Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([F:9])[C:3]=1[C:10]#[N:11].[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14].Cl>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:10]#[N:11])=[C:4]([F:9])[CH:5]=2)=[CH:19][CH:20]=1)[CH2:13][CH3:14]
Reactant: N#Cc1c(F)cc(I)cc1F
Reactant: C#Cc1ccc(CCC)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCc1ccc(C#Cc2cc(F)c(C#N)c(F)c2)cc1
Yield: 27.3 %

Procedure:
5.6 g of this 1,3-difluoro-2-cyano-5-iodobenzene was dissolved in 35 ml of N,N-dimethylformamide, to which was added 7.3 mg of bis(triphenylphosphine) palladium (II) chloride and 34 m of cuprous iodide. Next, 3 g of the 4-propylphenylacetylene obtained in Step 2 was added and allowed to react at 50° to 60° C. for 0.5 hour. After completion of the reaction, 35 ml of 9% hydrochloric acid was added to the reaction solution. After being extracted with chloroform, the crystals were washed with water three times to distill off the chloroform. The residue was purified by silica gel-chloroform column chromatography, followed by recrystallization with a mixed solvent of acetone and methanol to obtain 1.6 g of 4-propyl-3',5'-difluoro-4'-cyanotolan. The melting (C-I) point of this compound was 83.3° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH3:14].[CH2:23]([Sn](CCCC)(CCCC)C(OCC)=C)[CH2:24]CC>C1(C)C=CC=CC=1.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>[Si:16]([O:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[CH:23]=[CH2:24])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1c(C(C)O[Si](C)(C)C(C)(C)C)oc(=O)c2ccccc12
Temperature: 25 °C

Procedure:
To a degassed solution of 4-bromo-3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-isochromen-1-one (intermediate A8, 6 g, 15.7 mmol) in toluene (120 ml), PdCl2(PPh3)2 (0.6 g, 079 mmol) was added followed by tributyl(1-ethoxyvinyl)tin (5 ml, 17.2 mmol) and the resulting mixture was heated to reflux overnight. Additional PdCl2(PPh3)2 (0.6 g) was added at room temperature, and the mixture was refluxed for 30 minutes. The mixture was cooled to room temperature, then filtered through a celite pad. The filtrate was evaporated to dryness and the crude was purified by flash chromatography on Biotage silica gel cartridges (cyclohexane to cyclohexane:EtOAc=80:20) to afford 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-vinyl-1H-isochromen-1-one as a pale yellow oil (Intermediate B59.1, 5.8 g).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33](O)=[O:34])[CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:29]3[CH2:30][CH2:31][CH2:32][O:27][CH2:28]3)=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1CCCOC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCCOC1

Procedure:
The title compound, light yellow solid (78 mg, 71%), MS (ISP) m/z=439.3 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-tetrahydro-pyran-3-carboxylic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1.[H][H]>CO.O1CCOCC1.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Yield: 94 %

Procedure:
To a solution of dimethyl 4-[2-(2-naphthoxy)ethoxy]benzylidenemalonate (2.22 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.10 g, 94%). HRMS calcd for C24H24O6: 408.4476. Found: 408.4475. MA calcd for C24H24O6: C, 70.58%; H, 5.92%. Found: C, 70.71%; H, 5.89%.
Reaction SMILES: [C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]([CH3:7])[CH3:6].[CH:17]1(C(O)=O)[CH2:22]CCC[CH2:18]1>>[C:1](=[O:16])([S:14][CH3:15])[O:2][O:3][CH:4]([O:8][C:9]([CH:10]1[CH2:11][CH2:22][CH2:17][CH2:18][CH2:12]1)=[O:13])[CH:5]([CH3:7])[CH3:6]
Reactant: O=C(O)C1CCCCC1
Reactant: CSC(=O)OOC(OC(=O)C(C)C)C(C)C
Product: CSC(=O)OOC(OC(=O)C1CCCCC1)C(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyisobutoxy) S-methyl thiocarbonate (11) and replacing isobutyric acid with cyclohexanecarboxylic acid affords O-(1-cyclohexanoyloxyisobutoxy) S-methyl thiocarbonate (16) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH:14][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: -20 °C
Yield: 31.1 %

