorous reaction!) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×60 ml). The combined organic layers were washed with water (60 ml) and brine (60 ml), dried (MgSO4) and concentrated in vacuo to afford the crude material as an orange oil. Purification by flash column chromatography eluting with hex:EtOAc; 4:1 afforded the title compound (3.35 g, 55%) as a pale green solid. 1H NMR (270 MHz; CDCl3) 1.44 (3H, d, J=6.7 Hz, CH3), 2.87 (1H, dd, J=14.1, 6.9 Hz, one of CH2), 3.19 (1H, dd, J 14.1, 7.4 Hz, one of CH2), 3.85 (3H, s, OCH3), 4.65 (1H, sext, J=6.9 Hz, CH), 5.12 (2H, s, CH2Ph), 6.65-6.71 (2H, m, 2×CH), 6.81 (1H, d, J=8.2 Hz, CH), 7.25-7.43 (5H, m, 5×CH). 13C NMR (67.5 MHz; CDCl3) 18.71 (CH3), 40.80 (CH2), 56.08 (OCH3), 71.17 (CH2), 84.64 (CH), 112.0 (CH), 115.15 (CH), 121.93 (CH), 127.47 (CH), 127.87 (C), 128.0 (CH), 128.67 (CH), 136.99 (C), 148.14 (C), 149.13 (C), LC/MS (APCI−) tr=1.1 min, m/z 300.01 (M−H)−.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH2:25])[C:17]=1[F:26])(=[O:12])[CH3:11].[F:27][C:28]([F:43])([C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([F:42])=[CH:34][CH:33]=1)[C:29](Cl)=[O:30].FC(F)(C1C2C(=CC=CC=2)C(F)=CC=1)C(O)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH:25][C:29](=[O:30])[C:28]([F:43])([F:27])[C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]([F:42])=[CH:34][CH:33]=2)[C:17]=1[F:26])(=[O:12])[CH3:11]
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Reactant: O=C(Cl)C(F)(F)c1ccc(F)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C(F)(F)c1ccc(F)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccc(F)c3ccccc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of DIEA (7.8 mL) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethyl acetate (4.6 g, 19 mmol), prepared as in step 8 of Example 1, in DCM (60 mL) was added 2,2-difluoro-2-(4-fluoronaphthyl)acetyl chloride (prepared by refluxing 2,2-difluoro-2-(4-fluoronaphthyl)acetic acid, as prepared in the preceding step, with oxalyl chloride) (7.8 g, 30 mmol) in DCM (40 mL). The mixture was stirred at room temperature for 1 hour. Additional DCM (100 mL) was added, and the resulting mixture was washed with 10% citric acid (3×40 mL) and brine, and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography eluting with DCM to give the title compound (5.3 g, 61%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 8.45 (m, 2H), 8.21 (d, J=7.0 Hz, 2H), 7.87 (s, 1H), 7.85 (t, J=4.1 Hz, 1H), 7.66 (m, 2H), 7.22 (t, J=8.3 Hz, 1H), 4.34 (t, J=6.4 Hz, 2H), 3.36 (t, J=6.4 Hz, 2H), 2.00 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]=[C:22]=[S:23]>C(Cl)Cl>[NH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:22]([NH:21][C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])=[S:23]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: NNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NN(CCO)C(=S)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.61 g (0.10 mol) 2-hydroxyethylhydrazine was dissolved in 100 mL methylene chloride at 0°-5° C. After dropwise addition of 10.2 g (0.10 tool) triethylamine, 20.4 g (0.10 mol) 2,4-dichlorophenylisothiocyanate dissolved in 70 mL methylene chloride was added over a period of 4 h. The reaction mixture was left to warm up to room temperature, stirred for a further 2 h, the precipitate filtered off, washed with methylene chloride and the desired compound isolated.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:1]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:2]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH2:3]1
Reactant: OCc1ccccc1
Reactant: O=CC[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@@H](OCc2ccccc2)C[C@@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
2-deoxy-D-glucose (Compound 1a, 2.5 g, 15.2 mmol) was dissolved in benzyl alcohol (20 mL), and then Dowex® 50W-X8 (H+ form, 3.5 g) was added. The reaction solution was stirred at 60° C. for 24 hours. Then the resin was filtered off, and the product was purified by flash column chromatography with CHCl3—MeOH (15:1) to give Compound 1 (2.67 g, 10.5 mmol) in 69 percent yield.
Reaction SMILES: [Na].Cl.[NH2:3][CH2:4][CH2:5][SH:6].Cl.Cl[CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[NH2:3][CH2:4][CH2:5][S:6][CH2:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COc1cccnc1CCl
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1cccnc1CSCCN
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of sodium (1.65 g) in ethanol (75 ml) was added cysteamine hydrochloride (2.9 g) and after stirring for 5 minutes a solution of 2-chloromethyl-3-methoxypyridine hydrochloride (4.5 g) in ethanol (75 ml) was added over 25 minutes. The mixture was stirred for 2 hours at 15° and the sodium chloride was filtered off and the filtrate was evaporated to give 2-[2-aminoethylthiomethyl]-3-methoxypyridine (4.6 g) as a colourless oil.