Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:6][CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH:10]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: NCCc1ccc(C(CCCCCC(=O)O)c2cccnc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C(O)CCCCCC(c1ccc(CCNS(=O)(=O)c2ccc(F)cc2)cc1)c1cccnc1
Yield: 66 %

Procedure:
Prepared analogously to Example 13 from 7-(4-(2-aminoethyl)phenyl)-7-(3-pyridyl)heptanoic acid and 4-fluorobenzenesulphonic acid chloride. Yield: 66% of theory, Resin, Rf value: 0.20 (silica gel: chloroform/methanol=10:1) C26H29FN2O4S (484.6) Calculated: C 64.44 H 6.03 N 5.72 Found: 64.48 5.99 5.72
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>CCCCCC.O1CCCC1>[CH:10]1[C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([B:26]([OH:29])[OH:27])=[CH:7][CH:6]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
21.8 g (67.5 mmol) of 9-(4-bromophenyl)-9H-carbazole was put into a 500 mL three-neck flask. The air in the flask was replaced with nitrogen. To the mixture were added 200 mL of tetrahydrofuran (THF), and then the solution was cooled to −78° C. Into this solution, 48.9 mL (74.3 mmol) of n-butyllithium (a 1.52 mol/L hexane solution) was dropped, and the solution was stirred at the same temperature for 2 hours. After the stirring, 17.4 mL (155 mmol) of trimethyl borate was added to the solution, and the solution was stirred for about 1 hour at the same temperature. Then, the mixture was stirred for 24 hours while the temperature of the solution was being increased to room temperature. Thereafter, to the solution was added about 200 mL (1.0 mol/L) of hydrochloric acid, and then the solution was stirred at room temperature for 1 hour. The organic layer of the mixture was washed with water, and then the aqueous layer was extracted with acetate ether. The extract was combined with the organic layer and then washed with a saturated saline solution. The organic layer was dried with magnesium sulfate. After the drying, the mixture was subjected to suction filtration, and then the obtained filtrate was condensed. The obtained residue was recrystallized with chloroform/hexane to give 12.8 g of a white powdered solid, which was the object of the synthesis, at a yield of 65.9%. A synthesis scheme of Step 2 is shown in (f-2) given below.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH:7]1[O:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[CH2:8]1)=[O:4].[CH:15]([O-:17])=[O:16].[Na+].O>CS(C)=O>[CH:15]([O:17][CH2:2][C:3]([NH:5][CH2:6][CH:7]1[O:13][CH:12]2[N:9]([C:10](=[O:14])[CH2:11]2)[CH2:8]1)=[O:4])=[O:16]
Reactant: O=C(CCl)NCC1CN2C(=O)CC2O1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=COCC(=O)NCC1CN2C(=O)CC2O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A mixture of (3RS,5RS)-3-(N-Chloroacetylaminomethyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one(260 mg), Sodium formate(97 mg) in Dimethyl sulfoxide(5 ml) was stirred at room temperature for 15 hrs, then 70° C. for 3days. The reaction mixture was poured into water, extracted with Chloroform and dried over Magnesium sulfate. The residue which obtained after removal of solvent in vacuo, was purified by flash chromatography (Ethyl acetate). The title compound was obtained as oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[N:7][C:8]([O:12][CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:18]3[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:17]=3[O:16][CH3:15])=[N:7][C:8]([O:12][CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)c2ccc(Br)cc2n1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1nc(-c2ccc(C(F)(F)F)cc2OC)c2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.39 %

Procedure:
The crude residue from step 2 was dissolved in 22 mL dioxane and was treated with PdCl2(dppf)-CH2Cl2 adduct (0.608 g, 0.745 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (1.802 g, 8.19 mmol), potassium carbonate (4.12 g, 29.8 mmol), and 8 mL water was added. The reaction mixture was allowed to stir at room temperature overnight. LC/MS showed product, so the aqueous layer was removed, and the reaction mixture was concentrated. Purification of the crude residue by silica gel column chromatography (0-50% EtOAc/heptane) gave 7-bromo-2-methoxy-4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline (0.166 g, 0.402 mmol, 5.39% yield). (M+H)+=413.0.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:17])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[CH2:25]([O:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][CH:10]([CH3:11])[CH3:5])[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:26]([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1c(O)c(=O)[nH]c2ccccc12
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC(C)C)c(=O)n(CC(C)C)c2ccccc12
Temperature: 50 °C