Procedure:
L-alanyl-L-proline t-butylester (2.42 g, 10 mmole) was dissolved in methylene chloride (50 ml), and triethylamine (1.01 g, 10 mmole) was added thereto with cooling to -20° C and stirring. Methylene chloride (5 ml) solution of ethanesulfonylchloride (1.29 g, 10 mmole) was added dropwise to the solution while keeping the temperature thereof to -20° C. and then stirred overnight at room temperature. The solution was washed with 10% aqueous citric acid, water, 5% aqueous sodium bicarbonate and water in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give oily residue of N-ethanesulfonyl-L-alanyl-L-proline t-butylester(yield: 1.04 g, 31.1%).
Reaction SMILES: Cl[C:2]1[C:11]([S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.[K]>CN(C)C=O>[CH3:18][N:17]([CH:16]=[N:15][S:12]([C:11]1[C:2]([O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:3]([N+:20]([O-:22])=[O:21])[CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:14])=[O:13])[CH3:19]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)N=CN(C)C)c1
Reactant: Oc1cccnc1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2cccnc2)c(S(=O)(=O)N=CN(C)C)c1
Temperature: 0 °C

Procedure:
A solution of 200 g (0.57 mole) of methyl 4-chloro-5-dimethylaminomethyleneaminosulfonyl-3-nitro-benzoate and 93 g (0.7 mole) of potassium 3-hydroxypyridine in 1 l of dimethylformamide is stirred for 1.5 hours at 80° C. and, after cooling, is introduced into 4-5 l of ice-water, while stirring vigorously. The product which has precipitated is filtered off, washed with H2O and recrystallized from dimethylformamide/CH3OH.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:25][C:23]1([CH2:22][C:21]([O:27][CH2:28][CH3:29])=[O:26])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture consisting of 5-benzyloxytryptophol (4.5 g, 0.017 mol), benzene (200 mL), ethyl acetoacetate (3.4 g, 0.026 mol) and p-toluenesulfonic acid (0.5 g) is refluxed for 2.5 hours using a Dean-stock trap to remove the water. The reaction mixture is cooled to room temperature and washed with 5% sodium bicarbonate, (1×200 mL), water (200 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated to give 8.0 g of crude product as a thick oil, which is flash chromatographed on silica gel using 20% ethyl acetate/hexane as an eluent to afford 5.5 g oil which solidifies upon standing, m.p. 96°-98° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[CH3:5][CH:6]([CH3:8])[O-:7].[CH3:9][CH:10]([CH3:12])[O-:11].[Ti+3:13].[NH2:14]CCCCCCO>>[CH3:1][CH:2]([CH3:4])[O-:3].[CH3:5][CH:6]([CH3:8])[O-:7].[CH3:9][CH:10]([CH3:12])[O-:11].[NH2:14][Ti+3:13][CH2:1][CH2:2][CH2:4][CH2:5][CH2:6][CH3:8]
Reactant: [Ti+3]
Reactant: NCCCCCCO
Agent: CC(C)[O-]
Product: CCCCCC[Ti+3]N
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 200 %

