Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH:12][C:13]#[N:14])=[O:5])C.Br.N[CH2:17][CH2:18][CH2:19][SH:20].C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl>[O:5]=[C:4]1[C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=[C:13]2[S:20][CH2:19][CH2:18][CH2:17][N:14]12
Reactant: NCCCS
Reactant: CCOC(=O)C1CCCCC1=CC#N
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: O=c1c2c(cc3n1CCCS3)CCCC2

Procedure:
To 15 ml. of o-dichlorobenzene were added 5.8 g. of 2-cyanomethylene-cyclohexane-carboxylic acid ethyl ester, 6.5 g. of 3-aminopropanethiol hydrobromide and 3.1 g. of sodium acetate. Then, by treating the mixture as in Example 95, 800 mg. of 6-oxo-3,4,7,8,9,10-hexahydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline was obtained.
Reaction SMILES: [NH3:1].[O:2]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH:16]3[O:18][CH2:17]3)[CH:11]=2)[CH:6]=[CH:5][C:3]1=[O:4]>C(O)C>[NH2:1][CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][C:3](=[O:4])[O:2]2)=[CH:8][CH:9]=1
Reactant: O=c1ccc2ccc(OCCC3CO3)cc2o1
Reactant: N
Solvent: CCO
Product: NCC(O)CCOc1ccc2ccc(=O)oc2c1
Temperature: 65 °C
Yield: 50 %

Procedure:
5 ml of 30% aqueous ammonia and Gd (OTf3) (0.039 g, 0.065 mmol) are added to a solution of racemic 4-(7-coumarinyloxy)-1,2-epoxybutane (0.150 g, 0.65 mmol) in 2 ml of ethanol. It is heated at 65° C. for 15 hours, the solvent is evaporated, the residue is diluted in ethyl acetate, and it is washed with an NaCl-saturated solution. The residue provides the crude amine (0.081 g, yield 50%) that is used without purification for the next stage.
Reaction SMILES: [N:1]1([C:7]([C:9]2([C:21]#[N:22])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>N.CO.[Ni]>[N:1]1([C:7]([C:9]2([CH2:21][NH2:22])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)N1CCC(C#N)(C(=O)N2CCOCC2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCCS(=O)(=O)N1CCC(CN)(C(=O)N2CCOCC2)CC1
Yield: 98.7 %

