Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:13][CH2:14][N+:15]([O-])=O)[C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[NH2:15][CH2:14][CH2:13][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(CC[N+](=O)[O-])c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCN)c1cccc(Br)c1
Reaction time: 0.02 h
Yield: 83.5 %

Procedure:
To a solution of methyl 2-(3-bromophenyl)-4-nitrobutanoate (3.1 g, 11 mmol) and NiCl2-6H2O (5.4 g, 23 mmol) in methanol (12 mL) was added NaBH4 (1.3 g, 34 mmol). The reaction mixture was stirred for 1 minute and was quenched by adding ice water. The mixture was filtered, and the filtrate was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to give methyl 4-amino-2-(3-bromophenyl)-butanoate (2.5 g, 82%) as a white solid, which was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]([OH:16])=O)[CH3:2].Cl.[Cl:18][CH2:19][CH2:20][CH2:21][NH2:22].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.O>[Cl:18][CH2:19][CH2:20][CH2:21][NH:22][C:14]([C:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:7][C:3]=1[CH2:1][CH3:2])=[O:16]
Reactant: CCc1onc(-c2ccccc2)c1C(=O)O
Reactant: NCCCCl
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1onc(-c2ccccc2)c1C(=O)NCCCCl
Yield: 80.2 %

Procedure:
A solution of 3.1 g of 5-ethyl-3-phenylisoxazole-4-carboxylic acid (prepared as described in J. Org. Chem. 1985, 50, 5660-5666), 2.94 g of 3-chloropropylamine hydrochloride, 2.62 mL of 92% diethyl cyanoposphonate and 4.38 mL of triethylamine in 50 mL of anhydrous dimethylformamide was stirred at room temperature for 3 hours, poured into 500 mL of water and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water, dried (sodium sulphate) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography (ethyl acetate-petroleum ether 3:7) to give 3.35 g (73%) of the title compound. M.p. 75-76° C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18].F[C:21]1[C:26]([F:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C(Cl)Cl>[C:16]([C:3]1[C:2](=[O:1])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:21]3[C:26]([F:27])=[CH:25][C:24]([C:28]([F:31])([F:29])[F:30])=[CH:23][N:22]=3)=[CH:10][CH:9]=2)[CH2:5][C:4]=1[OH:15])(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(S)cc2)CC1=O
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCC(=O)C1=C(O)CC(c2ccc(Sc3ncc(C(F)(F)F)cc3F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 4.0 g (0.0145 mol) of 3-hydroxy-5-(4-mercaptophenyl)-2-propionyl-cyclohex-2-en-1-one in 50 mL of acetonitrile was added 3.90 g (0.0212 mol) of 2,3-difluoro-5-(trifluoromethyl)pyridine and 4.50 g (0.0326 mol) of powdered potassium carbonate. The mixture was stirred one hour at ambient temperature and then heated at reflux for 1.5 hours and cooled to room temperature. The reaction mixture was diluted with 150 mL of water and 150 mL of methylene chloride. The organic layer was separated, washed twice with 150 mL portions of water and dried over Na2SO4. The solvent was removed in vacuo leaving 5.7 g of the crude product which was purified by column chromatography using methylene chloride as the eluent. Recrystallization of the crude from ethanol gave the above named product in a yield of 2.25 g (35 percent of theoretical). The product melted at 152°-154° C.; 1H NMR (CDCl3): δ 1.10 (t, 3H, CH3CH2 --), 2.55-3.65 (m, 7H, ring protons and CH3CH2 --), 7.15-8.50 (m, 6H, ArH), 18.2 (s, 1H, OH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:19])[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Cc1cc(C(=O)Cc2ccccc2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)C(C)c2ccccc2)ccn1
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
1-(2-Methyl-pyridin-4-yl)-2-phenyl-ethanone (233 mg, 1.1 mmol, solution in 5 mL DMF) was added over 15 min to a suspension of NaH (55% in mineral oil, 58 mg, 1.3 mmol) in DMF (2 mL). After 30 min, methyl iodide (0.07 mL, 1.2 mmol) was added slowly drop by drop. The mixture was poured onto ice and extracted with ethyl acetate. The combined organic layers were washed (brine), dried (Na2SO4), and the solvent was evaporated. Purification by column chromatography (silica gel, heptane:ethyl acetate=100:0-50:50) afforded the title compound (142 mg, 54%). 1H NMR (300 MHz, DMSO-D6) 8.56 (1H, d), 7.68 (1H, s), 7.61 (1H, d), 7.30-7.27 (4H, m), 7.20-7.18 (1H, m), 4.92 (1H, q), 1.40 (3H, d); MS (m/e)=226.3 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:12])[CH:10]=O)[CH:6]=[CH:7][CH:8]=1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.[NH3:21]>C(O)C>[CH3:20][O:19][C:13]([C:14]1[CH:10]([CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:12])[C:14]([C:13]([O:19][CH3:20])=[O:18])=[C:15]([CH3:17])[NH:21][C:15]=1[CH3:17])=[O:18]
Reactant: COC(=O)CC(C)=O
Reactant: COc1cccc(C(C)C=O)c1
Reactant: N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C(C)c1cccc(OC)c1

