Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])C(=O)[NH:9]2)=[CH:5][CH:4]=1)[CH3:2].[OH-:14].[Na+].OO.Cl>>[CH2:1]([C:3]1[CH:11]=[C:10]([NH2:9])[C:6](=[CH:5][CH:4]=1)[C:7]([OH:13])=[O:14])[CH3:2]
Reactant: CCc1ccc2c(c1)NC(=O)C2=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: CCc1ccc(C(=O)O)c(N)c1
Temperature: 50 °C

Procedure:
In a 500 ml flask, was placed 16.84 gm of 6-ethyl isatin which was covered with 216 ml of 1.5M sodium hydroxide solution. With stirring, the mixture was warmed to 50° C. Heating was discontinued and the solution was treated with a 30% solution of hydrogen peroxide (24 ml) which was added at such a rate to maintain the temperature at between 50° to 65° C. The mixture was left to slowly cool to room temperature and was then acidified to pH 4 with concentrated hydrochloric acid. The precipitated product was then collected by filtration: mp. 117°-120° C.; yield 8.93 gm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]2.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5]2
Reactant: Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1ccc2cc(CBr)ccc21
Yield: 59.8 %

Procedure:
A solution of tert-butyl 5-methylindole-1-carboxylate (2.07 g, 9.0 mmol) in CCl4 (50 mL) was treated with N-bromosuccinimide (1.60 g, 9.0 mmol) and benzoyl peroxide (75% in H2O, 276 mg, 9.0 mmol), refluxed for 3 h, concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (20:1)] to give the title compound (1.67 g, 60%) as an orange oil: NMR δH (400 MHz, CDCl3) 8.11 (1H, br d, J 8.5 Hz), 6.72 (1H, d, J 3.5 Hz), 7.59 (1H, d, J 1.5 Hz), 7.35 (1H, dd, J 8.5, 1.5 Hz), 6.54 (1H, d, J 4.0 Hz), 4.64 (2H, s) and 1.67 (9H, s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([N:23]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:15]=2)[CH2:10][CH2:9]1.[F:36][C:37]1[CH:38]=[C:39]([S:44][C:45]2[CH:46]=[C:47]3[C:53]([NH2:54])=[N:52][NH:51][C:48]3=[N:49][CH:50]=2)[CH:40]=[C:41]([F:43])[CH:42]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C1(C)C=CC=CC=1.O1CCCC1>[F:36][C:37]1[CH:38]=[C:39]([S:44][C:45]2[CH:46]=[C:47]3[C:53]([NH:54][C:18](=[O:20])[C:17]4[CH:21]=[CH:22][C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH3:7])[CH2:13][CH2:12]5)=[CH:15][C:16]=4[N:23]([CH:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[C:24](=[O:29])[C:25]([F:26])([F:27])[F:28])=[N:52][NH:51][C:48]3=[N:49][CH:50]=2)[CH:40]=[C:41]([F:43])[CH:42]=1
Reactant: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Reactant: Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
0.95 ml (11.21 mmol) of oxalyl chloride and 2 drops of anhydrous dimethylformamide are added to 2.97 g (5.61 mmol) of a solution of 4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid in 95 ml of dichloromethane. The reaction mixture is stirred for 2 hours at room temperature. The solvents are evaporated, the solid formed is taken up in toluene and the solvent evaporated. This operation is repeated three times until a white solid is obtained. The acid chloride is dissolved in 35 ml of anhydrous tetrahydrofuran at −20° C. and then the solution formed is added to a solution containing 1.56 g (5.61 mmol) of 5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine and 3.71 ml (21.30 mmol) of N-ethyl-N-isopropylpropan-2-amine in 30 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 3 hours at −20° C. and then overnight at room temperature. The precipitate obtained is filtered and rinsed with tetrahydrofuran and water and then dried to yield 2 g (53%) of N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>C(O)C.[Pd]>[C:13]1([C:4]2[N:1]=[C:36]([CH2:32][NH:1][C@H:4]3[C:13]4[C:8](=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:10]=[CH:11][CH:12]=4)[CH2:7][CH2:6][CH2:5]3)[O:35][C:34]=2[C:33]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of (1R)-1-azido-5-t-butyldiphenylsilyloxy-1,2,3,4-tetra-hydronaphthalene (0.95 mg) and 10% Pd/C (0.2 g) in a mixture of ethanol (20 ml) and THF (20 ml) was stirred under H2 for 2 hours. The catalyst was filtered off and filtrate was evaporated. The residue was dissolved in DMF (10 ml) and then K2CO3 (600 mg) and (4,5-diphenyloxazol-2-yl)methyl bromide (700 mg) were added thereto. After being stirred for 2 hours at room temperature, the mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-(4,5-diphenyloxazol-2-yl)methylamino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.4 g). MS (m/z): 636 (M+ +1) IR (Neat): 3400 cm-1NMR (CDCl3, δ): 1.09 (9H, s), 1.6-2.2 (4H, m), 2.6-3.2 (2H, m), 3.91 (1H, m), 4.06 (2H, s), 6.30 (1H, d, J=8 Hz), 6.72 (1H, t, J=8 Hz), 6.93 (1H, d, J=8 Hz), 7.2-7.8 (10H, m)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH2:6]([O:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[S:28](=[O:33])(=[O:32])[N:29]([CH3:31])[CH3:30])[NH:17][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>C(C(C)=O)C>[CH2:6]([O:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[S:28](=[O:33])(=[O:32])[N:29]([CH3:31])[CH3:30])[N:17]([CH2:2][CH2:3][CH2:4][Cl:5])[C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(OCc3ccccc3)cc1N2
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Product: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(OCc3ccccc3)cc1N2CCCCl
Yield: 108.8 %