Procedure:
A mixture of 4-(morpholin-4-ylcarbonyl)-1-(propylsulfonyl)piperidine-4-carbonitrile (I-4) (3.29 g, 10 mmole) and Raney Ni (2 g) in 2M NH3-MeOH (100 mL) was hydrogenated (55 psi) overnight at room temperature. Next morning, LCMS indicated that the hydrogenation was completion. Raney Ni was filtered and washed with MeOH (5×60 mL). The collected MeOH solution was concentrated to afford the title amine (I-5) (3.29 g, 99%) as a white solid. Analytical LCMS: single peak (214 nm), 1.723 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19]C(C)C)=[O:18])[CH:3]=1.[OH-].[K+]>O1CCCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1
Reactant: COc1ccc(-c2nc(C(=O)OC(C)C)cc(Cl)c2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C(=O)O)cc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a mixture of isopropyl 4,5-dichloro-6-(4-methoxyphenyl)picolinate (5.25 g, 15.4 mmol) in tetrahydrofuran (40 mL) and water (10 mL) was added potassium hydroxide (1.26 g, 22.4 mmol). The reaction was allowed to stir at room temperature for 12 h. After 1 hour of stirring, solids precipitated from the mixture. HCl (aq) (2N, 25 mL) was added to the reaction mixture to form a clear biphasic mixture. The mixture was added to water (75 mL) in a reparatory funnel and extracted with EtOAc (2×75 mL). The combined organic layers were washed with water (25 mL) and saturated NaCl (50 mL) and then concentrated under reduced pressure to provide 4.57 g (99% yield) of 4,5-dichloro-6-(4-methoxyphenyl)picolinic acid as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.72-7.64 (m, 2H), 7.07-6.99 (m, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.78, 161.05, 157.26, 146.30, 143.76, 133.54, 130.98, 128.72, 123.45, 113.77, 55.48.; mp=164-181° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:11].N([O-])=O.[Na+].N(O)=O.C([O-])(O)=O.[Na+].[C:25]([Cu])#[N:26].[C-]#N.[K+]>OS(O)(=O)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:25]#[N:26])=[CH:6][C:5]=1[Cl:11]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: O=C([O-])O
Agent: O=NO
Agent: O=N[O-]
Solvent: O
Product: COC(=O)c1ccc(C#N)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Amino-2-chloro-benzoic acid methyl ester (25 g, 72.7 mmol) was dissolved in 10% aqueous H2SO4 (150 mL) and the solution was cooled to 0° C. A solution of NaNO2 (11.15 g, 16.88 mmol) in water (50 mL) was added dropwise maintaining the temperature between 0-5° C. The mixture was stirred for 10 min., excess nitrous acid was neutralized using a saturated aqueous NaHCO3 solution. The resulting mixture was then added to a precooled (0-5° C.) suspension of CuCN (13.87 g, 155 mmol) and KCN (10.07 g, 155 mmol) in water (200 mL). It was stirred for 10 min., then allowed to attain room temperature. It was stirred for 0.5 h and finally heated on a steam bath for 0.5 h. Excess saturated FeCl3 solution was then added to the reaction mixture.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[C:26](O)([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C>[C:26]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
To a mixture of the compound (6.9 g) obtained in Example 63 and methylene chloride (70 ml) were added t-butanol (20 ml), N,N-dimethylaminopyridine (2.63 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.9 g) and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 7.64 g of the titled compound (yield, 97%).
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[CH3:12])(=O)C.[CH2:20]([CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH3:21].S(=O)(=O)(O)O>>[CH2:20]([CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([O:25][C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:11]([C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:13])[CH3:12])=[O:24])[CH3:21]
Reactant: CCCCC(CC)C(=O)O
Reactant: CC(=O)Oc1ccccc1C(C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Product: CCCCC(CC)C(=O)Oc1ccccc1C(C)(C)c1ccccc1
Temperature: 25 °C