Procedure:
16.4 g of 2-(3-methoxyphenyl)-propionaldehyde, 23.2 g of methyl acetoacetate and 2.1 ml of NH3 (33% strength) in 50 cm3 of ethanol were heated under reflux for 4 hours. After the mixture had cooled, the product crystallised out. It was purified by recrystallisation from ethanol.
Reaction SMILES: [CH:1]([C:3]1[C:4]2[CH2:28][CH2:27][CH2:26][CH2:25][C:5]=2[S:6][C:7]=1[NH:8][C:9](=[O:24])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]1)=[O:2].[BH4-].[Na+].C(O)(=O)C>CCO.C(OCC)C>[OH:2][CH2:1][C:3]1[C:4]2[CH2:28][CH2:27][CH2:26][CH2:25][C:5]=2[S:6][C:7]=1[NH:8][C:9](=[O:24])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]1
Reactant: O=Cc1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1CO)CCCC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97.5 %

Procedure:
N-(3-Formyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(3-trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetamide (1.30 g, 3.16 mmol) was added portionwise, with stirring, to a solution of sodium borohydride (359 mg, 9.49 mmol) in EtOH (300 mL). The resulting mixture was stirred at RT for 40 min. Acetic acid was added dropwise until the effervescence ceased. The resulting mixture was concentrated in vacuo to afford an off-white solid. The solid was dissolved in diethyl ether (200 mL) and washed with water (100 mL). The organics were dried over sodium sulfate and concentrated in vacuo to yield the title compound as a yellow solid (1.27 g, 3.08 mmol, 97%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:26]Br>>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:26][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Fc1cc(F)cc(CBr)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)cc(F)c2)c1
Yield: 53.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (220 mg, yield: 53.3%).
Reaction SMILES: NOS(O)(=O)=O.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.CC(C)([O-])C.[K+].[NH2:22]OS(O)(=O)=O.N1C2C(=CC=CC=2)C=C1.CN1CCCC1=O.CC(C)([O-])C.[K+].CN1CCCC1=O>CN1CCCC1=O.CC(C)([O-])C.[K+].CN1CCCC1=O>[N:7]1([NH2:22])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NOS(=O)(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nn1ccc2ccccc21
Reaction time: 3.08 h
Yield: 90.2 %

