Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:19][C@@H:18]([O:20][CH2:21][CH2:22]OS(C)(=O)=O)[C@H:17]([OH:28])[CH2:16]2)[N:10]=1>O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:16][C@H:17]3[O:28][CH2:22][CH2:21][O:20][C@@H:18]3[CH2:19]2)[N:10]=1
Reactant: CS(=O)(=O)OCCO[C@@H]1CN(c2cccc(Br)n2)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(N2C[C@H]3OCCO[C@@H]3C2)n1

Procedure:
1.49 g of 60% oily sodium hydride was added little by little to a solution of 150 ml of N,N-dimethylformamide containing 11.82 g of 2-bromo-6-[(3R,4R)-3-hydroxy-4-(2-methanesulfonyloxyethyl)oxypyrrolidine-1-yl]pyridine under stirring in an ice bath. Then, after stirring at room temperature for one hour, 372 mg of 60% oily sodium hydride was added thereto. After stirred for further 45 minutes, the reaction mixture was poured into water and extracted twice with ethyl acetate. The organic phase was washed with water and brine, and the solvent was removed. The residue was crystallized from ethyl acetate/hexane, to give 5.35 g of the target compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1>>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:25][CH2:24][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCc1ccncc1
Product: CCN(CC)C(=O)c1ccc(NCc2ccncc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 87 h
Yield: 49.2 %

Procedure:
Following general procedure 2B, N,N-diethyl-4-fluoro-3-nitrobenzamide (0.272 g, 1.13 mmol) and 4-pyridinylmethanamine (0.11 mL, 1.12 mmol) were stirred at room temperature for 87 h. The crude product was purified by column chromatography (100% EtOAc, then 9:1 CH2Cl2:MeOH) to provide the title compound (0.181 g, 60%). 1H-NMR (CD3OD): δ 8.49 (d, J=6.4 Hz, 2H), 8.27 (d, J=2.8 Hz, 1H), 7.50–7.42 (m, 3H), 6.87 (d, J=8.4 Hz, 1H), 4.77 (s, 2H), 3.44 (br s, 4H), 1.21 (t, J=7.2 Hz; 6H). MS (ESI) (M+H)+=329
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][C:18]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:27][C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][CH2:20][N:15]([CH2:13][CH2:12][CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:16][CH2:17]1
Reactant: O=C(CCC1COc2ccccc2O1)N1CCC(O)(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccccc2)CCN(CCCC2COc3ccccc3O2)CC1
Reaction time: 12 h

Procedure:
The solution of 5 g of 1-[3-(1,4-benzodioxan-2-yl)propionyl]-4-hydroxy-4-phenylpiperidine in 50 ml of tetrahydrofuran is added to the stirred mixture of 2 g of lithium aluminum hydride and 50 ml of tetrahydrofuran at room temperature. Stirring is continued for 12 hours, whereupon the reaction mixture is decomposed with a few drops of ethyl acetate, 2 ml of water, 4 ml of 15% aqueous sodium hydroxide and 4 ml of water. It is filtered, the filtrate evaporated and the residue recrystallized from isopropanol, to yield the 2-[3-(4-hydroxy-4-phenylpiperidino)propyl]-1,4-benzodioxan melting at 95°-98°. The hydrochloride thereof is prepared in the above illustrated manner and recrystallized from isopropanol, mp. 155°-157°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1[CH:33]=[C:32]2C(C(NC3C=CC(C(O)=O)=CC=3)=[CH:29][CH:30]=[N:31]2)=CC=1>>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:10]([CH2:11][CH2:6][N:31]([CH2:30][CH3:29])[CH2:32][CH3:33])[CH2:9][CH3:8])=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: O=C(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Product: CCN(CC)CCN(CC)C(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1

Procedure:
4-(7-Chloro-4-quinolylamino) benzoyl chloride hydrochloride (prepared by refluxing 9.0 grams of 4-(7-chloro-4-quinolylamino) benzoic acid and evaporating the excess thionyl chloride, was added in portions to a cooled, stirred mixture of 4.32 grams of N,N,N1 -triethylethylene diamine and 32 grams of sodium carbonate in 60 milliliters of chloroform and 70 milliliters of water. After stirring for 2 days at room temperature the reaction mixture was filtered, the chloroform layer separated, dried and evaporated to give an oil. This was triturated with hexane to give a light brown solid, which was triturated with acetone to give 5.3 grams of the title compound as a quarter hydrate.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14]>C(OCC)C>[Br:14][CH2:11][C:3]1[C:4]([CH:8]([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: Cn1nc(C(F)F)c(CO)c1Cl
Solvent: CCOCC
Product: Cn1nc(C(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 8 h
Yield: 286.3 %

