Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][N:25]([NH2:27])[CH3:26].CO.C(Cl)(Cl)Cl>CO.CN(C=O)C>[Cl:1][CH:2]1[C:10](=[C:11]=[N:27][N:25]([CH3:26])[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CN(C)N
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN(C)N=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 100 mg, 0.26 mmol) was dissolved in MeOH (5 mL) to which was added asym-dimethylhydrazine (0.5 mL). The resulting solution was stirred at room temperature for 16 h, then evaporated under vacuum to yield a yellow residue. The residue was dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on silica gel with 10% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield 87 mg (78%) of 4.35 as a white powder: mp dec >170° C.; Rf0.4 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.36 (s, 1H), 7.35 (s, 1H), 5.91 (d, 1H), 5.36-5.31 (m, 2H, D2O exch.), 5.21 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.96 (d, 1H), 3.70 (b, 2H), 2.93 (s, 6H). 13C-NMR (125 MHz, DMSO-d6): δ 133.01, 125.64, 125.62, 125.37, 124.26, 124.04, 121.97, 114.85, 110.14, 88.58, 85.75, 71.18, 69.66, 61.14, 42.58. HRMS (ES) m/z calcd. for C16H18Cl3N3O4□Na 444.0261, found 444.0269. Anal calcd for C16H18Cl3N3O4: C, 45.46; H, 4.29; N, 9.94. Found: C, 45.79; H, 4.61; N, 10.06.
Reaction SMILES: C(OC([N:8]1CCC[C@H]1C(O)=O)=O)(C)(C)C.[ClH:16].NC1C2C(=CC(CN)=CC=2)C=CN=1.C([N:33]([CH2:37][CH3:38])[CH:34]([CH3:36])[CH3:35])(C)C.F[P-](F)(F)(F)(F)F.[N:46]1(OC(N(C)C)=[N+](C)C)[C:50]2[CH:51]=[CH:52]C=[CH:54][C:49]=2N=N1>CN(C)C=O>[ClH:16].[NH2:8][C:37]1[C:38]2[C:54](=[CH:49][C:50]([NH2:46])=[CH:51][CH:52]=2)[CH:36]=[C:34]([CH3:35])[N:33]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccc2c(N)nccc2c1
Solvent: CN(C)C=O
Product: Cc1cc2cc(N)ccc2c(N)n1
Reaction time: 0.08 h

Procedure:
To a stirred solution of N-tert-butoxycarbonyl-L-proline, Boc-Pro-OH, (6.73 g, 31.25 mmol) in anhydrous N,N-dimethylformamide (100 ml) under an argon atmosphere was added finely ground 1-amino-6-aminomethylisoquinoline hydrochloride (10.0 g, 40.63 mmol) and N,N-diisopropylethylamine (16.17 g, 125.00 mmol). After stirring the slurry for 15 minutes at room temperature 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (17.67 g, 46.88 mmol) was added, portionwise, over 5 minutes, eventually resulting in complete dissolution of the suspended 1-amino-6-amino-methylisoquinoline hydrochloride. The reaction mixture was stirred at room temperature under an argon atmosphere for a further 90 minutes after which time a yellow precipitate of (S)-2-[[[(1-amino-6-isoquinolyl)methyl]amino]carbonyl]-1-pyrrolidine carboxylic acid 1,1-dimethylethyl ester hydrochloride (b) had formed. The precipitate was collected by filtration, washed with dichloromethane (300 ml) until the filtrate was colourless, and then dried under vacuum to give 7.8 g (56%) of title compound (94% pure by HPLC-Luna C18(2) 46×30 mm, gradient, mobile phase acetonitrile:water, 5-100%/4 min, constant 0.1% trifluoroacetic acid). Further product was isolated from the filtrate by evaporating under vacuum to remove dimethylformamide and excess diisopropylethyl amine and adding 500 ml dichloromethane. The resulting precipitate was removed by filtration, washed with dichloromethane (300 ml) and dried under vacuum to give 4.6 g (33%) (91% pure by HPLC-Luna C18(2) 46×30 mm, gradient acetonitrile:water, 5-100%/4 min, constant 0.1% trifluoroacetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[CH2:12]3)[C:4]=2[CH:3]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:29])[C@@H:13]([CH2:17][CH2:18][O:19][CH3:20])[CH2:12]3)[C:4]=2[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(Cl)cc32)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(Cl)cc32)CCN1C
Product: Cl
Reaction time: 0.17 h
Yield: 252.8 %

