Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1OS(C(F)(F)F)(=O)=O)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[CH2:48]([O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[CH2:48]([O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=1[CH2:20][N:7]([CH2:6][C:5]1[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=[C:3]([C:2]([F:47])([F:1])[F:46])[CH:4]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: O=S(=O)(Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2ccccc2OCc2ccccc2)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Trifluoromethanesulfonic acid 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl ester (620 mg) is dissolved in 1,4-dioxane (10 ml) and thereto are added 2-benzyloxyphenyl boronic acid (398 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (142 mg) and cesium carbonate (567 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the insoluble materials are removed by filtration through Celite™. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give (2′-benzyloxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (617 mg). MS (m/z): 747 [M+H]+
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[CH2:7]([NH2:10])[CH2:8][CH3:9].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[C:1]([CH2:3][C:4]([NH:10][CH2:7][CH2:8][CH3:9])=[O:6])#[N:2]
Reactant: CCCN
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCNC(=O)CC#N
Temperature: 0 °C

Procedure:
500 mg (5.88 mmol) Cyanoacetic acid are dissolved in 30 ml dimethylformamide, 382 mg (6.47 mmol) n-propylamine, 874 mg (6.47 mmol) 1-hydroxy-1H-benzotriazole hydrate and 718 mg (5.88 mmol) 4-dimethylaminopyridine are added. The reaction mixture is stirred at 0° C., then 1.24 g (6.47 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 18 hours, then water and ethyl acetate are added. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH:6](OCC)[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].C=O.[C:27](O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][P:4]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH:6]1[CH2:27][CH2:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(OCC)P(=O)(CCCNCc1ccc(Cl)cc1)OCC
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(CCCNCc1ccc(Cl)cc1)C1CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g of 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl ester are dissolved in 10 ml of methanol, 0.36 g (0.53 ml)of a 35% aqueous formaldehyde solution is added, and the mixture is stirred at room temperature for one hour. 0.4 g of glacial acetic acid and 0.40 g of sodium cyanoborohydride are added, and the mixture is stirred at room temperature for 2 hours, concentrated by evaporation under reduced pressure, taken up in dichloromethane and washed with 5% aqueous sodium hydrogen carbonate solution. The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation under reduced pressure. The oily residue is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(tetrahydrofuran-2-yl)phosphinic acid ethyl ester in the form of a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH2:18]([O:20][C:21]([C:23]1[C:27]2[CH:28]=[CH:29][C:30](Br)=[CH:31][C:26]=2[O:25][N:24]=1)=[O:22])[CH3:19].N#N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH2:18]([O:20][C:21]([C:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:7]3[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=3[CH3:1])=[CH:31][C:26]=2[O:25][N:24]=1)=[O:22])[CH3:19]
Reactant: Cc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1noc2cc(Br)ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: N#N
Solvent: C1COCCO1
Product: CCOC(=O)c1noc2cc(-c3ccc(O)cc3C)ccc12
Temperature: 50 °C
Yield: 92.6 %

Procedure:
A solution of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.624 g, 2.67 mmol) and 6-bromo-benzo[d]isoxazole-3-carboxylic acid ethyl ester (0.360 g, 1.33 mmol) in 1,4-dioxane (20 mL) is evacuated and re-filled with N2 3 times. To this solution, Pd2(dba)3 (0.010 g), tricyclohexyl phosphine (PCy3, 10 mg), and aqueous K3PO4 (1.5 mL, 1.30 M) are added. The resulting mixture is heated at 50° C. for 2 hours under N2. The reaction mixture is cooled to room temperature and filtered through a pad of celite. The filtrate is concentrated, and the residue is purified via silica gel chromatography eluting with 25% ethyl acetate in hexanes to give the title compound (0.366 g, 93%). ES/MS m/e 298.0 (M+1); 296.0 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][CH2:15][F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][N:28]([C:11]3[C:10]([F:13])=[C:9]4[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]4[CH2:14][CH2:15][F:16])=[CH:3][C:2]=3[F:1])[CH2:27]2)[CH2:23][CH2:22]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(CCF)c2c(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 33.2 %

Procedure:
Using 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (120 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (98.0 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]1=[O:25].Cl>C(O)C.O.[Fe]>[NH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[C:3]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])[CH:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc([N+](=O)[O-])cc(Cl)c2Cl)c1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc(N)cc(Cl)c2Cl)c1=O
Temperature: 65 °C
Yield: 23.2 %