Procedure:
A solution of 2.0 g (10.0 mmoles) of (5-chloro-3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanol dissolved in 50 ml of diethyl ether was cooled to −10° C. Thereto was added 1.0 g (3.5 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 2.6 g (yield: 100.0%) of 4-bromomethyl-5-chloro-3-difluoromethyl-1-methyl-1H-pyrazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:27](C1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1)[CH3:28]>>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)=[CH:26][CH:25]=1)[CH3:28]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: CCc1ccc(C2CCc3cc(O)ccc3O2)cc1
Product: CCc1ccc(C2CCc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)cc1

Procedure:
2-[2-(4-Ethylphenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 205 mg of 2-(4-ethylphenyl)chroman-6-ol. The product was recrystallised from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.36 (d, 2H, J 8.1 Hz), 7.24 (d, 2H, J 8.1 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.00 (d, 1H, J 2.7 Hz), 6.96 (dd, 1H, J 8.8, 2.7 Hz), 6.89 (d, 1H, J 2.7 Hz), 5.11 (dd, 1H, J 10.1, 2.2 Hz), 2.98 (m, 1H), 2.75 (m, 1H), 2.62 (q, 2H, J 7.5 Hz), 2.16 (m, 1H), 2.01 (m, 1H), 1.19 (t, 3H, J 7.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@H:11]2[CH2:17][O:16][C@@H:13]([CH:14]=[O:15])[C@@H:12]2[OH:18])=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@@H:11]2[C@@H:12]([OH:18])[C@H:13]([CH2:14][OH:15])[O:16][CH2:17]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](C=O)[C@@H]2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CS[C@H]2CO[C@@H](CO)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a room temperature solution, under argon, of 10.9 g of product from Example 322 in 115 ml of absolute ethyl alcohol is added 1.57 g of sodium borohydride. The reaction is stirred at room temperature for 1 hour. Wateris added dropwise with stirring and the mixture is concentrated in vacuo. The residue is extracted with methylene chloride, washed with water, driedand concentrated in vacuo to give after chromatography (Silica gel: 50-75% ethyl acetate/hexane) 7.68 g of the desired product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCN(C)C)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cccc(OCCN3CCCC3)c2o1
Agent: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: Nc1ccccc1NC(=O)c1cc2cccc(OCCN3CCCC3)c2o1

Procedure:
was prepared from (2-{[7-(2-Pyrrolidin-1-yl-ethoxy)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (24) in an analogous manner to that described for the preparation of (1) example 1, step 5; yellow solid; exact MW [M+H] calc'd: 366.18; MW found [M+H]: 366.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.BrN1C(=[O:16])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Ca+2]>ClC(Cl)(Cl)Cl.O>[OH:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1ccc(CO)cn1
Temperature: 25 °C

Procedure:
The compound of Example 1A (13 g, 110 mmol) is dissolved in 400 ml tetrachloromethane, and 29.4 g (165 mmol) N-bromosuccinimide and 0.4 g (1.6 mmol) dibenzoylperoxide are added. The reaction mixture is refluxed for three hours, cooled down to room temperature and filtered. The solution is washed with aqueous sodium thiosulfate, dried over magnesium sulfate, and the solvent is removed in vacuo. The residue is dissolved in 200 ml dioxane and 200 ml water, calcium carbonate (44 g, 440 mmol) is added, and the mixture is stirred at reflux for 2 hours. After cooling down to room temperature, the mixture is filtered, and dichloromethane is added. After phase separation, the organic phase is dried over magnesium sulfate, and the solvent is removed in vacuo. The product is purified by chromatography (silica, eluent: cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([NH:21][C:22](=[O:40])[CH:23]([NH:32][C:33](OC(C)(C)C)=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.O=C(Cl)OC(Cl)(Cl)Cl>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:41])[C@@H:12]([N:21]2[C:22](=[O:40])[CH:23]([C:24]3[CH:25]=[CH:26][C:27]([S:30][CH3:31])=[CH:28][CH:29]=3)[NH:32][C:33]2=[O:34])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)C(NC(=O)OC(C)(C)C)c2ccc(SC)cc2)[C@@H](C)c2ccccc2)n1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(SC)cc3)C2=O)n1
Reaction time: 0.33 h