Procedure:
A solution of 33.8 kg (32.8 kg corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) and 15.8 kg (15.6 kg corrected for 99% purity) of indole in 120.2 kg of N-methylpyrrolidinone (NMP), is prepared and chilled to 0–5° C. A second solution is prepared from 67.0 kg (63.7 kg corrected for 95% purity) of potassium tert-butoxide and 122.6 kg of NMP. An amination vessel is charged with 47.0 kg of NMP and an initial charge of 2.2 kg of the potassium tert-butoxide/NMP solution. The HOSA/indole/NMP solution and the remaining potassium tert-butoxide/NMP solution are then simultaneously and proportionally metered using a metering pumping system consisting of a dual head plunger pump together with coriolis mass flow meters into the amination vessel over a period of 185 minutes while maintaining a reaction temperature of 20–30° C. to yield a solution containing 15.9 kg (90.2% yield) of 1H-indol-1-amine as determined by external standard HPLC assay.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:16])=O>ClCCl.CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:16])=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCOc1ccc(CO)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOc1ccc(CCl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A solution of 4.20 g (23.1 mmol) (4-allyloxy-2-fluoro-phenyl)-methanol in 80 ml dichloro-methane and 0.5 ml DMF was cooled to 0° C. 2.17 ml (3.57 g, 30.0 mmol) thionyl chloride were added slowly and then stirred for 1 h at room temperature. Dichloromethane was distilled off. The residue was taken up in 100 ml ethyl acetate and washed with concentrated sodium carbonate solution. The organic phase was dried and evaporated to give 4.47 g (97%) 1-allyloxy-3-fluoro-4-chloromethyl-benzene as colored oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][C:12]#[N:13])=[O:9])=[CH:6][CH:5]=1.BrBr.[C:18](OCC)(=[O:20])[CH3:19]>BrBr>[CH3:1][O:2][CH2:3][C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH:11]([O:20][CH2:18][CH3:19])[C:12]#[N:13])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: COCc1ccc(C(=O)NCC#N)cc1
Agent: BrBr
Product: CCOC(C#N)NC(=O)c1ccc(COC)cc1
Temperature: 30 °C

Procedure:
A solution of 2-(4-methoxymethylbenzoylamino)-acetonitrile (5.0 g) in dry ethyl acetate (40 ml) was treated with a couple of drops of bromine and stirred at 30° C. until initiation of the reaction occurred. The bromine was then added dropwise keeping the temperature at 25°-30° C. After completion of the addition the mixture was filtered through celite, and the filtrate treated with ethanol (5 ml), with stirring, followed by triethylamine (5.0 g), at room temperature. After completion of the addition the mixture was stirred for 5 minutes, filtered through celite, and washed with water, dried over magnesium sulphate and evaporated at less than 30° C., giving a brown oil, (5.0 g). This was purified by preparative HPLC to yield the product as white needles (1.6 g), mpt 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.ClC1C=CC(C(=O)CC)=CC=1.[Cl-].[In+3].[Cl-].[Cl-].[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:38]2[C:37]3[C:41](=[C:33]([CH2:32][S:31][CH3:30])[CH:34]=[CH:35][CH:36]=3)[NH:40][CH:39]=2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCC(O)(CCO)c1ccc(Cl)cc1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CCC(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(CCO)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3.04 g (14.10 mmol) of 3-(4-chlorophenyl)pentane-1,3-diol (preparation in analogy to the synthesis of Example 88A and 89A starting from 1-(4-chloropenyl)propan-1-one and ethyl acetate) and 3.12 g (14.10 mmol) of indium(III) chloride were added to 2.50 g (14.10 mmol) of the compound from Example 8A in 60 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off through kieselguhr. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 2.13 g (40% of theory) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>ClCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:21]#[C:22][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1cccc(C#N)c1
Temperature: 25 °C