Procedure:
0.1 moles of titanium-tri-isopropoxide (Tyzor TPT Dupont, Wilmington, Del.) and 0.1 moles of 6-amino-1-hexanol were added to a 50 ml beaker and stirred at room temperature for 1 minute to form 0.1 mole of amino-hexyl-titanium-tri-isopropoxide. The reaction mixture was heated to 70° C. for 10 minutes to evaporate the isopropyl alcohol formed during the reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1.Cl>O1CCCC1>[OH:13][CH2:12][C:11]1[CH:15]=[CH:16][C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Oc2ccccn2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccccn2)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
Under an atmosphere of argon, 4-(2-pyridyloxy)benzoic acid (1.08 g, 5.02 mmol) was dissolved in 20 mL of dehydrated tetrahydrofuran. Under cooling with ice and stirring, 1 mol/L borane-tetrahydrofuran complex (15.1 mL, 15.1 mmol) was added dropwise for 5 minutes and the mixture was allowed to stand overnight at room temperature. Under cooling with ice, 2 mL of 6 mol/L hydrochloric acid were added dropwise and, after stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was poured into 100 mL of ice water and, after salt was saturated, the mixture was made alkaline with potassium carbonate, which was extracted with ethyl acetate. The extracted solution was dried over anhydrous sodium sulfate and then concentrated to obtain 1.01 g (100%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[F:57][C:58]([F:64])([F:63])[CH2:59][C:60](O)=[O:61]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:60](=[O:61])[CH2:59][C:58]([F:64])([F:63])[F:57])[CH2:25][CH2:26]3)=[CH:17][CH:16]=1)=[N:8]2
Reactant: O=C(O)CC(F)(F)F
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)CC(F)(F)F)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g, 0.54 mmol) in THF (10 mL) was added EDCl (0.105 g, 0.54 mmol), HOBt (0.074 g, 0.54 mmol), Et3N (0.08 mL, 0.54 mmol) and trifluoropropionic acid (0.070 g, 0.54 mmol). The reaction was stirred at room temperature for 4 hours and concentrated in vacuo. Purification by flash chromatography, eluting with 20% to 100% of 92:7:1 CHCl3/MeOH/concentrate NH4OH in CH2Cl2, afforded the title compound (0.135 g, 52%). 1H NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.03 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.70-3.78 (m, 2H), 3.60-3.67 (m, 4H), 3.34-3.38 (m, 4H). APCI MS m/z 477 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][CH2:25][C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][CH:27]=4)[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(-c2ccn(CCc3c[nH]c4ccccc34)n2)sc1C(=O)NCc1ccc(F)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)thiazole-5-carboxylic acid 4-fluoro-benzylamide and 3-(2-bromo-ethyl)-1H-indole as describe in Example 83 and isolated as a yellow solid (0.056 g, 40% yield). 1H NMR (400 MHz, CDCl3) δ 8.01 (bs, 1H), 7.56 (d, J=8 Hz, 1H), 7.31-7.38 (m, 2H), 7.20-7.25 (m, 1H), 7.10-7.16 (m, 2H), 6.81 (d, J=2 Hz, 1H), 6.70 (d, J=2 Hz, 1H), 5.99-6.04 (m, 1H), 4.59 (d, J=4 Hz, 2H), 4.45 (t, J=7 Hz, 2H), 3.35 (t, J=7 Hz, 2H), 2.76 (s, 3H); MS (M+H)+=460.2; Rt=1.47 min; HRMS (M+H)+=460.16.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:16][C:12]3([CH2:15][O:14][CH2:13]3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[BrH:18].C([O-])(O)=O.[Na+]>CCOCC>[Br:18][CH2:13][C:12]1([CH2:15][OH:14])[CH2:16][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:11]1
Reactant: Br
Reactant: Cc1ccc(S(=O)(=O)N2CC3(COC3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CC(CO)(CBr)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
6-(p-Toluenesulfonyl)-2-oxa-6-azaspiro[3.3]heptane (7.99 g, 31.5 mmol) was suspended in Et2O (300 mL) and cooled to 0° C. A solution of HBr (48% in AcOH; 10 mL) in Et2O (20 mL) was added dropwise over 20 min. The resulting mixture was warmed to rt and stirred for 1 h. Reaction was monitored by LC-MS. NaHCO3 (aq. satd., 200 mL) was added and the resulting phases were separated. The aq layer was extracted with Et2O (100 mL) and then combined Et2O layer was dried (MgSO4), filtered, concentrated to dryness to give the title compound as a white solid (10.2 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 3.69 (d, J=4.8 Hz, 2H), 3.62 (d, J=8.5 Hz, 2H), 3.55 (d, J=8.5 Hz, 2H), 3.46 (s, 2H), 2.48 (s, 3H), 1.55 (t, J=5.0 Hz, 1H); MS ESI 333.9, 335.9 [M+H]+, calcd for [C12H16BrNO3S+H]+334.0, 336.0.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[N:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Temperature: 60 °C
Yield: 84.9 %

Procedure:
To a suspension of 3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (22.01 g, 71.38 mmol) in EtOH/H2O (200 mL/50 mL) was added iron powder (79.73 g, 1428 mmol) and NH4Cl (3.818 g, 71.38 mmol). The reaction mixture was heated to reflux for three hours, cooled to 60° C. and filtered through a pad of Celite. The pad of Celite was washed with 20:1 EtOH/Et3N (800 mL) and 1:1 MeOH/DCM (600 mL). The combined filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (800 mL), washed with saturated NaHCO3 aqueous solution, dried (Na2SO4) and concentrated under reduced pressure to give the product (16.87 g).
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(OC)c(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Product: COc1ccc(OC)c(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)c1
Yield: 70.9 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2,5-dimethoxyphenyl)benzamide (170.0 mg, 0.34 mmol) and acetic anhydride (0.16 ml, 1.70 mmol), the procedure of Inventive Example 94 was repeated to obtain 132.0 mg (71.5%) of the title compound in a colorless amorphous form.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:24][C:2]2[N:7]3[N:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:10]=[C:6]3[N:5]=[C:4]([S:17][CH3:18])[N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCC1
Reactant: CSc1nc(Cl)n2nc(-c3ccccc3)cc2n1
Product: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 80 °C
Yield: 78 %