Procedure:
Cumylphenyl 2-ethylhexanoate was prepared in accordance with the following procedure: a 2-liter flask equipped with a mechanical agitator, a ten theoretical plate fractionating column, an automatic reflux splitter pot, vapor thermo-controllers, a condenser, receivers, and external heating and cooling devices, was charged with 2 moles of cumylphenyl acetate, 5 moles of 2-ethylhexanoic acid and 5 grams of 98% sulfuric acid. Heat was supplied externally and the distillate was collected at a 20:1 reflux ratio at a vapor temperature below 120° C. at atmospheric pressure. A total of 64 cc of distillate was collected in 24 hours. The residual pot contents were cooled to ambient temperature and extracted 5 times with 2 l. of 8% sodium bicarbonate dried over anhydrous Na2SO4 and fractionated to give 408 g. (58 mole %) of a pale yellowish oil. The oil had a boiling point at 0.2 mm Hg of 252°-257° C., a specific gravity 20/20 of 1.045 and a saponification value of 2.82 meq/g. The cumylphenyl 2-ethylhexanoate ester has a theoretical saponification value of 2.85 meq/g.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O.[CH3:24][S:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[CH:19]([CH:21]1[CH2:23][CH2:22]1)[C:32]1[C:31]2[C:35](=[C:27]([CH2:26][S:25][CH3:24])[CH:28]=[CH:29][CH:30]=2)[NH:34][CH:33]=1
Reactant: OC(c1ccc(C(F)(F)F)cc1Cl)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3Cl)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.6 ml (33.8 mmol) of trifluoroacetic acid were added to 7.07 g (28.2 mmol) of the compound from Example 150A and 5.00 g (28.2 mmol) of the compound from Example 8A in 620 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 960 mg (7% of theory) of the title compound.
Reaction SMILES: C([O:8][C:9]([N:11]([CH3:25])[C@H:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=[O:14])=O)C1C=CC=CC=1.O.C1C(=O)N(OC([O:37][CH2:38][CH:39]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]3[C:40]2=[CH:41][CH:42]=[CH:43][CH:44]=3)=O)C(=O)C1>CO.C(#N)C.CCOC(C)=O.[Pd]>[CH:50]1[C:51]2[CH:39]([CH2:38][O:37][C:9]([N:11]([CH3:25])[C@H:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:13]([OH:15])=[O:14])=[O:8])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:46]=2[CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CN(C(=O)OCc1ccccc1)[C@H](CCC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@H](CCC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (1.40 g, 3.98 mmol) in MeOH (18.79 ml) was added 10% Pd/C (0.424 g, 0.398 mmol) and the reaction mixture was placed under a hydrogen atmosphere using. The reaction was allowed to stir at room temperature for 18 h. The catalyst was removed by filtration on CELITE® and the filtrate was concentrated under reduced pressure to give a white solid. The crude material was dissolved in Acetonitrile (9.40 ml), Water (9.40 ml) and TEA (1.111 mL, 7.97 mmol). The solution was cooled to 0° C. using and icebath and the FMOC-OSU (1.344 g, 3.98 mmol) was added. The reaction mixture was allowed to stir while warming up to room temperature for 18 hours. The crude product was diluted in 200 mL EtOAc and washed with 1N HCl aqueous solution and brine. The organic phase was dried over anhydrous sodium sulfate. After filtration and concentration a clear oil was obtained, which was purified by silica gel chromatography using 100% hexanes to 100% EtOAc. (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid was obtained as a colorless oil (0.481 g, 28%). 1H NMR (400 MHz, chloroform-d) δ 7.81-7.68 (m, 2H), 7.63-7.49 (m, 2H), 7.43-7.21 (m, 4H), 5.95 (br. s., 3H), 4.76 (dd, J=10.7, 4.5 Hz, 1H), 4.60-4.48 (m, 1H), 4.47-4.32 (m, 2H), 4.29-4.10 (m, 1H), 2.87 (s, 3H), 2.43-1.82 (m, 4H), 1.51-1.36 (m, 9H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:17][CH:16]=3)=[CH:9][N:8]2[C:30]=1[CH3:31].[F:32][C:33]1([F:38])[CH2:37][CH2:36][NH:35][CH2:34]1>>[F:32][C:33]1([F:38])[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:29])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[CH:17][CH:16]=4)=[CH:9][N:8]3[C:30]=2[CH3:31])[CH2:34]1
Reactant: Cc1c(CCCO)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Reactant: FC1(F)CCNC1
Product: Cc1c(CCCN2CCC(F)(F)C2)nc2ccc(NC(=O)c3ccc(OCc4ccccn4)cc3)cn12
Yield: 36.8 %

Procedure:
The compound (25.0 mg) obtained in Example 14 and 3,3-difluoropyrrolidine (3.4 mg) were processed in the same manner as in Example 19 to obtain the entitled compound (5.9 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6](O)[C:7](=[CH2:15])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].S(Br)([Br:23])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][CH:18]=[O:19])[CH:6]=[C:7]([CH2:15][Br:23])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: C=C(CCN(C)C(C)=O)C(O)C(NC=O)C(=O)OCC
Reactant: O=S(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C=C(CBr)CCN(C)C(C)=O)NC=O
Reaction time: 1 h