Procedure:
2-Benzyloxy-6-dimethylsulphamoyl-10-(3-chloro-propyl)phenothiazine (m.p. 124°-126°C.; 89.0 g.) is prepared by reacting 1-bromo-3-chloropropane (92 g.) with 2-benzyloxy-6-dimethylsulphamoylphenothiazine (69.0 g.) in the presence of powdered potassium hydroxide (16.4 g.) in methyl ethyl ketone (230 cc.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[C:10]2=[O:26])=[CH:5][CH:4]=1.[CH3:27]I>CS(C)=O>[CH3:25][O:24][C:22]([CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH3:27])=[CH:8][CH:7]=3)[C:10]2=[O:26])=[CH:15][CH:16]=1)=[O:23]
Reactant: CI
Reactant: COC(=O)CCc1ccc(N2CCN(c3ccc(CN)cc3)C2=O)cc1
Solvent: CS(C)=O
Product: CNCc1ccc(N2CCN(c3ccc(CCC(=O)OC)cc3)C2=O)cc1

Procedure:
Prepared from 1-(4-aminomethyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one by alkylation with methyliodide in dimethylsulphoxide.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[C:11](=O)([O-])[O-:12].[Na+].[Na+].Cl>O.CC(C)=O>[OH:6][CH:5]([C@H:3]1[O:4][C:11](=[O:12])[NH:1][CH2:2]1)[CH:7]([OH:8])[CH2:9][OH:10]
Reactant: O=C([O-])[O-]
Reactant: NC[C@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1NC[C@@H](C(O)C(O)CO)O1
Reaction time: 8 h
Yield: 28.2 %

Procedure:
1-Amino-1-deoxy-D-ribitol (2.1 g, 0.014 mole prepared from D-ribose as described by Wolfron et. al. J. Org. Chemi. 23, 571 [1958]) was dissolved in water (30 ml), and sodium carbonate (2.9 g, 28 mole) and a solution of p-nitrophenyl-chloroformate (3.2 g, 0.016 mole) in acetone (10 ml) were added at 0° C. The solution was stirred and allowed to stand at room temperature overnight. The solution was acidified with 5N hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase was evaporated and the residue extracted with ethanol. Chromatography on silica eluting with a gradient of chloroform and ethanol gave 5-(S)-(1',2',3'-trihydroxypropyl)-1,3-oxazolidin-2-one (0.7 g) an an oil.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[O:8][C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=3[N:24]=2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCCC1Cl
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Product: c1ccc(CN2CCC(c3nc4c(o3)CCCC4)CC2)cc1
Temperature: 160 °C
Yield: 70.9 %