Procedure:
To a solution of ethyl 3-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylate (250 mg, 1.07 mmol) in DMF (6 mL) was added cesium carbonate (908 mg, 2.79 mmol), 1-bromo-2-methylpropane (294 mg, 2.14 mmol). The reaction was heated at 50° C. for 16 h. The reaction mixture was allowed to cool to rt and washed with EtOAc. The organic phase was then washed with H2O and dried over Na2SO4 and concentrated in vacuo to give the crude product. Intermediate 28 was isolated via ISCO flash chromatography using a 40 g silica gel cartridge eluted with a 30-minute gradient from 0 to 100% EtOAc in hexane (350 mg, 1.01 mmol, 95% yield). LC-MS (ESI) m/z 346 (M+H), RT=2.30 min (Method B).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.[NH2:15][NH2:16]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:15][NH2:16])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2[nH]ccc2c1

Procedure:
A 100 mL round bottomed flask was charged with methyl 1H-indole-5-carboxylate (1.6 g, 9.13 mmol) and ethanol (20 mL). To this was added hydrazine monohydrate (10 g) and the mixture was placed under reflux for 7 days. The reaction mixture was concentrated to dryness and chloroform (80 mL) was added. The mixture was decanted and the insoluble white residue was washed once more with chloroform to remove traces of starting material. The white solid (1.54 g, 96%) was dried en vacuo and 1H NMR analysis was consistent with the solid compound. 1H NMR (DMSO d6, 400 MHz) δ 10.7 (br s, 1 H), 9.6 (br s, 2H), 8.21-8.15 (m, 1 H), 7.71 (dd, J=8.6 and 1.7 Hz, 1 H), 7.50 (d, J=8.6 Hz, 1 H), 7.44-7.39 ( m, 1 H) and 6.58-6.53 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.I[CH3:14].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][O:10][CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(CO)c1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of the material from Step 2 (500 mg, 2.18 mmol) in 8 mL of DMF was added iodomethane (0.68 mL, 10.9 mmol) and NaH (60% in oil, 131 mg, 3.28 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water, and extracted with EtOAc and hexane. The organic layer was separated, washed with saturated sodium bicarbonate, dried over MgSO4, and concentrated. The crude was purified by flash silica column (eluting with 5% EtOAc in hexane) to get 1-bromo-4-(1-methoxy-2-methylpropan-2-yl)benzene (460 mg, 87%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)[C:3]1=[O:31].C1CCN2C(=NCCC2)CC1.[O:43]=O>>[CH3:1][N:2]1[C:3](=[O:31])[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:18]=2)=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:6]1=[O:43]
Reactant: O=O
Reactant: CN1CC(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)C(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 48 %

Procedure:
To a stirred solution of 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (200 mg, 0.49 mmol) in AcN (10 mL) was added DBU (224.5 mg, 1.47 mmol) dropwise and then the reaction mixture was stirred for 6 h under a continuous flow of oxygen. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (2×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford 1-methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (100 mg, 48%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.18-8.09 (m, 1H), 8.0-7.95 (m, 3H), 7.65-7.59 (m, 3H), 7.48-7.39 (m, 1H), 7.28-7.18 (m, 4H), 7.1-7.09 (m, 2H), 5.25 (s, 2H), 2.86 (s, 3H); MS: M−H: m/z=420.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.C(Cl)Cl.CO>[F:22][C:10]1[C:9]2[O:8][C:5]3[C:4]([C:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]=2[CH:13]=[C:12]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:11]=1)=[CH:3][C:2]([C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: NC1=NC2(CO1)c1cc(-c3cccnc3)ccc1Oc1c2cc(-c2cccnc2)nc1F

Procedure:
A mixture of 7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (40.0 mg, 0.104 mmol), pyridin-3-ylboronic acid (21.73 mg, 0.177 mmol), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ii) (2.95 mg, 4.16 μmol) and potassium phosphate (66.2 mg, 0.312 mmol) in 1.5 ml of dioxane/water=2:1 was heated at 120 C microwave for 20 min. LCMS showed mostly conversion to the mono coupling product. 10 mg of pyridin-3-ylboronic acid (21.73 mg, 0.177 mmol) was added and the reaction was heated at 140 C under microwave for 20 min. The reaction mixture was directly loaded to CC (SiO2, DCM to DCM/MeOH=100:1 to 100:6) to give crude final product which was further purified by prep TLC (DCM/MeOH) to give 1-fluoro-3,7-di(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as a white solid. MS (M+1): 426.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:25]([N:27]([CH2:42][CH3:43])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:37]([CH3:38])=[C:36]([CH:39]=O)[NH:35][C:34]=1[CH3:41])=[O:32])[CH3:26].N1CCCCC1>C(O)C>[CH2:42]([N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][NH:30][C:31]([C:33]1[C:37]([CH3:38])=[C:36](/[CH:39]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)(=[O:12])=[O:11])=[CH:21][CH:20]=3)[NH:35][C:34]=1[CH3:41])=[O:32])[CH3:43]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3cccc(C(F)(F)F)c3)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(C(F)(F)F)c4)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.2 %