Procedure:
15.8 g (55.2 mmol) of 6-(N-acetyl-N-methylamino)-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 150 ml of dichloromethane, and 5.1 ml (66.2 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, 1N KHCO3 solution and again with water, dried over MgSO4, filtered and concentrated by evaporation. 6-(N-acetyl-N-methylamino)-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish-orange oil which is reacted further in the crude state.
Reaction SMILES: Br[C:2]1[S:27][C:5]2=[N:6][C:7]([CH3:26])=[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:28].O(C([N:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1)=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C.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:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:26])[N:6]=[C:5]3[S:27][C:2]([C:39]4[CH:40]=[N:36][NH:37][CH:38]=4)=[C:3]([CH3:28])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1NS(=O)(=O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
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: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(C)c2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (Description 63) (350 mg, 0.695 mmol), 1-tert-butoxylcarbonyl-1H-pyrazole-4-boronic acid, pinacol ester (221 mg, 0.751 mmol), tetrakis(triphenylphosphine)palladium(0) (40.1 mg, 0.035 mmol) and potassium carbonate (288 mg, 2.084 mmol) in 1,4-dioxane (1.5 mL), DMF (1.5 mL) and water (0.5 mL) was heated at 100° C. overnight (ca. 16 h). The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in cyclohexane, to give the title compound (150 mg). LCMS (A) m/z: 491 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10](OCC)=[O:11].O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11]
Reactant: CCOC(=O)Cc1cccc(C)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CCO)c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
LiAIH4 (3.1 g, 0.083 mol) was suspended in dry tetrahydrofuran (100 ml) in argon atmosphere. Ethyl 2-(2-bromo-3-methylphenyl)acetate (8.5 g, 0.033 mol) solved in dry tetrahydrofuran (50 ml) was added and the mixture was stirred at room temperature for 4 h. The mixture was cooled on ice and 3.1 ml of water was added dropwise, followed by 3.1 ml of 15% sodium hydroxide and then 9.3 ml of water. After 15 h. the solids were removed by filtration and washed thoroughly with tetrahydrofuran. The filtrate was removed under reduced pressure. Purification of the residue by filtrating through silica gel using methylene chloride:methanol (9:1) as eluent gave 7.0 g (98.6%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1([N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CCN(CC)CC.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][C:2]1([N:5]2[CH2:10][CH2:9][N:8]([S:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:18])([F:30])[F:31])(=[O:28])=[O:27])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC1(N2CCNCC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(N2CCN(S(=O)(=O)c3ccccc3C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
1-(1-Methylcyclopropyl)piperazine (TFA salt) (50.9 mg, 0.200 mmol) was dissolved in dichloromethane (1.0 mL) and NEt3 (0.3 mL) was added. To this mixture, 2-trifluoromethylbenzenesulfonyl chloride (73.4 mg, 0.300 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo and the resulting crude mixture was purified by HPLC (25-40% acetonitrile in water (0.05 TFA buffer). The product containing fractions were concentrated in vacuo until only water was left, basified with NaHCO3 (sat. aq., 20 mL) and extracted with dichloromethane (3×7 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a white solid (56.6 mg, 81%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.28-0.32 (m, 2 H), 0.39-0.44 (m, 2 H), 0.98 (s, 3 H), 2.59 (t, J=4.80 Hz, 4 H), 3.08 (m, 4 H), 7.84-7.93 (m, 2 H), 7.99-8.04 (m, 2 H); ESI-MS: m/z 349.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:1]([NH2:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[CH:8](=[NH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Agent: NCCOCCO
Solvent: O
Product: N=Cc1ccccc1