Procedure:
A mixture of 2.43 g 2-chlorocyclohexanone and 1 g 1-benzylpiperidine-4-carboxylic acid amide (WO2005/61483) is heated to 160° C. in the microwave until there is no further reaction. The product is purified by chromatography. 963 mg of the product are obtained. Analytical HPLC-MS (method B): RT=1.28 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:13]([P:16](=[O:22])([CH2:19][CH2:20][CH3:21])[CH2:17][OH:18])[CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[CH2:13]([P:16](=[O:22])([CH2:19][CH2:20][CH3:21])[CH2:17][O:18][S:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:11])[CH2:14][CH3:15]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: CCCP(=O)(CO)CCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCP(=O)(CCC)COS(=O)(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A solution of 7.20 g of 2-chloro-6-methylbenzenesulfonyl chloride dissolved in 30 ml of THF was added dropwise over 30 minutes to a reaction mixture 5.80 g of di-n-propyl(hydroxymethyl)-phosphine oxide, (Example 23), 30 ml of THF, and 4.04 g of triethylamine. The addition caused a mild exotherm and the reaction was allowed to stir at room temperature over the weekend. Most of the THF was removed and the resulting material was partitioned between 200 ml of ethyl acetate and 70 ml of water, the organic phase rewashed with an additional 70 ml of water, dried with magnesium sulfate, filtered and concentrated to yield 6.5 g of the crude desired product as a dark tan oil. The crude product was diluted with 4 ml of methylene chloride and flash chromatographed on Merck silica gel (230-400 mesh) using blends of isopropanol and ethyl acetate, similar fractions were combined and concentrated under reduced pressure to yield the partially purified product. This material was dissolved in 150 ml of ethyl acetate, washed with three 50 ml portions of water, dried with magnesium sulfate, filtered and concentrated to yield 2.4 g of the desired product as a white solid: melting point 51°-53° C.
Reaction SMILES: [N+](C1C=C(C=CC=1)C([N:9]1[CH:13]=[C:12]([C:14]23[CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)[N:11]=[N:10]1)=O)([O-])=O.N>CO>[N:9]1[NH:10][N:11]=[C:12]([C:14]23[CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)[CH:13]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)n1cc(C23CCN(CC2)C3)nn1
Agent: N
Solvent: CO
Product: c1n[nH]nc1C12CCN(CC1)C2
Reaction time: 72 h
Yield: 84.4 %

Procedure:
A solution of 4-(1-m-nitrobenzoyl-1,2,3-triazol-4-yl)-1-azabicyclo[2.2.1]heptane (D25) (1 g, 0.0032 mole) in methanol (50 ml) was saturated with ammonia gas. The solution allowed to stand at room temperature for 3 days and then concentrated in vacuo to a gum. The gum was chromatographed on alumina in a gradient of 10-20% methanol in chloroform, elution with 15% methanol in chloroform produced a gum which crystallised from ethyl acetate to afford the title compound (D26, 450mg, 0.0027 mole, 85%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)[CH:3]=1.[NH2:31][C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=3)[CH:3]=[C:2]([NH:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1cc(-c2cnn(COCC[Si](C)(C)C)c2)cc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Product: C[C@H](Nc1cc(-c2cnn(COCC[Si](C)(C)C)c2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
68 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine-2-amine obtained by Step 3, 17 mg of 2-aminopyrazine, 15 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 21 mg of sodium t-butoxide and 8 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 70 mg of the objective compound as colorless oil.
Reaction SMILES: OO.[NH2:3][C:4]([CH3:22])([CH3:21])[CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.C([O-])([O-])=[O:24].[K+].[K+].CS(C)=O>O>[NH2:3][C:4]([CH3:22])([CH3:21])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:24])=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(N)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(N)Cc1ccc(Oc2ccc(C(N)=O)cc2)cc1
Reaction time: 1 h
Yield: 169.7 %

Procedure:
Aqueous 30% H2O2 (62.1 mL, 548 mmol) was added dropwise to a mixture of 4-(4-(2-amino-2-methylpropyl)phenoxy)benzonitrile (53.2 g, 200 mmol), K2CO3 (15.78 g, 114 mmol) and DMSO (270 mL) over 20 min while the temperature was held at 20° C. with a cooling bath. The mixture was stirred at this temperature for 1 h after the addition was complete, and then water (209 mL) was added slowly. The slurry was cooled in an ice bath with stirring for 1 h, and the product was then filtered, washed with water and dried in vacuo at 50° C. to yield 55.0 g (97%) of white solid. Analysis by HPLC indicated purity of >99%. NMR.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[H-].[Na+].CS(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=3)=[O:42])[CH2:34][CH2:33]2)=[O:31])[CH2:13]1)(=O)=O.[Cl-].[Na+]>CN(C)C=O>[C:1]([S:3][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:14]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH2:38][CH2:39][O:40][C:41]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=3)=[O:42])[CH2:36][CH2:37]2)=[O:31])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCOC(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
51 μl of thioacetic acid were added to a suspension of 26 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 1.4 ml of anhydrous dimethylformamide, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 340 mg of (2S,4R)-4-methanesulfonyloxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (b1) above] in 2 ml of anhydrous dimethylformamide was added to the mixture, and the resulting mixture was stirred at 80°-90° C. for 4 hours, after which the reaction mixture was allowed to cool to room temperature. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified in a similar manner to that described in step (a), above, to afford the title compound (166 mg). The infra-red absorption spectrum and nuclear magnetic resonance spectrum of the product thus obtained were identical with those of the compound obtained as described in step (a), above.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][C:2]21[CH2:12][CH:11]2[C:13]([O:15]CC)=[O:14].C1(C(OCC)=O)C2(CCCCC2)C1>>[CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][C:2]21[CH2:12][CH:11]2[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C1CC12CCC1CCCCC1C2
Agent: CCOC(=O)C1CC12CCCCC2
Product: O=C(O)C1CC12CCC1CCCCC1C2