Procedure:
To a solution of 5-(3-Trifluoromethyl-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (100 mg, 0.28 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (75 mg, 0.28 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. The solvent was evaporated and the residue was purified on a silica gel column eluting with MeOH—CH2Cl2 1:9 to provide 105 mg (62%) of 2,4-dimethyl-5-[2-oxo-5-(3-trifluoromethyl-phenylmethanesulfonyl)-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a pale orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].O1CCCC1.C([Li])CCC.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CCCCCC.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:7]=1
Reactant: O=C1CCCCC1
Reactant: Oc1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Oc1ccc(Cl)cc1C1(O)CCCCC1
Temperature: -30 °C

Procedure:
A mixture of 20.75 g of 2-bromo-4-chloro-phenol, 200 ml of anhydrous tetrahydrofuran cooled to -30° C. was stirred and then 172 ml of a solution of butyllithium in hexane titrating 1.16 M/l were added thereto with stirring over 45 minutes at -30° C. The mixture was stirred for 41/2 hours at -30° C. and was then cooled to -78° C. at which 10.35 ml of cyclohexanone were added over one hour. The mixture was stirred at -75° to -78° C. for 17 hours and the temperature was then allowed to return to room temperature. The mixture was poured into a water-concentrated hydrochloric acid mixture and was then extracted with ether. The ether extracts were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 25 g of raw residue. The latter was chromatographed over silica gel H under pressure and elution with methylene chloride yielded 7 g of 4-chloro-2-(1-hydroxycyclohexyl)-phenol melting at 110° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[I-:10].[Na+]>CC(C)=O>[I:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: C=CCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCCCCCCI
Yield: 91.4 %

Procedure:
8-Iodooct-1-ene was prepared by refluxing 5 g of 8-bromooct-1-ene (26 mmol) and 10 g of sodium iodide in 50 ml of acetone for 1 hour. The acetone was stripped and the residue was partitioned between water and ether. The aqueous phase was washed with brine, dried over magnesium sulfate and stripped to give 5.66 g of 8-iodooct-1-ene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31](O)=[O:32])=[N:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOCC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:31]([C:26]4[CH:27]=[CH:28][C:29](=[O:30])[N:24]([CH3:23])[N:25]=4)=[O:32])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: Cn1nc(C(=O)O)ccc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cccc(F)c4)nc23)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (30 mg, 0.10 mmol), 1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (34 mg, 0.22 mmol), and HATU (84 mg, 0.22 mmol) was added 0.8 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.30 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The resulting fine yellowish suspension from the reaction mixture was filtered, rinsed with first DMF and then ether, to provide the final product as a yellowish solid (14.4 mg, 33% yield). MS (apci) m/z=434.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6].[CH:19]([N-:22]C(C)C)(C)[CH3:20].[Li+].C(NC(C)C)(C)C.C([Li])CCC>O1CCCC1.CCCCCC.C(#N)C>[OH:6][C:5]([C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:20][C:19]#[N:22]
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccccc1C(O)(CC#N)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
As in Example 97, a solution of 2,2'-dimethoxybenzophenone (24.2 g) and acetonitrile (6 mL) in tetrahydrofuran (120 mL) was added to a chilled (-70° C.) solution of lithium diisopropylamide prepared from diisopropylamine (16 mL) and 1.55M n-butyl lithium in hexane (74 mL) in dry tetrahydrofuran (120 mL). After the reaction was kept at -70° C. for 15 minutes, it was allowed to warm to room temperature and then was worked up in the usual manner to furnish 26.4 g of beta-hydroxy-beta-(2-methoxyphenyl)-2-methoxybenzenepropanenitrile, mp 170°-180° C. A sample was recrystallized from methanol to give the analytical specimen, mp 181°-182° C.
Reaction SMILES: ClC(Cl)(Cl)CC([O:6][C:7]([CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:21])[CH2:14][CH2:13]1)=[O:8])C>C1COCC1.OP([O-])(O)=O.[K+].[Zn]>[C:7]([CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:21])[CH2:14][CH2:13]1)([OH:8])=[O:6]
Reactant: CC(CC(Cl)(Cl)Cl)OC(=O)CCCN1CCC(COC(=O)c2c[nH]c3ccccc23)CC1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C(O)CCCN1CCC(COC(=O)c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1H-indole-3-carboxylic acid 1-[3-(2,2,2-trichloroethyl-ethoxycarbonyl)-propyl]piperidine-4-ylmethyl ester (0.48 g, 1.0 mmol) was dissolved in a mixture of THF (25 ml) and aqueous 1 M KH2PO4 (5 ml). Zn-powder (0.66 g, 10.0 mmol) was added and the resulting mixture stirred at room temperature for 24 h. The reaction mixture was filtered through a pad of kiselguhr and the filtrate evaporated in vacuo. The residue was separated with flash chromatography (SiO2, EtOAc/MeOH (2:1)). The expected product was obtained as a white solid (0.29 g, 84.2%). Conversion to the hydrochloride salt was effected using etheral HCl.
Reaction SMILES: [N:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O-:10].[Na+]>CO>[N:1]1([C:7](=[NH:8])[O:10][CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CN1CCCCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCCCC1