Procedure:
Diglycolamine (1000.9 g) and benzaldehyde (1060.7 g) were heated under vacuum at 95° C. until the % water was less than 0.1% to yield the diglycolamine-benzaldehyde imine.
Reaction SMILES: [CH2:1]1[CH2:26][O:25][C:3]2([CH2:8][CH2:7][C@H:6]3[C@H:9]4[C@H:19]([C:20](=[N:22]O)[CH2:21][C@:4]23[CH3:5])[C@:17]2([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]4)[O:2]1.[Na]>C(O)CC>[NH2:22][C@@H:20]1[CH2:21][C@@:4]2([CH3:5])[C@@H:6]([CH2:7][CH2:8][C:3]32[O:2][CH2:1][CH2:26][O:25]3)[C@H:9]2[C@H:19]1[C@:17]1([CH3:18])[C@@H:12]([CH2:11][CH2:10]2)[CH2:13][C@H:14]([OH:24])[CH2:15][CH2:16]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2C(=NO)C[C@@]2(C)[C@H]1CCC21OCCO1
Agent: [Na]
Solvent: CCCO
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2[C@H](N)C[C@@]2(C)[C@H]1CCC21OCCO1
Yield: 58.8 %

Procedure:
A solution of 17,17-ethylenedioxy-11-oximino-5α-androstan-3α-ol (0.700 g) in propanol (20 ml) was refluxed under nitrogen. To this solution were added small pieces of sodium (total 0.8 g) over a period of 80 mins. The reaction mixture was evaporated to low volume then diluted with water. No precipitation occurred and the solution was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with water (×4), dried (magnesium sulphate) and evaporated to a solid (0.575 g). Crystallisation from ethyl acetate/petrol gave colourless crystals of the title compound (0.396 g), m.p. 170°-171°, [α]D -36°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]([NH:8][C:9]([C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10])[CH2:6][CH3:7].Cl[C:20](OC(Cl)(Cl)Cl)=[O:21]>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]([N:8]1[C:9](=[O:10])[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[NH:17][C:20]1=[O:21])[CH2:6][CH3:7]
Reactant: CC[C@H](CC(=O)OC)NC(=O)c1ncccc1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Yield: 99 %

Procedure:
A solution of 1.6 g of (R)-3-[(3-amino-pyridine-2-carbonyl)-amino]-pentanoic acid methyl ester and 0.86 mL of trichloromethyl chloroformate in 25 mL of tetrahydrofuran is stirred at 90° C. for 3 h. The resulting mixture is diluted with saturated sodium bicarbonate solution and the product is extracted with ethyl acetate. The organic layer is washed with water and brine, dried (sodium sulfate), filtered and concentrated. The residue is purified by flash chromatography on silica to give 1.75 g (99%) of (R)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.OC1C=C([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])C=C(C)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:22]([OH:24])(=[O:23])=[O:21]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 164.4 %

Procedure:
Diethyl azodicarboxylate (524 mg, 3.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (900 mg, 3.0 mmol), as prepared in step (c) of the Example 1,4-cyanobenzyl alcohol (400 mg, 3.0 mmol; Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (790 mg, 3.0 mmol) in tetrahydrofuran (20 miL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a white solid (0.95 g, 76%). 1H-NMR (300 MHz, CDCl3) δ 2.26 (s, 3H), 5.03 (s, 1 H), 6.57 (t, 1 H, J=2.2 Hz), 6.59 (s, 1H), 6.67 (s, 1H), 7.38 (t, 1 H, J=5.8 Hz), 7.49 (d, 2H, J=4.2 Hz), 7.60 (m, 2H), 7.67 (d, 2H, J=3.5 Hz) and 7.96 (d, 1H, J=3.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C[OH:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:11]3[C:12](=[O:15])[O:13][CH2:14][C:10]=3[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:26])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Reactant: CO
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2c(-c3ccc(F)cc3)sc3c2COC3=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2-(4-Fluorophenyl)-3-(4-(methylthio)phenyl)-4H-thieno-[2,3-c]furan-6-one (548 mg) (from Step 4) was dissolved in 10 mL of 10:1 CH2Cl2/-MeOH and treated with 476 mg of MPPM at 0° C. After stirring for 15 min at 0° C. and 1.5 h at room temperature, the reaction mixture was quenched with 20 mL of sat. NaHCO3, and extracted with 50 ml of EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give 490 mg of the title compound.