Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:8]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:8]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Yield: 87 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 87% of theory, C27H30N6O4S (534.6); Rf value: 0.13 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=535; (M+H+Na)++=279.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=2[Cl:23])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].CN.[NH:26]1[CH:30]=CC=N1.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:23])=[CH:14][C:15]([Cl:22])=[C:16]([S:18]([NH:26][CH3:30])(=[O:20])=[O:19])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: Cn1nc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: c1cn[nH]c1
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 4-chloro-3-(5-chlorosulfonyl-2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole (0.43 g, 1 mmole) in 2 ml tetrahydrofuran was added dropwise to a 40% aqueous methylamine solution dissolved in 20 ml tetrahydrofuran to react the pyrazole derivative with methylamine. After the addition was finished, the reaction was continued further for 30 minutes at room temperature. Then ethyl acetate was added to the reaction product solution to extract the objective product. The extract solution was washed with water, dehydrated, and evaporated to dryness, giving the title compound (0.42 g) in paste form, yield 100%.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol (300 mg, 099 mmol) in ethyl acetate (10 ml) were added 3-phenylpropionyl chloride (220 ml, 1.48 mmol) and saturated aqueous sodium hydrogen carbonate (10 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (321 mg, 75%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:29]#[N:30])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:29]#[N:30])=[O:8])[CH:2]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1cccc(C(=O)C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
m-Toluoyl cyanide was prepared according to the general procedure reported by G. A. Olah et al. [supra]. Under dry conditions, 2.4170 g of m-toluoyl chloride (99%, Aldrich) (15.63 mmol), 40 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 2.4 mL of trimethylsilyl cyanide (18 mmol) were added to a 100-mL round bottom flask. To this solution 0.39 mL of tin (IV) chloride (3.3 mmol) was added. On addition of the tin (IV) chloride the color of the solution changed from clear to yellow. The reaction mixture was stirred for 2 hr at room temperature. After 2 hr of stirring, the color of the solution was dark brown. The reaction was quenched with 120 mL of ice-cold water and then extracted with two 120 mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 120-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield 2.125 g of a dark brown oil. This oil was distilled at 45°-48° C. (0.2 mm) to yield 1.410 g (62%) of m-toluoyl cyanide as a white solid: IR (CCl4) (partial) 2220, 1685, 1600, 1580 cm-1.
Reaction SMILES: [O:1]=[C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]2[C:4]([S:5][C:6]3[CH:20]=[C:19]([CH2:21][C:22]([OH:24])=O)[CH:18]=[CH:17][C:7]=32)=[N:3]1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC>O1CCCC1>[CH3:25][N:27]([CH3:28])[C:22](=[O:24])[CH2:21][C:19]1[CH:18]=[CH:17][C:7]2[N:8]3[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:10][C:2](=[O:1])[N:3]=[C:4]3[S:5][C:6]=2[CH:20]=1
Reactant: O=C(O)Cc1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1ccc2c(c1)sc1nc(=O)cc(-c3ccccc3)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A solution of 3 g of 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetic acid in 40 ml of tetrahydrofuran and 2 g of 1,1'-carbonyldiimidazole were admixed. The mixture was stirred at room temperature for 1 hour until dissolution took place. Excess dimethylamine (30% in ethanol) was added and the mixture was stirred for a further 40 minutes. The solvent was then removed under vacuo and the residue was taken up in dichloromethane and washed with water, bicarbonate solution water then dried over MgSO4, filtered and evaporated to dryness to obtain 1.1 g of N,N-dimethyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetamide as a pale buff solid which was purified by flash chromatography on silica. It had a melting point of 238°-40° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=O)=[CH:9][N:10]=2)[CH:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Brc1ccc2ncc(CN3CCOCC3)n2c1
Yield: 42.4 %

Procedure:
Reflux a solution of 6-bromo-imidazo[1,2-a]pyridine-3-carbaldehyde (J. Med. Chem. 1970, 13(6), 1048-51; 0.45 g, 1.99 mmol), morpholine (1.7 g, 19.9 mmol), and acetic acid (0.12 mL, 1.99 mmol) in toluene (200 mL) for 3 h. Concentrate to dryness and re-dissolve in methanol (100 mL). Add sodium borohydride (0.226 g, 5.99 mmol) in portions and stir for 30 min. Concentrate to ˜25 mL, dilute with saturated aqueous sodium bicarbonate, extract into ethyl acetate, combine and concentrate. Flash chromatography gives the titled compound (0.25 g, 42%). MS ES+ m/e 295.8, 297.8 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.54 (d, J=10 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J=10 Hz, 1H), 3.81 (s, 2H), 3.52 (t, J=4 Hz, 1H), 2.35 (t,J=4 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH2:19][CH2:20]Br)[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:16][O:18][CH2:19][CH3:20])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(Br)cc1C
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 82.3 %

Procedure:
To a solution of 4-bromo-2-methylphenol (9.3 g) in DMF (50 ml) was added potassium carbonate (9.62 g) and then was added dropwise 2.-bromoethyl ethyl ether (7.99 g), and the mixture was stirred at 70° C. for 3 days. To the mixture was added dropwise 2-bromoethyl ethyl ether (1.52 g), and the mixture was stirred at 70° C. for 4.5 hours and cooled. To the mixture was added water, and the mixture was extracted with ether. The organic layer was washed with 1N sodium hydroxide solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was distilled under reduced pressure (3 mmHg, 170° C.) to give colorless oil of 4-bromo-2-methyl-(2-ethoxyethoxy)benzene (10.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH2:25]>O1CCCC1>[CH3:1][O:2][C:3]([CH:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:10]1)[CH2:25][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH2:23])=[O:21]
Reactant: C=C(CBr)c1ccccc1
Reactant: COC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Product: C=C(CC(C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77.9 %

Procedure:
Lithium hexamethyldisilylazide (1.0 M in THF; 7.31 mL, 7.31 mmol) was added to solution of benzyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1.94 g, 6.65 mmol) in tetrahydrofuran (35 mL) at −78° C. After 40 min, [1-(bromomethyl)vinyl]benzene (1.08 mL, 7.31 mmol) was added and the reaction mixture was warmed to ambient temperature. After 18 h, the mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→40% hexanes/ethyl acetate) gave the title compound (2.11 g). MS 408.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:20][C:5]2[NH:6][C:7](=[O:19])[N:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]=[C:38](C(Cl)(Cl)Cl)[O:37][N:36]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-:45].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][C:2]1[S:20][C:5]2[N:6]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[NH:39][C:38](=[O:45])[O:37][N:36]=4)=[CH:25][CH:24]=3)[C:7](=[O:19])[N:8]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A mixture of 6-methyl-3-(2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.25 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.45 g), potassium carbonate (0.15 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and methanol (5 mL). 1N Aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and extracted with chloroform. The obtained chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.18 g, 38%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=2)[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([CH3:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=2)[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cccs2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2cccs2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Hexyl-6-methyl-6-[3-(2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 69, 64 mg, 0.19 mmol) was dissolved in tetrahydrofuran (20 ml) at 0° C. Lithium aluminium hydride (1M in tetrahydrofuran, 0.4 ml, 0.4 mmol) was added under nitrogen and then the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding aqueous sodium hydroxide solution (2N, 0.8 ml), followed by solid isodium hydrogen carbonate and ethyl acetate. The reaction mixture was stirred vigorously and then filtered through Celite®. The filtrate was concentrated in vacuo and the residue chromatographed on silica gel eluting the product with hexane:ethyl acetate (2:1) as a colourless oil (66 mg, 64%).