Procedure:
2-{(2S,3S)-2-[2-tert-Butoxycarbonylamino-2-(4-methylsulfanyl-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (110 mg, 0.18 mmol) was dissolved at 0° C. in a 30% solution of trifluoroacetic acid in dichloromethane. After 2.5 hours the reaction mixture was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate and then extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to an off white solid. The solid was dissolved in a solution of diisopropyl ethyl amine (0.16 mL, 0.92 mmol) in dichloromethane (5 mL) and the resulting solution was added in a dropwise manner to a 0° C. mixture of diphosgene (16 μL, 0.13 mmol) in dichloromethane (5 mL). The mixture was stirred for 20 minutes and then partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and concentrated to the crude product. After purification by chromatography over silica gel gradient eluted up to 3:2 ethyl acetate/hexanes and precipitation of the material obtained from chromatography from dichloromethane with excess hexanes, 2-{(2S,3S)-2-[4-(4-methylsulfanyl-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester, was isolated as a white amorphous solid (45 mg, 46%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Cl:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(CCc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-4-hydroxy-1-phenethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 433 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@:3]1([CH3:10])[C:7]([OH:9])=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH2:19])=[N:16][CH:17]=1.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][NH:19][C:7]([C@:3]2([CH3:10])[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:9])=[N:16][CH:17]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN1CCC[C@@]1(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCC[C@@]1(C)C(=O)NNc1ccc(F)cn1
Yield: 69 %

Procedure:
To a suspension of (S)-1,2-dimethyl-pyrrolidine-2-carboxylic acid (660 mg, 4.61 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (488 mg, 3.84 mmol) and Et3N (1.1 mL, 7.7 mmol) in DCM (20 mL) were added HOBt.H2O (51 mg, 0.38 mmol) and EDCI.HCl (884 mg, 4.61 mmol) and the mixture stirred at RT overnight. The mixture was partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. FCC, using 0-10% MeOH in DCM, gave the title compound as a brown solid (668 mg, 69%). LCMS (Method 4): Rt 0.40, m/z 253 [MH+].
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1)=O.[CH2:25]([S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[CH2:33]2)(=[O:29])=[O:28])[CH3:26]>>[CH2:25]([S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])/[C:33]/2=[CH:1]\[C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]1)(=[O:28])=[O:29])[CH3:26]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(CC(=O)O)CC1)CCCC2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(CC(=O)O)CC1)CCCC3)C(=O)N2
Yield: 30.8 %

Procedure:
{(4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid (50 mg, 0.15 mmol), prepared as described in Example 18, was condensed with 5-ethylsulfonyloxindole (66 mg, 60% pure) following the same procedure used in example 1. The formed solid was purified by flash chromatography, eluting with (dichloromethane: methanol 8:1, 5:1:0.01 acetic acid) to give 25 mg of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:16])[N:37]([O:38][CH3:39])[CH3:36])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)O)cs1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 72 h
Yield: 88069.2 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-thiazole-4-carboxylic acid (14 g, 0.0573 mol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (10.06 g, 0.0573 mol) and N-methyl morpholine (5.79 g, 0.0573 mol) in tetrahydrofuran was stirred for 2 hours at room temperature. N,O-Dimethylhydroxylamine hydrochloride (5.59 g, 0.0573 mmol) and triethylamine (5.59 g, 0.0573 mol) were added and the mixture was stirred for 3 days. The reaction mixture was evaporated and ethyl acetate was added. The reaction mixture was washed with 1 N aqueous hydrochloric acid and then washed with saturated aqueous sodium bicarbonate. [4-(Methoxy-methyl-carbamoyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (14.5 g, 88%) was obtained as a tan tar after drying (magnesium sulfate) and evaporation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:9](=[S:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)=[C:6]([NH2:8])[CH3:7])[CH3:2].BrBr.C(OCC)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:7])=[N:8][S:14][C:9]=1[NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(C(=S)NC1CC1)=C(C)N
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1c(C)nsc1NC1CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.2 %

Procedure:
To a vigorously stirred solution of 1 g of 3-amino-2-cyclopropylthiocarbamoyl-but-2-enoic acid ethyl ester (4.4 mmol) in chloroform (16 ml) was added dropwise a solution of 1.4 g of bromine in chloroform (8 ml) at 0° C. After completion of the addition the reaction mixture was stirred at 0° C. for additional 5 min. Then diethyl ether and sat. NaHCO3-solution were added and the mixture was extracted with diethyl ether. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (100% DCM) to give 5-cyclopropylamino-3-methyl-isothiazole-4-carboxylic acid ethyl ester (410 mg, 40%) as a brown liquid. 1HNMR (CDCl3, 300 MHz): δ 0.73 (m, 2H), 0.81 (m, 2H), 1.36 (t, J=7.2 Hz, 3H), 2.50 (s, 3H), 2.63 (m, 1H), 4.29 (q, J=7.2 Hz, 2H), 7.80 (br s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[F-].[Cs+].Cl[C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)[CH:21]=[N:20][CH:19]=1.O>CS(C)=O>[N:26]1[N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[C:24]([C:22]2[N:23]=[C:18]([NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[CH:19]=[N:20][CH:21]=2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1cncc(-c2cnn3ccccc23)n1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Temperature: 100 °C
Reaction time: 22 h
Yield: 34 %

