Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][CH:23]([OH:25])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:12][CH2:13][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][C:23](=[O:25])[CH2:22]3)(=[O:19])=[O:20])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
To a stirred solution of 1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-azetidin-3-ol (Example 30) (143 mg, 0.28 mmol.) in dichloromethane (10 mL) was added Dess-Martin periodinane (230 mg, 0.56 mmol.) and the mixture stirred at ambient temperature for 18 hours. Ethyl acetate (20 mL) was added and the solution washed with 10% sodium thiosulfate solution (20 mL), water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate:dichloromethane:iso-hexane (1:1:2), to afford the desired product (98 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:22]3[CH2:21][CH2:20][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=4)[C:23]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1C(Br)CCCC1c1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (48 mg, 0.18 mmol) and of crude 6-bromo-2-(4-trifluoromethoxyl-phenyl)-cyclohexanone (65 mg, 0.19 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (16 mg, 17%) as a pale-brown oil. MS ISP (m/e): 501.0 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.61 (s, 1H), 7.35 (s, 1H), 7.08-7.20 (m, 4H), 6.82 (s, 1H), 6.65 (d, 1H), 4.06 (m, 1H), 3.56 (s, 3H), 2.75 (m, 2H), 2.28 (s, 3H), 2.25 (m, 1H), 1.77-1.98 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:28]([O:30][CH3:31])=[O:29])=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22]CC)=[O:21])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+]>C1COCC1.CO>[OH:1][C:2]1[C:3]([C:28]([O:30][CH3:31])=[O:29])=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:10]=[C:11]([C:15]2[O:19][N:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2cccc(/C=C/COc3cccc(O)c3C(=O)OC)c2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(O)cccc1OC/C=C/c1cccc(-c2cc(C(=O)O)no2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Example 1E in THF/MeOH (1:1 10 mL), was added 2N NaOH (225 μL, 0.45 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes and quenched with 1N HCl and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to provide the titled compound. MS (ESI(+)) m/e 413 (M+18)+; 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.06(s, 1H), 7.83(d, J=7.5 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.49(s, 1H), 7.19(t, J=8.4 Hz, 1H), 6.79 (d, J=15.9 Hz, 1H), 6.65 (dt, J1=15.9 Hz, J2=5.8 Hz, 1H), 6.61(d, J=8.4 Hz, 1H), 6.52(d, J=8.4 Hz, 1H), 4.75(d, J=5.0 Hz, 2H), 3.79 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:35]=[C:34]([CH2:36][O:37]C3CCCCO3)[O:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:35]=[C:34]([CH2:36][OH:37])[O:33][N:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)on3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)on3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M45) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (103 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11]>>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: COC(CN)OC
Product: COC(CNC(=O)C(C)C)OC
Yield: 77 %

Procedure:
The product is prepared analogously to Example 1 from isobutyryl chloride and aminoacetaldehyde dimethyl acetal. Distillation at 98° C. and 0.01 mbar gives a yield of 77 %. According to GC; the product has a purity of 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[OH:32])=[O:14])=[CH:4][CH:3]=1
Reactant: Cn1ccnc1COc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: Cn1ccnc1COc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 5d, using 5-(4-chloro-phenyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)-nicotinic acid and (1R,2R)-2-amino-1-cyclohexanol as starting materials to yield 5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)-nicotinamide, MS (ISP) 441.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:23]([O:25]CC)=[O:24])[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:23]([OH:25])=[O:24])[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:23]([OH:25])=[O:24])[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH3:22])[CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCCN(CC)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCCN(CC)C2)cc1