Procedure:
To a solution of commercially available 3-iodobenzonitrile (25 g, 0.109 mol), copper (I) iodide (2.08 g, 0.0109 mol), PdCl2(PPh3)2 (3.82 g, 0.0054 mol) and triethylamine (45.7 ml, 0.327 mol) in 250 of dry dichloromethane was added 12.8 g (0.131 mol) of trimethylsilylacetylene drop wise at 0° C. over a period of 10 min. The reaction mixture was stirred at RT over night. The reaction mixture was diluted with additional dichloromethane, filtered over Celite and the filtrate was concentrated. The crude material was purified by silica gel (60-120) column chromatography using 95:5 petrolium ether/ethyl acetate as eluent. A2.1 (20 g, 92%) was obtained as a brown solid 1H NMR, 400 MHz, CDCl3: 7.79 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.43 (t, 1H), 0.26 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.C(N(CC)CC)C.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:8]1([C:6]2[CH:7]=[C:2]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:3]=[C:4]([NH2:14])[N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nc(C#Cc2ccccc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chloro-6-phenylpyrimidin-2-ylamine (2.0 g, 9.7 mmol), (PPh3)2PdCl2 (204 mg, 0.29 mmol), triethylamine (4.9 g, 48.5 mmol) in DMF (10 mL) was stirred at 25° C. for 0.5 hour under a nitrogen atmosphere. Then phenylacetylene (1.29 g, 12.70 mmol) was added to it and the mixture was stirred at 100° C. for 4 hours under a nitrogen atmosphere. The mixture was cooled to temperature in the range of 20-40° C., diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layers were collected, combined, washed with water (30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography using EtOAc-petroleum ether to give the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([N+:23]([O-:25])=[O:24])=[C:18](F)[CH:17]=2)[CH2:11][S:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:36])([F:35])[C@H:30]([OH:34])[CH2:31][O:32][CH3:33].C(O[K])(C)(C)C.C(OC(C)(C)C)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:17]=[C:18]([O:34][C@H:30]([CH2:31][O:32][CH3:33])[C:29]([F:36])([F:35])[F:28])[C:19]([N+:23]([O-:25])=[O:24])=[C:20]([F:22])[CH:21]=2)[CH2:11][S:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC[C@@H](O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Agent: CC(C)(C)OC=O
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC[C@@H](Oc1cc(C[C@@H]2CSC[C@H](NC(=O)OC(C)(C)C)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (1 g, 2.47 mmol) and (R)-1,1,1-trifluoro-3-methoxy-propan-2-ol (392 mg, 2.72 mmol) in THF (13 mL) was added tert-BuOK (277 mg, 2.47 mmol) in small portions at 0° C. over a period of 30 min. After 1 h the cooling bath was removed and the orange solution was stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc (500 mL) and washed with ice cooled K2CO3 solution and cold brine. The organic phase was dried over Na2SO4, filtered and evaporated to yield a brown-yellowish foam: TLC Rf=0.50 (toluene-ETA 85:15); HPLC RtE=1.157 min; ESIMS [M+H-Boc]+=429; 1H NMR (600 MHz, DMSO-d6): δ 7.28 (s, 1H), 7.10 (d, 1H), 6.71 (d, 1H), 5.65 (broad, 1H), 4.95 (d, 1H), 3.83 (dd, 1H), 3.73 (dd, 1H), 3.42 (m, 1H), 3.31 (s, 3H), 3.25 (dd, 1H), 2.93 (m, 1H), 2.54 (d, 1H), 2.48-2.35 (m, 2H), 2.32-2.20 (m, 2H), 1.94 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(Cl)[Cl:18]>[Pd]>[ClH:18].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: ClCCl
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Product: Cl
Product: Nc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 1 h

Procedure:
A mixture of 1-(4-nitro-phenyl)-piperidine-4-one (Synthesis 1981, 606) (4.0 g, 18 mmol) and 500 mg of 10% Pd/C in 75 mL of methylene chloride was hydrogenated under H2 (5˜10 psi) for 1 hour. The catalyst was then removed by filtering through a short pad of silica gel. The filtrate was treated with hydrogen chloride gas and the precipitate was collected to give 2 g of the title compound as a tan solid; 1H NMR (300 MHz, DMSO-d6) δ 2.44 (t, J=6.0 Hz, 4H), 3.65 (t, J=6.0 Hz, 4H), 7.14 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H); MS (ES) m/z: 190.9 (MH+); HRMS Calcd. for C11H15N2O (MH+): 190.1106. Found: 190.1096.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:13]([C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].Cl>CN(C=O)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[C:1]1[N:15]=[N:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])=[CH:28][CH:29]=2)[CH:2]=1
Reactant: C#Cc1n[nH]c2ccc(C)cc12
Reactant: [N-]=[N+]=Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c2c1
Temperature: 80 °C
Yield: 83.6 %