Procedure:
In flask were placed 7.47 grams (0.019 mole) of 3-(2,3-dichloro-5-nitrophenylmethyl)-1-methyl-6-trifluoromethyluracil and 5.68 grams (0.94 mole) of powdered iron in 115 mL of ethanol and 9 mL of water. Dropwise, 9.0 mL of concentrated hydrochloric acid was added to the reaction mixture. Upon completion of the addition the reaction mixture was heated to 65° C. and maintained at this temperature for three hours. After being cooled to ambient conditions, the reaction mixture was filtered through Celite filter aid, and the collected precipitate was washed several times with ethanol. The solid removed by filtration was then dissolved in ethyl acetate, and this solution was washed twice with a saturated aqueous solution of sodium chloride. The dark brown solution was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, leaving 1.62 grams of 3-(5-amino-2,3-dichlorophenylmethyl)-1-methyl-6-trifluoromethyluracil as a solid. This reaction was repeated.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[O:8][CH2:9][C:10]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([C:27]#[C:28][CH3:29])[CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Cl.O>C1COCC1.CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[O:8][CH2:9][C:10]1([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([C:27]#[C:28][CH3:29])[CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CC(CC(=O)OC)c1ccc(OCC2(COc3cccc(C(C)(C)C)c3)CC2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3cccc(C(C)(C)C)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
410 mg of methyl 3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoate were dissolved in a mixture of THF/MeOH/2N NaOH=1:1:1 (5 ml of each) and stirred at room temperature. After 45 min, the mixture was acidified to pH 1 by adding 4N HCl. 50 ml of water were added, the mixture was extracted three times with 50 ml each time of ethyl acetate. The combined organic phases were dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by means of RP-HPLC. This gave 148 mg of 3-{4-[1-(3-tert-butylphenoxymethyl)cyclopropylmethoxy]phenyl}hex-4-ynoic acid.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc(OCC(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCC(=O)Cl)cc1
Reaction time: 2 h

Procedure:
To a suspension of commercially available 2-(4-cyanophenoxy)acetic acid (4.0 g, 22.6 mmol) in dichloromethane (80 mL) was added oxalyl dichloride (2.17 mL, 24.8 mmol). To this mixture was added N,N-dimethylformamide (30 μL) dropwise and stirred for 2 hours during which cessation of evolution of gas was observed. The resulting solution was diluted with dichloromethane (50 mL) and the solvent was removed under reduced pressure to provide the title compound as an oil which became a solid upon storing in the refrigerator.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[I-].[K+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>CO.C1C=CC=CC=1.O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.19 g of sodium methoxide in 40 ml of methanol is added 3.21 g of 4-chlorophenol. A few crystals of potassium iodide are added, followed by a solution of 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The solution is heated at reflux overnight. After cooling to room temperature, the solution is poured into 100 ml of water and extracted with two 100 ml portions of ether. The combined extracts are washed with 50 ml of 5% NaOH, 50 ml of saturated brine and dried over MgSO4. The solvent is evaporated at reduced pressure and the residue is triturated with petroleum ether to give the product as white crystals, mp 100°-101.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[N:15]=[C:14]2[NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN1C(=O)CCC1.CO>[N:4]1([CH2:3][CH2:2][O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH2:32])=[O:31])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: ClCCN1CCCCC1
Reactant: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(O)cc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CO
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(OCCN3CCCCC3)cc12
Temperature: 90 °C

Procedure:
To 1-(2-chloroethyl)piperidine (45 μmol) was added the solution of 2-(6-hydroxy-2-(pyridin-3-yl)quinazolin-4-ylamino)benzamide (30 μmol) in NMP (200 μL) PS-BEMP (90 μmol) was added to the vials by resin dispenser. After the reaction mixture was heated at 90° C. for 12 h, the residue was diluted with methanol and purified by mass triggered PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([OH:14])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.CCCCCC>FC(F)(F)C(O)=O>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]2[C:4]([C:12](=[O:14])[CH2:11][CH2:10][S:9]2)=[CH:5][CH:6]=1
Reactant: O=C(O)CCSc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1CCSc2c1ccc(Cl)c2Cl
Temperature: 25 °C
Reaction time: 68.2 h
Yield: 13.2 %

Procedure:
The 3-(2,3-dichlorophenylthio)propanoic acid from Step 1 (3.88 g, 15 mmol) was dissolved in trifluoroacetic acid (10 mL), treated with trifluoroacetic anhydride (5 mL) and stirred at room temperature for 68.2 hours. The reaction mixture was poured into 10% Na2CO3 (100 mL), extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil. The crude material was passed through a column of silica gel eluting with 40% ethyl acetate/hexane to give 7,8-dichlorothiochroman-4-one as a white solid (0.46 g, 13%): mp 93°-102° C.; 1H NMR (CDCl3) 300 MHz 7.99 (d, J=8.7 Hz, 1H) 7.27 (d, J=8.7 Hz, 1H) 3.25 (m, 2H) 2.97 (m, 2H). Mass spectrum: M+=233.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=O)[CH2:10][CH2:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=O.[CH:20]1[CH2:24][CH:23]=[CH:22][CH:21]=1>CO.CS(C)=O>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[CH:10]=[CH:11][C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[C:20]2[C:21]=1[CH:22]=[CH:23][CH2:24]2
Reactant: O=C(CCC(=O)c1ccco1)c1ccco1
Reactant: C1=CCC=C1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: C1=Cc2c(-c3ccco3)ccc(-c3ccco3)c2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.6 %