Reaction SMILES: Br[C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH3:17][C@:16]12[CH2:18][C:19](=[O:20])[C@H:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:21]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12Br
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Yield: 80.6 %

Procedure:
Under argon gas, 1 g of 9α-bromo-11β-hydroxy-4-androstene-3,17-dione is agitated in 5 ml of "Dowtherm" A for 3 minutes at 250° C. To work up the reaction mixture, the solvent is removed by steam distillation, the residue is dried and recrystallized from methylene chloride-isopropyl ether, thus obtaining 635 mg of 4-androstene-3,11,17-trione, mp 214°-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([C:10]([OH:12])=O)[CH:3]=1.C(OC([N:20]1[CH2:25][CH2:24][O:23][C@@H:22]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=2)[CH2:21]1)=O)(C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([C:10]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([C@@H:22]3[O:23][CH2:24][CH2:25][NH:20][CH2:21]3)=[CH:27][C:28]=2[F:33])=[O:12])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Reactant: N#Cc1cc(Cl)cc(C(=O)O)n1
Product: Cl
Product: N#Cc1cc(Cl)cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2F)n1

Procedure:
In analogy to Example 83, step a) using 4-chloro-6-cyano-2-pyridine carboxylic acid (CAS 1060812-13-6) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 1 step h) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 359.1 ([M+H]+)
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](OCC)=[O:42])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)[C:23]([OH:25])=[O:24])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.C(O)(C(F)(F)F)=O.Cl>[O-]CC.[Na+].C(O)C>[CH:1]1([NH:7][C:8](=[O:9])[NH:10][C:41](=[O:42])[CH2:40][CH2:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][C:29]3[CH:28]=[CH:27][C:26]([C:22](=[CH:21][C:15]4[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]([O:12][CH3:11])[CH:14]=4)[C:23]([OH:25])=[O:24])=[CH:31][CH:30]=3)=[CH:38][CH:37]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(C(=Cc3cc(OC)cc(OC)c3)C(=O)O)cc2)cc1
Reactant: NC(=O)NC1CCCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(=O)NC4CCCCC4)cc3)cc2)cc(OC)c1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
Cyclohexylurea (1.3 g, 9 mmol) was dissolved in sodium ethoxide in ethanol (21% w/w, 3 mL) at 75° C. To this solution 5 was added (0.5 g, 1.1 mmol) in one lot. The resulting mixture was stirred at 75° C. for 5 min, then cooled quickly to 40-50° C. TFA (0.5 mL) was added and then 5% aqueous HCl (1N, 0.6 mL). After stirring at room temperature for 1 hr, the mixture was left overnight at 4° C. The solid separated was filtered and refluxed in ethyl acetate (4 mL) for 20 min. The mixture was allowed to cool to room temperature, filtered and the crude product was purified by silica gel chromatography using hexane-ethyl acetate (1:1). Yield: 0.27 g, 45%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([S:12](=[O:15])(=[O:14])[NH2:13])=[C:10]([NH2:16])[C:9]([CH3:17])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl[C:19](OCC)=O.[CH:24]1([N:31]2[CH2:35][CH2:34][CH2:33][C:32]2(C)[CH2:36][NH2:37])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N>O.Cl.C(N(CC)CC)C.CC(C)=O>[CH:24]1([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[CH:36]([CH3:19])[NH:37][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([CH3:17])[C:10]([NH2:16])=[C:11]([S:12](=[O:15])(=[O:14])[NH2:13])[C:3]=2[O:2][CH3:1])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC1(CN)CCCN1C1CCCCCC1
Reactant: CCOC(=O)Cl
Reactant: COc1c(C(=O)O)cc(C)c(N)c1S(N)(=O)=O
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: COc1c(C(=O)NC(C)C2CCCN2C2CCCCCC2)cc(C)c(N)c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
6.5 g of 2-methoxy-4-amino-5-methyl sulphamoyl benzoic acid, 75 ml of acetone, 14 ml of water and 3.5 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The solution is cooled to between 0° and +5° C. and 2.7 g of ethyl chloroformate is added drop by drop. The reaction medium is agitated for 45 minutes at room temperature then cooled to 0° C. again. 6.8 g of 1-cycloheptyl methyl-2-amino methyl pyrrolidine is added drop by drop. The medium is reacted for 2 hours then left to stand. The solvents are expelled and the solid residue dissolved in 50 ml of water and 20 ml of hydrochloric acid (density 1.18). The suspension obtained is made alkaline with ammonia. It is extracted 3 times with 50 ml of methylene chloride. The organic phase is washed twice with 50 ml of water, dried over magnesium sulphate and filtered. The filtrate is evaporated to dryness under vacuum. The residue is dissolved in 80 ml of water and 20 ml of hydrochloric acid (density 1.18). The hydrochloride crystallises. It is drained, washed with water and dried in an oven at 50° C.