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 45B for the product from Example 1A. MS m/z 208 (M)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:19]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1)[CH2:19][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCN(Cc2cc(F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (4 g, 20 mmol), 3-fluoro-5-(trifluoromethyl)benzyl bromide (4.6 g, 18.1 mmol) and diisoproylethylamine (4.7 ml, 27.1 mmol) in dichloromethane (25 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (32 ml) was added and the reaction mixture was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D7 (4 g, 80%) as a solid. C13H16F4N2 requires 276. Found 277 (MH+)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:22])[O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH3:21])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:24]1C=CC(CCO)=C(CC)C=1.N(C1C=C(C=CC=1)C#N)=C=O>>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:22])[O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][CH3:24])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1cc(Br)ccc1CCO
Reactant: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Agent: N#Cc1cccc(N=C=O)c1
Product: CCc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Yield: 57 %

Procedure:
Using a procedure analogous to that used to prepare 30C, 36B (687 mg, 3 mmol) was reacted with 3-isocyanatobenzonitrile (432 mg, 3 mmol) to give 56A (630 mg, 57%) as an oil. MS (ESI) m/z 373.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:39])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:13]=2)=[CH:6][C:5]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[CH:4][N:3]=1>C(O)(=O)C>[NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:39])[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[CH:6][C:5]([C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)=[CH:4][N:3]=1
Reactant: Cc1cc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CC(=O)O
Product: Cc1cc(N)nc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)c1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
405 mg of N-[2-amino-5-(4-chloro-phenyl)-pyridin-3-yl]-3-[4-methyl-6-(trityl-amino)-pyridin-2-yl]-propionamide (compound B8) are dissolved in 24 ml of aqueous acetic acid (50% strength) and heated at 80° C. for 3 h. Subsequent workup according to the procedure described herein for example B5 yields 36 mg of the title compound as an oil. ESI-MS: 382.2/384.2 (MH+, 100%/36%). TLC: Rf=0.40 (dichloromethane/methanol 10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)[CH:11]=[C:4]2[N:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:17]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nc(-c3ccc(N4CCOCC4)nc3)cc2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: O
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccc(N4CCOCC4)nc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resulting 5,7-dichloro-2-(6-morpholin-4-yl-pyridin-3-yl)-pyrazolo[1,5-a]-pyrimidine was dissolved in 1,4-dioxane (4 mL), morpholine (500 μL, 5.74 mM) was added to the solution and then the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the residue obtained was diluted with water, the precipitated solid was recovered through filtration and then dried under reduced pressure to thus give the title compound (59.6 mg, overall yield of these three steps: 5.1%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>>[Cl:1][C:2]1[N:3]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1[N+](=O)[O-]
Yield: 35 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-methyl-3-nitrophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-methyl-3-nitrophenyl)-1H-indole-3-carboxaldehyde (35% yield) as a light cream solid. ESI/MS 315 (M+H); 356 [(M+1+CH3CN) adduct]; RT=3.35 min.
Reaction SMILES: [CH:1]([N:4]=[C:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>C(Cl)Cl>[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:15]([Cl:17])=[O:16])([CH3:7])=[CH2:6]
Reactant: CC(C)=NC(C)C
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)N(C(=O)Cl)C(C)C

Procedure:
99 parts of acetone isopropylimine and 94 parts of triethylamine are dissolved in 400 parts of methylene chloride, and the whole reacted with 120 parts of phosgene at a temperature of 30° to 40° C., as described in Example 1. After isolation, 131 parts (81% of the theory) of N-isopropenyl-N-isopropylcarbamyl chloride is obtained having a boiling point of 69° C. at 3 mm.