Procedure:
3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidinecarboxylic acid 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidinecarboxylic acid was prepared starting from ethyl 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-ethyl-3-piperidinecarboxylate (3.2 g, 8.0 mmol) dissolved in THF:Methanol (15:25 ml) and NaOH (15 ml). The resulting reaction misture was worked up as outlined in example 1 (step 7). Yield 2.11 g (71%), white solid: mp 159.2° C.; MS (ES): m/z 366.3 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:19](=O)[CH3:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][O:23][C:24]([NH2:26])=[NH:25].OS(O)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:22][O:23][C:24]1[NH:26][C:19]([CH3:20])=[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:25]=1
Reactant: COC(=N)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1=NC(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)(C)C)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 122.7 %

Procedure:
A mixture of 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, t-butyl ester (6.80 g, 23.3 mmol), o-methylisourea hydrogen sulfate (5.22 g, 30.3 mmol), and sodium bicarbonate (5.87 g, 69.9 mmol) in dimethylformamide (35 ml) was stirred at room temperature overnight under argon. After 23 hours at room temperature, the reaction was heated at 60° C. (oil bath) for 5.5 hours. It was then partitioned between ethyl acetate and 5% sodium bicarbonate. The organic phase was washed several times with water, washed with saturated sodium chloride, and dried over potassium carbonate. Evaporation gave crude title compound as a light brown oil (9.93 g).
Reaction SMILES: ClCl.[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])=[CH:21][CH:20]=2)[C:7]1=[O:38])(=[O:5])[CH3:4].[NH:39]1[CH:43]=[C:42]([C:44]2[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=2)[N:41]=[CH:40]1.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)/[C:8](=[C:18](/[NH:48][C:47]2[CH:46]=[CH:45][C:44]([C:42]3[N:41]=[CH:40][NH:39][CH:43]=3)=[CH:50][CH:49]=2)\[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])=[CH:21][CH:20]=2)/[C:7]1=[O:38])(=[O:5])[CH3:4]
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1C(=O)/C(=C(\Nc2ccc(-c3c[nH]cn3)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
A solution of 0.50 g (1 mmol) of the chlorine compound obtained in (b) in 20 ml of CH2Cl2 is added to a cold (Ti =-60° C.) stirred suspension of 0.35 g (1.5 mmol) of 4-(1H-imidazol-4-yl)aniline×2 HCl (melting point: 350° C.) and 0.77 ml (4.5 mmol) of Hunig's base in 20 ml CH2Cl2 and stirred overnight at ambient temperature. After evaporation in vacuo and evaporation twice with toluene in vacuo the residue obtained is triturated with EtOH.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:3].[S:11]1[CH:15]=[C:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[N:13]=[CH:12]1>N1C=CC=CC=1>[CH2:7]([CH:6]([CH2:9][CH3:10])[CH2:5][O:4][C:2]([N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]1[N:13]=[CH:12][S:11][CH:15]=1)=[O:3])[CH3:8]
Reactant: CCC(CC)COC(=O)Cl
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Solvent: c1ccncc1
Product: CCC(CC)COC(=O)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
17.9 G (0.108 moles) of 2-ethyl-1-butyl chloroformate is added dropwise with protection from moisture to a stirred suspension of 21.7 (0.108 moles) of 2-(4-thiazolyl)-benzimidazole in 150 ml. of pyridine. The addition is carried out over a period of 35 minutes after which the reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo. The gummy residue is treated with 250 ml. of methylene chloride, filtered and washed twice with 250 ml. of 0.25 N-hydrochloric acid containing ice and 200 ml. of saturated sodium bicarbonate solution. The methylene chloride is dried and evaporated to dryness in vacuo affording 23.8 g. (67%) of a yellow-orange residual oil which is purified by column chromatography, the extract of which thin layer chromatography demonstrates to be pure 1-(2-ethyl-1-butoxycarbonyl)-2-(4-thiazolyl)-benzimidazole.
Reaction SMILES: [CH2:1]([CH:8]([C:22]#[N:23])[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C#N)Cc1ccccc1)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)Cc1ccccc1)OCC

Procedure:
A solution of 3.5 g of ethyl 2-benzyl-2-cyanoethyl(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 25 g of an 8% solution of ammonia in ethanol. To this are added 2 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-benzylpropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+46.3 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]CC.[Na+].CS(C)=O.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cccnc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: Clc1ncccc1OCc1ccccc1