Procedure:
Combine (S)-2-chloro-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.474 g, 1.27 mmol) and 37% formaldehyde solution (0.1 mL, 1.34 mmol) in 1,2-dichloroethane (20 mL). Stir for 10 minutes and add sodium triacetoxy borohydride (0.542 g, 2.55 mmol). Stir an additional 30 minutes and then pour solution onto saturated sodium bicarbonate solution. Extract with methylene chloride to give 0.555 g of the crude product. Silica gel chromatography, eluting with methylene chloride:methanol (100:5), gives 0.490 g of the title compound as the free base. The dihydrochloride salt precipitates in ethyl acetate as a solid: mp 205° C.; mass spectrum (ion spray): m/z=385 (M+1).
Reaction SMILES: C(OC)(=O)C1C=CC=CC=1.Cl[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.[I-:26].[Na+]>CC(C)=O.C(OCC)C>[I:26][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(OCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: COC(=O)c1ccccc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCI)cc1

Procedure:
4-[3-4-[(2-Benzothiazolyl )carbonyl]-1-piperidinyl]propoxy]benzoic acid, methyl ester ##STR22## Dissolve 4-(3-chloropropoxy)benzoic acid, methyl ester (6.97 g, 30.5 mmol) in anhydrous acetone (100 mL) and add powdered sodium iodide (16.0 g, 107 mmol). Heat at reflux under an argon atmosphere for 38 hours. Dilute with ethyl ether (100 mL) and filter through Celite® filter aid. Wash the filtrate with water and brine, then dry (MgSO4). Evaporate the solvent in vacuo to give 4-(3-iodopropoxy)benzoic acid, methyl ester as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)=[CH:12][C:11]([C:21](O)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=NC=C(F)C=3)=CC([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=3)=[CH:12][C:11]([C:21]([N:46]3[CH2:44][CH2:47][NH:48][C:49](=[O:51])[CH2:50]3)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cncc(F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CCN1

Procedure:
100 mg (0.30 mmol) of the compound of Example 60A is reacted analogously to the synthesis of the compound of Example 98 with 33 mg (0.33 mmol) of 2-oxopiperazine. 92 mg (74% of theory) of the title compound is obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:5][CH:4]=1.O1[CH:20]=[CH:19][C:18](=[O:21])[CH:17]=[CH:16]1.C(O)C>O>[O:21]=[C:18]1[CH:19]=[CH:20][N:2]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3[S:13][C:12](=[O:14])[NH:11][N:10]=3)=[CH:7][CH:8]=2)[CH:16]=[CH:17]1
Reactant: Nc1ccc(-c2n[nH]c(=O)s2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1ccn(-c2ccc(-c3n[nH]c(=O)s3)cc2)cc1

Procedure:
A mixture of 5-(4-aminophenyl)-1,3,4-thiadiazol -2(3H)-one hydrochloride (1,25 g). 4H-pyran-4-one (0.58 g), ethanol (10 ml) and water (50 ml) was stirred under reflux under nitrogen for 31/2 hours. The cooled reaction mixture was filtered and the collected orange solid was washed with aqueous potassium hydrogen carbonate and water and was dried. The crude product (1,35 q) was treated with boiling dimethylformamide (200 ml) and the resultant suspension was cooled and filtered. The collected solid was washed with ethanol and ether, dried and suspended in water (100 ml). Sufficient aqueous sodium hydroxide (2N) was added to the suspension to form a solution which was filtered. The filtrate was acidified to pH 6 with hydrochloric acid which caused the precipitation of the title compound as a yellow solid, 0.96 g, m.p. 343-4° C. (decomp).
Reaction SMILES: C([SiH](CC)CC)C.B(F)(F)F.CCOCC.[C:17]([O-:20])([OH:19])=[O:18].[Na+].ClCCl.[C:25](#[N:27])[CH3:26]>>[C:25](#[N:27])[CH3:26].[C:17](=[O:18])([O-:20])[O-:19].[NH4+:27].[NH4+:27]
Reactant: O=C([O-])O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCl
Product: O=C([O-])[O-]
Product: [NH4+]
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
One-step procedure: To a solution of 20 mg of cyclic depsipeptide according to formula (II) and 0.027 mL triethylsilane in 2 mL of dichloromethane/acetonitrile (1:1) at −50° C. 0.014 mL of boron trifluoride etherate were slowly added. The reaction mixture was allowed to warm up to −5° C. and kept at this temperature for additional 30 minutes, poured into a saturated NaHCO3 solution, and was extracted with EtOAc. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification of the residue obtained by HPLC (XTerra [5 cm]; acetonitrile/ammonium carbonate buffer pH10 gradient) provided 9.8 mg of a derivative of the cyclic depsipeptide according to formula (II) wherein the Ahp has been converted into 3-amino-piperidin-2-one. ESI MS: 935.36 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 35 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
3.8 g (25 mmol) of methyl 5-aminopyridine-2-carboxylate are dissolved in 75 ml of anhydrous pyridine and treated in portions with 5.8 g (30 mmol) of 4-fluorobenzenesulfonyl chloride, the temperature of the reaction solution increasing to 35° C. After 1 h, the mixture is concentrated in vacuo, and the residue is triturated with water, filtered off with suction, washed with water and dried. 7.3 g of product are obtained, M.p. 183°-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5](C(OC)=O)=[CH:4][N:3]=1.[CH3:12][Mg]Cl.[Cl-].[NH4+].C([O:20][CH2:21][CH3:22])(=O)C>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]([OH:20])([CH3:22])[CH3:12])=[CH:10][CH:11]=1
Reactant: CCOC(C)=O
Reactant: C[Mg]Cl
Reactant: COC(=O)c1ccc(N)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(N)nc1
Reaction time: 15 h