Procedure:
4-Chloro-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazine (2.5 g, 9 mmol) was dissolved in cyclopentylamine (30 mL) and the resulting solution heated to 80° C. for 2 hours. Excess cyclopentylamine was removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give a foam. This foam was purified by silica gel chromatography (ethyl acetate:hexane 1:1) go give 2.3 g (78%) of N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4amine as a solid. 1H-NMR (CDCl3): δ 7.96 (m, 2H), 7.47 (m, 3H), 6.63 (d, 1H), 6.56 (s,1H), 4.54 (m, 1H), 2.61 (s, 3H), 2.2–2.0 (m, 2H), 1.9–1.5 (m, 6H); MS m/z 326 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH3:14])[C:10]=2[NH2:15])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:15][C:10]1[C:11]([CH3:14])=[N:12][NH:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:22]
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2cccc(OC)c2)cc1

Procedure:
The preparation took place in analogy with Example 15a), starting with 300 mg of 5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (50) and 277 mg of 3-methoxybenzoyl chloride. The following was obtained: 59. C19H19N3O3 (337.38) MS (ESI) 338 (M+H)
Reaction SMILES: O[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.S(Cl)([Cl:12])=O.N1C=CC=CC=1>ClCCCl>[Cl:12][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1
Reactant: O=S(Cl)Cl
Reactant: CC1(CO)COC(=O)N1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC1(CCl)COC(=O)N1
Temperature: 110 °C
Yield: 70.6 %

Procedure:
To a suspension of 4-(hydroxymethyl)-4-methyloxazolidin-2-one (1.89 g, 14.4 mmol) in 1,2-dichloroethane (10 ml) was added thionyl chloride (5.0 ml, 69 mmol) dropwise over 10 min. Pyridine (5.0 ml, 62 mmol) was added, and the solution heated to 110° C. for 2 h. The solution was cooled to RT, concentrated, and the residue purified by flash chromatography (30%→100% EtOAc in hexanes) to give the title compound as a white solid (1.52 g, 10.2 mmmol, 71%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 3H), 3.55 (s, 2H), 4.12 (d, J=9.2 Hz, 1H), 4.33 (d, 8.8 Hz, 1H), 5.8 (br s, 1H). ESI/APCI calculated for C5H8ClNO2: 149.02. Found: 150 (MH+).
Reaction SMILES: C([NH:11][C@:12]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:24][C@@:12]([C:21]([OH:23])=[O:22])([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH2:11]
Reactant: [H][H]
Reactant: C[C@@](Cc1ccc(O)cc1)(NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: C[C@](N)(Cc1ccc(O)cc1)C(=O)O

Procedure:
200 milligrams of (S)-N-carbobenzyloxy-α-methyltyrosine is mixed together with 20 milligrams of 10 percent palladium on carbon catalyst and 10 milliliters of methanol and the mixture subjected to hydrogen at a pressure of 40 psi for several hours. Thereafter, the catalyst is removed and the filtrate concentrated to obtain a (S)-α-methyltyrosine product.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:16](=O)[CH3:17]>OS(O)(=O)=O>[CH3:16][CH:17]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH:2]([C:13]([OH:15])=[O:14])[NH:1]1
Reactant: CC=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=S(=O)(O)O
Product: CC1NC(C(=O)O)Cc2c1[nH]c1ccccc21
Yield: 69 %

Procedure:
L-tryptophan (5.10 g, 25 mmol), H2SO4 (0.01 M, 30 ml) and 40% acetaldehyde (9 ml) were added in a 250 ml round-bottom flask, and then stirred and reacted at room temperature for 8 h. After filtration, wash with water and drying, white solids (4.0 g, 69%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[CH3:13][CH:14](O)[CH:15]=[CH2:16].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2cc(OC)ccc2C1=O
Yield: 31 %

Procedure:
A solution of 50.0 g of 5-methoxy-1-indanone, 80 ml of 3-buten-2-ol, 132 ml of 2,2-dimethoxypropane and 600 mg of p-toluenesulfonic acid in 500 ml of toluene was brought to boiling. The resulting methanol/acetone mixture was distilled off and the reaction solution was subsequently boiled under reflux for an additional 48 hours. After cooling, the solution was evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 5:1) yielded 19.2 g (31%) of (RS)-2-(2-buten-1-yl)-5-methoxy-1-indanone as a pale yellow oil.