Procedure:
2-Chloro-3-hydroxypyridine (9.47 g; 0.073 moles) was added to a solution of sodium ethoxide in ethanol (from sodium, 1.67 g; 0.073 g. atom). Sufficient dimethyl sulphoxide was added to dissolve all of the solid, and ethanol was removed in vacuo . To the resulting solution was added benzyl chloride (9.3 g; 0.073 moles) with cooling and stirring, and the reaction mixture was left to stir under reflux for 6 hours. Unreacted benzyl chloride, and solvent, were evaporated off under vacuum on a boiling water bath, and the residue was treated with water to precipitate out an oil which was extracted with chloroform, washed with N sodium hydroxide solution and dried over anhydrous magnesium sulfate. After removing the solvent, 2-chloro-3-benzyloxypyridine was obtained as a solid (11.63 g, mp 36°-8°).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:29])=[O:5])[CH3:2].C(N(CC)CC)C.[C:37]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)(=[O:39])[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:37]([N:40]1[CH2:45][CH2:44][CH:43]([N:20]2[CH2:21][C:16]3[C:15]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]4[CH3:28])=[N:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:8]([F:29])[CH:9]=4)=[N:18][C:17]=3[CH2:19]2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCN(C(C)=O)CC2)C3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
To (S)-1-ethyl-3-(2-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (intermediate 18) (100 mg, 0.23 mmol) and triethylamine (64 μL, 0.46 mmol) in dry THF (3 ml) was added 1-acetylpiperidin-4-one (56 μL, 0.46 mmol) and stirred at room temperature for 30 min. To this sodium triacetoxyborohydride (97 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature until analysis by LCMS indicated reaction was complete. The solvent was then removed in vacuo. Crude reaction mixture then was partitioned between ethyl acetate and water. The organic layer was recovered, dried with sodium sulphate and solvent removed in vacuo. Residue was then purified by prep HPLC (low pH) to afford a white solid (6.7 mg, 0.013 mmol, 6%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:5](=[O:7])[CH3:6])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(N)cc(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Acetic anhydride (6.7 mL) and 3-chloro-5-methyl-phenylamine (5.0 g, 35 mmol) was mixed and stand for 2.0 h. The reaction mixture was cooled to room temperature to give N-(3-chloro-5-methyl-phenyl)acetamide (5.1 g) as light yellow solids in 79% yield: 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 7.19 (s, 1H), 7.12 (s, 1H), 6.91 (s, 1H), 2.31 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([OH:30])=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[CH2:32][CH3:33])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:17][NH:18][C:19]([C:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=5)[S:10][C:3]=34)=[CH:27][CH:28]=2)[N:23]([CH3:31])[C:22]=1[CH2:32][CH3:33])=[O:20]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CCc1c(C(=O)NC)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1c(C(=O)NC)c2ccc(Oc3ccnc4cc(-c5nccn5C)sc34)cc2n1C
Yield: 39.4 %