Procedure:
Copper sulfate pentahydrate (70 mg; 0.28 mmol; 0.07 eq.) was added to a solution of 3-ethynyl-5-methyl-1H-indazole (665 mg; 4.26 mmol; 1.00 eq.), 4-(4-azidobenzoyl)morpholine (987 mg; 4.25 mmol; 1.0 eq.) and D-(−)-isoascorbic acid sodium salt (283 mg; 1.43 mmol; 0.34 eq.) in DMF (15 mL) and water (0.5 mL). The reaction suspension was heated in MW at 80° C. for 40 min then poured into HCl solution (1N) and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give a yellow solid (1.38 g, 83%). 1H NMR (300 Mz, DMSO-d6) δ: 13.25 (s, 1H), 9.36 (s, 1H), 8.20-8.10 (m, 3H), 7.68 (d, J=108.7 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.28 (dd, J=1.4, 8.6 Hz, 1H), 3.74-3.36 (m, 8H), 2.48 (s, 3H). HPLC (Condition A): Rt 3.21 min (purity 98.6%). MS (ESI+): 389.2, MS (ESI−): 387.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:16]CCCC)=[C:8]([C:13](=O)[CH3:14])[C:9]([OH:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].O.[NH2:22]N>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[NH:16][N:22]=[C:13]([CH3:14])[C:8]=2[C:9]([OH:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCCNc1c(C(=O)OCC)cnc(O)c1C(C)=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(O)c2c(C)n[nH]c12

Procedure:
8.4 g. of 3-acetyl-4-butylamino-2-hydroxypyridine-5-carboxylic acid ethyl ester (0.03 mol.) are dissolved in 20 ml. of acetic acid, 3 ml. of hydrazine-hydrate are added and the mixture is refluxed for 5 hours. After this time, the solvent is removed in vacuo and the crystalline precipitate of 4-hydroxy-3-methyl-1H-pyrazolo[4,3-c]pyridine-7-carboxylic acid ethyl ester is recrystallized from acetic acid, yield 5.1 g. (77%), m.p. 310°.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8](OC)=[O:9])[CH2:3][CH2:2]1.[Cl-].[NH4+:18].Cl.[CH3:20]N>>[CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([NH:18][CH3:20])=[O:9])[CH2:3][CH2:2]1
Reactant: CN
Reactant: COC(=O)c1ccc(O)c(CC2CC2)c1O
Reactant: [NH4+]
Agent: Cl
Agent: [Cl-]
Product: CNC(=O)c1ccc(O)c(CC2CC2)c1O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
The compound of Example 15 (112 mg) was dissolved in about 5 to 10 ml of a 40% aqueous solution of methylamine. A few crystals of ammonium chloride were added, and the reaction mixture was stirred for about 6 hours at 50° C. The reaction mixture was neutralized with 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was dried, concentrated, and chromatographed on silica gel using 15% ethyl acetate/85% hexane as eluant to give the product.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][NH:13][CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[O:15]1[CH2:19][CH2:18][NH:17][C:16]1=[O:20].[CH2:21]=O>ClCCl.O>[Br:1][C:2]1[C:3]2[CH2:4][C@@H:5]3[CH2:14][N:13]([CH2:21][N:17]4[CH2:18][CH2:19][O:15][C:16]4=[O:20])[CH2:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1NCCO1
Reactant: C=O
Reactant: Brc1cccc2c1C[C@@H]1CNCCN21
Solvent: ClCCl
Solvent: O
Product: O=C1OCCN1CN1CCN2c3cccc(Br)c3C[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
(10aR)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (0.10 g, 0.39 mmol) and 2-oxazolidinone (34 mg, 0.43 mmol) were dissolved in dichloromethane (5 mL). Formaldehyde (32 μL of a 36.5% solution in water) was added and the solution was stirred for 3 h at room temperature. The solvent was removed after drying with MgSO4. Chromatography on silica gel (dichloromethane/ethylacetate 3:1) yielded the desired product (114 mg, 82%), MS: m/e=352.3 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:18]1([NH:17][CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: c1ccc(COc2cccc(CCNC3CCCCC3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(CCNC2CCCCC2)c1

Procedure:
A stirred solution of the oil isolated in Step D (4.5 g, 14 mmol) and Pd/C (10%, 150 mg) in ethanol (100 mL) was hydrogenated under 1 atm of hydrogen overnight. The catalyst was filtered off, and the solvent was removed in vacuo to yield an oil.