Procedure:
To a solution of 0.7 g of methyl 6-aminonicotinate in 65 mL of THF, cooled to 10° C. and under argon, are added dropwise 15 mL of a 3M solution of methylmagnesium chloride in THF. The reaction mixture is stirred for 15 hours, while allowing the temperature to rise to 20° C., and is then cooled again in an ice bath. 100 mL of saturated ammonium chloride solution and then 200 mL of ethyl acetate are added slowly. The organic phase is dried and concentrated to dryness. The residue is taken up in ethyl acetate. The precipitate is filtered off by suction and dried to give 0.4 g of 2-(6-aminopyridin-3-yl)propan-2-ol in the form of a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O:10][C:11](=O)[CH2:12][C:13]([CH2:15][Cl:16])=O)C>>[Cl:16][CH2:15][C:13]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[C:11](=[O:10])[CH:12]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccccn1
Product: O=c1cc(CCl)nc2ccccn12
Temperature: 120 °C
Yield: 98.9 %

Procedure:
15 g (159.4 mmol) of 2-aminopyridine (10) was combined with approximately 80 g of polyphosphoric acid and heated to 120° C. to allow stirring. To the resulting solution was added slowly 30.5 mL (223.2 mmol) of ethyl-4-chloroacetoacetate and stirred at 120° C. under nitrogen for two hours. The hot reaction mixture was then poured over 1500 mL of ice water and stirred vigorously. The aqueous layer was separated and extracted with methylene chloride (6×, approximately 6 L). The combined organic layers were washed with saturated NaHCO3 and brine and dried over MgSO4 and activated carbon. The solvent was removed in vacuo yielding 30.7 g (157.7 mmol, 99%) of 2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (11) as a white solid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[N:21]1([C:7]([C@H:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C1CC[C@@H](C(=O)N2CCOCC2)N1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
The reaction vessel is charged with 30 g L-pyroglutamic acid and 4.71 g 1-hydroxybenzotriazole hydrate. The solids are then suspended in 190 ml anhydrous acetonitrile and the mixture is then heated to 45° C. Subsequently, 20.24 ml morpholine is added via a dropping funnel within 20 min, and the dropping funnel is then washed with 5 ml anhydrous acetonitrile. The resulting mixture is then heated to 65° C. and 29.32 g N-N′-diisopropylcarbodiimide added within 1 h via a dropping funnel. After complete addition, the dropping funnel is washed with 5 ml anhydrous acetonitrile and the reaction mixture is stirred at 65° C. for an additional 30 min. The resulting suspension is then cooled to ambient temperature, filtered and the filter cake washed with 3×30 ml acetonitrile. The filtrate is concentrated under heating and reduced pressure to approx. ½ of its original volume and the residue is then seeded with 16 mg (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one. Concentration under reduced pressure is continued until approx ⅓ of the original volume of the filtrate is reached. While further concentrating the filtrate under reduced pressure and removing approx. 95 ml of distillate, simultaneously 210 ml 2-methyltetrahydrofuran is added. The suspension is then cooled to 0° C. and the solids are isolated by filtration. The filter cake is washed with 3×20 ml icooled 2-methyltetrahydrofuran and dried at 55° C. under vacuum to give 42.54 g of (S)-5-(morpholine-4-carbonyl)pyrrolidine-2-one as fine white crystals (98.0% purity by HPLC, ee (HPLC)>99.6% [4-a, R1=H; R4=morpholine]).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])[CH3:16])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1F
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5.10 g (24.9 mmol) (4-bromo-2-fluoro-phenyl)-methanol in 30 mL DMF is added subsequently 4.06 g (26.1 mmol) tert-butyl-chloro-dimethyl silane, 2.57 g (37.3 mmol) imidazole and 456 mg (3.73 mmol) DMAP. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is diluted with EtOAc, washed five times with water and the combined organic phase is dried over MgSO4, filtered and the solvent is evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[CH:14]=O.[CH:21]([NH2:23])=[O:22]>CO.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[F:11][C:12]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:13]=1[CH:14]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[NH:23][CH:21]=[O:22]
Reactant: NC=O
Reactant: O=Cc1cc(F)ccc1F
Reactant: Cc1ccc(S(=O)O)cc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2cc(F)ccc2F)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a round bottom flask was added 4-methylbenzenesulfinic acid (5.00 g, 32.0 mmol, Preparation #3, Step A), (1S)-(+)-10-camphorsulfonic acid (0.074 g, 0.32 mmol), 2,5-difluorobenzaldehyde (3.83 mL, 35.2 mmol) and formamide (6.38 mL, 160 mmol). The reaction mixture was stirred at about 65° C. for about 16 h. The reaction mixture had solidified overnight. The solid was broken up and suspended in MeOH. The chunks of solid were ground to a powder with a spatula and the solid was filtered and washed with MeOH. The filter cake was dried under vacuum at about 60° C. to give the title compound (5.92 g, 56.8%) as a white powder. LC/MS (Table 1, Method a) Rt=2.37 min; MS m/z: 343.1 (M+NH3)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([S:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.[F:36][C:37]([F:44])([F:43])[C:38](OCC)=[O:39]>CO>[F:36][C:37]([F:44])([F:43])[C:38]([NH:21][C@@H:19]([CH3:20])[C@H:18]([S:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:39]
Reactant: C[C@H](N)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-ylthio)-1-phenylpropan-2-amine (0.024 g, 0.06 mmol) in MeOH (2.5 mL), 1,1,3,3-tetramethylguanidine (0.056 mL, 0.45 mmol) and ethyl trifluoroacetate (0.114 mL, 0.95 mmol) was added and the mixture was stirred at rt O/N and than submitted to purification on HPLC. The relevant fractions were collected freeze dried to give 16 mg of product (53% yield) which was analysed by LC/MS and NMR.
Reaction SMILES: Cl[CH2:2][C:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH2:5][O:4]1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:3]([OH:4])([CH2:5][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:2][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)=[CH:9][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: ClCC1(COc2ccc(Cl)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(COc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1