Procedure:
This material was prepared by the reaction 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine 1e (0.084 g, 0.34 mmole) with 2-ethyl-6-hydroxy-N,1-dimethyl-1H-indole-3-carboxamide 73g (0.078 g, 0.33 mmole) and Cs2CO3 (0.111 g, 0.34 mmole) in a manner as previously described for example 1 to give an off-white solid (0.058 g, 40%). 1H NMR (300 MHz, CD3OD δ 8.27 (1H, d, J=5.4 Hz), 7.68 (1H, d, J=8.6 Hz), 7.59 (1H, s), 7.24 (1H, d, J=1.9 Hz), 7.17 (1H, s), 6.96 (1H, s), 6.90 (1H, dd, J=1.9, 8.6 Hz), 6.50 (1H, d, J=5.4 Hz), 3.87 (3H, s), 3.58 (3H, s), 3.01 (2H, m), 2.85 (3H, s), 1.14 (3H, m). HRMS (MH+): Calcd: 446.1655. Found: 446.1651.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20](O)=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[CH3:31][O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH2:35]>C(Cl)Cl>[CH3:2][C:1]([CH3:3])([O:5][C:6]([NH:8][CH:9]([C:20]([NH:35][C@@H:34]([C:33]([O:32][CH3:31])=[O:37])[CH3:36])=[O:21])[CH2:10][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])=[O:7])[CH3:4]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Racemic t-butoxycarbonyl 2,6-dimethyltyrosine (3.9 g, 10 mmol) was dissolved in 30 ml of CH2Cl2 by adding 1.12 ml (10 mmol) of NMM. After bringing this mixture to reflux it was cooled to -30° C. and 1.32 ml (10 mmol) of IBCF were added to this stirred solution. The temperature was allowed to rise to -15° C. and then lowered to -50° C. (D)alanine methyl ester hydrochloride (1.54 g, 11 mmol) was added to the solution followed by 1.3 ml (11 mmol) of NMM. The mixture was allowed to warm to room temperature and stand for 16 h. The majority of the CH2Cl2 was removed under reduced pressure. Ethyl acetate (EtOAc, 200 ml) was added and this solution was washed twice with 100 ml portions of 0.5 molar KHSO4, once with 100 ml of H2O and dried over MgSO4. Removal of all solvent gave 3.9 g of the mixture of diastereomers. Recrystallization of this material from Skelly B(hexanes)/CH2Cl2 produced 1.6 g (4.2 mmol) of diastereomer F. Removal of the solvent from the filtrate gave 1.3 g (3.3 mmol) of diastereomer S contaminated by less than 10% of diastereomer DF. The mixture of diastereomers or either of the separated diastereomers were used in subsequent examples without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([S:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[NH2:12][C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8][CH2:9][CH2:10][OH:11]
Reactant: Nc1cccc(SCCO)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(SCCO)c1N
Yield: 86.2 %

Procedure:
2-(3-Amino-2-nitro-phenylsulfanyl)-ethanol (1.02 g, 4.8 mmol) was reduced by hydrogenation using 45 psi of H2 with 10% Pd—C (180 mg) in EtOAc (25 mL) for 6 h. After filtering through Celite, solvent was removed in vacuo. Purification by silica gel chromatography (EtOAc) gave 762 mg (87%) of 2-(2,3-diamino-phenylsulfanyl)-ethanol as a faintly yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.98 (dd, 1H, J=7.5, 1.5 Hz), 6.60-6.72 (m, 2H), 3.65 (t, 2H, J=5.7 Hz), 3.55 (br s, 5H), 2.91 (t, 2H, J=5.7 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24]C(=O)N[C:21]2=[O:26])=[CH:17][CH:16]=1)[CH3:11].Cl.[OH-:30].[Na+]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH:20]([SH:24])[C:21]([OH:26])=[O:30])=[CH:27][CH:28]=1)[CH3:11]
Reactant: [OH-]
Reactant: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1nc2ccccc2o1
Agent: Cl
Agent: [Na+]
Product: CN(CCOc1ccc(CC(S)C(=O)O)cc1)c1nc2ccccc2o1

Procedure:
A solution of 5-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]benzyl]-2,4-thiazolidinedione (Eur. Patent Appl., Publication No. 0306228) (1.0 g) in 10% aqueous sodium hydroxide solution (25 mL) was heated at reflux under a nitrogen atmosphere for 1.75 hrs. The mixture was cooled, acidified to pH3 with concentrated hydrochloric acid and extracted with ethyl acetate (300 mL). The organic solution was washed with brine (100 mL), dried (MgSO4) and evaporated. The residue was redissolved in boiling ethyl acetate, filtered and allowed to cool and crystallise to afford the title compound, mp 154°-6° C.