Reaction SMILES: N[C:2]1[C:6]([Br:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.[N:14]([O-])=O.[Na+].C(O)(=O)C.[S:22](=[O:24])=[O:23]>Cl.ClCCCl.O>[Br:7][C:6]1[C:2]([S:22]([NH2:14])(=[O:24])=[O:23])=[N:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=1
Reactant: O=S=O
Reactant: Nc1nn(-c2ccccn2)cc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: NS(=O)(=O)c1nn(-c2ccccn2)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
3 g of 3-amino-4-bromo-1-(2-pyridyl)pyrazole was suspended in 60 ml of hydrochloric acid, to which 2.5 ml of an aqueous solution containing 1.2 g of sodium nitrite was added dropwise at -10° to -5° C. to prepare a solution of diazonium salt. This solution of diazonium salt was added dropwise at 5° C. to 30 ml of acetic acid saturated with sulfur dioxide containing 0.5 g of cuprous chloride. After stirring at room temperature for 20 minutes, 100 ml of water and 300 ml of 1,2-dichloroethane were added and stirred to separate an organic layer. To the organic layer, added was 10 ml of 28% ammonia water, followed by vigorous stirring at room temperature for 1 hour. Thereafter, solvent was evaporated under reduced pressure and 200 ml of ethyl acetate was added. After further stirring, insolubles were filtered off and ethyl acetate was evaporated to obtain 2.2 g of the title compound as a crude product. This crude product was purified by a silica gel column chromatography (developed with ethyl acetate) to obtain 0.5 g of the title compound as a pure product. m.p.: 201° to 203° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[S:11][CH:12]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:17][CH2:18]2)[S:11][CH:12]=1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-(4-(2-fluorophenyl)thiazol-2-yl)piperazine (0.13 g, 0.50 mmol), triethylamine (0.10 mL, 0.75 mmol), and CH2Cl2 (1.7 mL) was cooled in an ice bath, and isobutyl chloroformate (0.10 mL, 0.75 mmol) was added. The reaction was stirred at 0° C. for 20 min, diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to yield isobutyl 4-(4-(2-fluorophenyl)thiazol-2-yl)piperazine-1-carboxylate. LC/MS: m/z 364.1 (M+H)+ at 3.87 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.[C:13]1([CH2:19][O:20][C:21](=[O:36])[NH:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH2:34]O)[CH:32]=3)[NH:27][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[C:13]1([CH2:19][O:20][C:21](=[O:36])[NH:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][NH2:1])[CH:32]=3)[NH:27][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(NCCc1c[nH]c2ccc(CO)cc12)OCc1ccccc1
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reaction time: 4 h

Procedure:
A solution of diethyl azodicarboxylate (1.48 g) in dry tetrahydrofuran (THF) (8 ml) was added over 2 min., keeping the temperature at 25°, to a stirred solution of phenylmethyl[2-[5-(-hydroxymethyl)-1H-indol-3-yl]ethyl]carbamate (2.6 g), triphenylphosphine (2.35 g) and phthalimide (1.75 g) in THF (20 ml). After 4 h, the solvent was evaporated in vacuo and the residue was dissolved in a solution of hydrazine hydrate (15 ml) in ethanol (100 ml).