Procedure:
Tert-Butyl (3R)-3-aminopiperidine-1-carboxylate (0.51 g, 2.54 mmol) and cesium fluoride (0.83 g, 5.46 mmol) were added to a stirred solution of 3-(6-chloropyrazin-2-yl)pyrazolo[1,5-a]pyridine (Preparation 27b, 0.42 g, 1.82 mmol) in dimethylsulfoxide (20 mL). The resulting mixture was stirred at 100° C. for 22 h before being poured onto 50 mL of water. The resultant suspension was extracted with ethyl acetate (×2) and the combined organic layers were dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified by flash chromatography (3:7 to 7:3 ethyl acetate/hexane) to give the title compound (0.244 g, 34%) as a yellowish foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:15])[C:11](=[O:14])[O:12][CH3:13])=[CH:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].[C:26](OCC)(OCC)(OCC)[CH3:27]>>[CH3:15][N:10]([CH2:9][CH2:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:26]([CH3:27])=[C:16]2[S:17]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:11](=[O:14])[O:12][CH3:13]
Reactant: COC(=O)N(C)CCc1ccc(N)c(CS(=O)(=O)c2ccccc2)c1
Reactant: CCOC(C)(OCC)OCC
Product: COC(=O)N(C)CCc1ccc2[nH]c(C)c(S(=O)(=O)c3ccccc3)c2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, step 3 starting from methyl (2-{4-amino-3-[(phenylsulfonyl)methyl]phenyl}ethyl)methylcarbamate (160 mg, 0.44 mmol), and triethyl ortho acetate, and was obtained as a white solid. Mp: 188-191° C., MS (+) 387 (M+H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:16][O:15][CH2:14][C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a stirred solution of 463 mg (2.43 mmol) of BOC-leucinol in 2 ml of tetrahydrofuran at -78° C. under argon is added 2.4 mL (2.4 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After 10 minutes, 0.3 ml (4.8 mmol) of methyliodide was added and the resulting mixture is allowed to warm to room temperature. It is then heated to reflux for 1 hour and then cooled. The mixture is partitioned between 40 ml of dichloromethane and 30 ml portions of dichloromethane. The combined residue is chromatographed on silica gel with 15% ethyl acetate in hexane to give 405 mg (1.75 mmol, 83%) of BOC-leucinol methyl ether. 1H-NMR (CDCl3): δ0.9 d (d, d×3H, J=6 Hz), 1.44, 3.33.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][CH2:23][CH2:24][N:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:25]1[CH2:24][CH2:23][N:22]=[C:21]1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: C(=C1CCN(Cc2ccccc2)CC1)c1ccc(C2=NCCN2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1cc(C2=NCCN2)ccc1CC1CCNCC1
Yield: 93.1 %

Procedure:
To a stirred solution of 1-benzyl-4-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzylidene]-piperidine (0.1 g, 0.3 mmol) in ethanol (20 mL), ammoniumformate (0.19 g, 3 mmol) and 10% Pd/C (20 mg) were added ad the mixture was refluxed for 8 hours. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The remaining crude material was purified by column chromatography using basic aluminum oxide (150 mesh, Aldrich) as adsorbent and 10% methanol in chloroform as eluent to yield 68 mg (92%) of the title compound.
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([NH2:12])[N:4]=1.O.Cl.[CH3:15][O:16][CH2:17][CH2:18][OH:19]>>[CH3:15][O:16][CH2:17][CH2:18][O:19][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([NH2:12])[N:4]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: COCCO
Agent: Cl
Agent: [Na]
Solvent: O
Product: COCCOc1nc(N)c2[nH]cnc2n1
Yield: 73 %

Procedure:
After sodium (3.00 g, 130 mmol) was dissolved in 2-methoxyethanol (150 ml), thereto was added 2-chloroadenine (3.00 g, 17.69 mmol) and the mixture was refluxed for 8 hours. After the mixture was allowed to cool, water (400 ml) was added thereto and neutralized with concentrated hydrochloric acid. The resulting precipitate was filtered and washed with methanol to give the captioned compound (3.06 g, 14.48 mmol, yield 73%) as a white solid.