Procedure:
A solution of 45.2 g. (0.41 mole) of 1-piperidinecarbonitrile and 11 g. (0.05 mole) of a 25% solution of sodium methoxide in methanol in 200 ml. of methanol is stirred at room temperature under a nitrogen atmosphere for 18 hours. The solvent is evaporated and the residue is taken up in ether. The ether solution is filtered through a small pad of Celite and evaporated to constant weight to give 57.8 g. (99%) of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](OC)([CH2:14][CH2:15][CH3:16])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].C(OC(C)C)(C)C>CO>[CH3:1][O:2][C:3]([CH2:14][CH2:15][CH3:16])=[CH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CCCC(CC(=O)Nc1ccccc1)(OC)OC
Solvent: CO
Solvent: CC(C)OC(C)C
Product: CCCC(=CC(=O)Nc1ccccc1)OC
Yield: 45.8 %

Procedure:
60 g of 3,3-dimethoxy-hexananilide were heated at 145° C until the distillation of methanol ceased and after cooling, isopropyl ether was added thereto. The precipitate formed was recovered by vacuum filtration to obtain 24 g of 3-methoxy-2-hexenanilide melting at 104° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[CH2:4][C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([OH:9])=O.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[CH3:13][N:2]([CH3:1])[C:3](=[O:12])[CH2:4][C:5]([CH3:11])([CH3:10])[CH2:6][C:7]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH:28]=1)=[O:9]
Reactant: CN(C)C(=O)Nc1cccc(N)c1
Reactant: CN(C)C(=O)CC(C)(C)CC(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC(C)(C)CC(=O)Nc1cccc(NC(=O)N(C)C)c1
Temperature: -5 °C
Yield: 22.7 %

Procedure:
N,N-Dimethyl-3,3-dimethyl glutaramic acid (2.6 grams) and 1.5 gram triethyl amine were mixed in 150 ml tetrahydrofuran. The mixture was stirred magnetically and cooled to -5° C. Methane sulfonyl chloride (1.7 gram) was added dropwise and stirred at -5° C. for one hour. 1-(3-amino phenyl)-3,3-dimethyl urea (2.49 grams) was dissolved in 35 ml tetrahydrofuran. This solution was added dropwise and stirred for one hour at -5° C. The cooling bath was then removed. When the reaction mixture reached room temperature it was concentrated by rotary evaporation. Methylene chloride (175 ml) was added and the mixture washed once with 10 percent w/w NaOH, twice with water and dried over sodium sulfate. Rotary evaporation yields 1.1 grams of the title compound. This compound will be referred to as compound No. 3.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:4])=[O:3].[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[CH:14][C:5]([S:2](=[O:4])(=[O:3])[NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:6][C:7]=1[O:15][CH2:16][CH3:17]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C(=O)OC
Reactant: CC(C)(C)N
Product: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C(=O)OC

Procedure:
In a manner analogous to the method described in example 29, methyl 4-chlorosulfonyl-2-ethoxy-benzoate was reacted with tert-butylamine to give 4-tert-butylsulfamoyl-2-ethoxy-benzoic acid methyl ester.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](O)=[O:11])[CH2:2]1.S(Cl)([Cl:16])=O>>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([Cl:16])=[O:11])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(C(=O)O)C1
Reactant: O=S(Cl)Cl
Product: CC1CCC(C(C)C)C(C(=O)Cl)C1

Procedure:
p-Menthane-3-carboxylic acid (1.84g.), was heated under reflux with thionyl chloride (4 ml.) for 3 hours. The excess of thionyl chloride was then distilled off in vacuo. The crude produce p-menth-3-oyl chloride was dissolved in diethyl ether (25 ml.) and the ethereal solution was added with stirring and cooling to a solution of ethylamine (1.0 ml. of 70% w/s solution in water) and sodium hydroxide (0.4g.) in water (25 ml.). The mixture was stirred for one hour and the ethereal layer was then separated. The aqueous layer was washed with ether (25 ml.) and the combined ethereal solution was washed with dilute hydrochloric acid and then water. The ether solution was dried (MgSO4) and evaporated to give a white crystalline solid. The solid was recrystallised from acetone: water (9:1) by dissolving the crystals at room temperature and then cooling to produce N-ethyl-p-menthane-3-carboxamide as a white crystalline solid, mp. 82.5°-84.5°.