Procedure:
9.4 g (0.04 mole) of 2-chloromethyl-2-(4-chlorophenoxymethyl)oxirane are added dropwise to a mixture of 13.6 g (0.2 mole) of 1,2,4-triazole and 13.8 g (0.1 mole) of potassium carbonate in 200 ml of acetone with stirring. The mixture is allowed to stir at room temperature for 15 hours and then under reflux for 22 hours. The reaction mixture is then filtered cold and the filtrate is evaporated in vacuo. The oily residue is dissolved in chloroform, and the solution is washed with water, dried over sodium sulphate and purified by chromatography (silica gel 60, Merck, chloroform/methanol=20:1). 5.8 g (43%) of theory) of 2-(4-chlorophenoxymethyl)-1,3-di(1,2,4-triazol-1-yl)-2-hydroxypropane of melting point 99° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 36.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-5-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.08 mmol) obtained in step 4 and ethanesulfonamide (36 mg, 0.33 mmol), the title compound (17 mg, 36%) was obtained.
Reaction SMILES: [P:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][NH2:24])=[O:22]>CO.C(Cl)Cl>[P:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[N:24][NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([Cl:17])[CH:19]=2)=[CH:13][CH:14]=1)([S:5][CH2:6][CH3:7])([O:3][CH3:4])=[O:2]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: CCSP(=O)(OC)Oc1ccc(C=O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCSP(=O)(OC)Oc1ccc(C=NNC(=O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O-methyl S-ethyl O-(4-formylphenyl) thiophosphate (0.02 mole) in methanol (50 ml) and 3-chlorobenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product O-methyl S-ethyl O-[4-(3-chlorobenzoylhydrazonomethyl)phenyl] thiophosphate.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-])=O)[CH:17]=1)[CH3:2]>[Pd].CCOC(C)=O>[NH2:23][C:18]1[CH:17]=[C:16]([C:4]2[N:3]([CH2:1][CH3:2])[C:11]3[C:6]([C:5]=2[C:14]#[N:15])=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: CCn1c(-c2ccc(O)c([N+](=O)[O-])c2)c(C#N)c2ccc(OC)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1c(-c2ccc(O)c(N)c2)c(C#N)c2ccc(OC)cc21
Reaction time: 1 h
Yield: 90.8 %

Procedure:
1-Ethyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-1H-indole-3-carbonitrile (369 mg, 1.1 mmol), prepared as in example 1Gd, was combined with EtOAc (20 mL) and Pd/C (150 mg, 10%). This mixture was hydrogenated at 30 p.s.i. for 1 h. This was filtered through celite. The filtrate was concentrated and triturated with ether to yield 2-(3-amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (307 mg, 91%), compound 322, as a white solid.