Procedure:
18.9 ml of a 30 percent strength solution of sodium methanolate (105 mmol) in methanol was initially introduced into the reaction vessel at 0° C, and a solution of 9.2 g (42.2 mmol) of 1,4-bis(2-furyl)-1,4-butanedione and 3.8 ml (46.2 mmol) of cyclopentadiene in DMSO were added dropwise in the course of 1 hour. After the mixture had been stirred at room temperature for 45 minutes it was poured onto ice-water and extracted with diethyl ether. After drying and evaporation, the residue was chromatographed on silica gel. 3.0 g (29 %) of the indene 14 could be obtained with hexane/methylene chloride (2:1) as the mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
Methyl 2-chloropyridine-4-carboxylate (2.50 g, 14.60 mmol) was dissolved in anhydrous THF (50 mL) and this solution was cooled to −78° C. under N2 atmosphere. Diisobutylaluminium hydride 1.0 M in hexanes (63.3 mL, 63.30 mmol) was added dropwise stabilizing the temperature between −50° C. and −70° C. The reaction mixture was stirred 1.5 h at −78° C. and allowed to stand at room temperature for 3 h. A solution of aqueous 10% NH4Cl was slowly added and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with water (3×20 mL), brine (2×20 mL), dried over MgSO4, filtered and evaporated. (2-Chloropyridin-4-yl)methanol SLA 07152 was obtained as a yellow oil (1.97 g, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:70]([NH2:74])([CH2:72][CH3:73])[CH3:71]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]2[O:15][CH2:14][CH2:13][CH2:12][O:11]2)[N:7]=[C:6]([NH:74][C@H:70]([CH2:72][CH3:73])[CH3:71])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(C2OCCCO2)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(C2OCCCO2)n1
Temperature: 25 °C
Yield: 68 %

Procedure:
Dissolve 2-chloro-6-[1,3]dioxan-2-yl-isonicotinic acid methyl ester (150 mg, 0.6 mmol), palladium (II) acetate (7.0 mg, 0.03 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (20 mg, 0.03 mmol) and cesium carbonate (482 mg, 1.3 mmol) in toluene (2 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen gas. Add (S)-(+)-sec-butylamine (0.074 mL, 0.74 mmol) and heat the sealed mixture overnight at 100° C. Cool to room temperature, dilute with diethyl ether and filter through filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes) to give the title compound (68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)=O)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.ClCCl>CC(C)=O>[CH:26]1([NH:29][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH2:28][CH2:27]1
Reactant: CS(=O)c1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Reactant: NC1CC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Fc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CC3)n2)ccn1

Procedure:
A solution of 2-(2-fluoro-4-pyridinyl)-3-[2-(methylsulfinyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine (430 mg, 90%, ˜1.1 mmol) in cyclopropylamine (4 mL, 57.7 mmol) was heated at 45° C. in a sealed glass tube for 6 hours. The excess cyclopropylamine was removed in vacuo to provide crude N-cyclopropyl-4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (370 mg, 97%). A small portion of the crude material was chromatographed (19:1 dichloromethane:acetone to 9:1 dichloromethane:acetone) to provide material as a light yellow solid. Rf 0.26 (9:1 dichloromethane:acetone); 1H NMR (CDCl3) δ 8.52 (d, 1H), 8.42 (d, 1H), 8.29 (d, 1H). 8.21 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 7.32 (s, 1H), 6.98 (t, 1H), 6.48 (d, 1H), 5.69 (br, 1H), 2.81 (m, 1H), 0.83 (m, 2H), 0.61 (m, 2H); MS m/z 347 (M+1).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].O1[C:9]2([CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:25]=[C:24]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[O:34][C:35]([F:38])([F:37])[F:36])[NH:23][N:22]=4)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[O:8]CC1>CO.O>[F:38][C:35]([F:36])([F:37])[O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][O:26][C:24]1[NH:23][N:22]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([CH:12]3[CH2:13][CH2:14][C:9](=[O:8])[CH2:10][CH2:11]3)=[N:16][CH:17]=2)[CH:25]=1
Reactant: FC(F)(F)Oc1ccccc1COc1cc(-c2ccc(C3CCC4(CC3)OCCO4)nc2)n[nH]1
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Solvent: CO
Product: O=C1CCC(c2ccc(-c3cc(OCc4ccccc4OC(F)(F)F)[nH]n3)cn2)CC1

Procedure:
Indium chloride (0.11 g, 0.536 mmol) was added to a solution of Example 93E (0.255 g, 0.536 mmol) in methanol (3 ml) and water (3 mL). The resulting solution was heated (85° C.) for hours before the methanol was evaporated. The residue was partitioned with ethyl acetate and water, and the organic phase was washed with brine, dried (magnesium sulfate), filtered, and concentrated. The crude product was used in the following step without further purification.
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:48]=[CH:47][C:41]([C:42]([O:44]CC)=[O:43])=[CH:40][CH:39]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1>>[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:47][CH:48]=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Agent: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoic acid (Compound 7), 500 mg (1.45 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound using 4 ml (4 mmol) of LiOH (1N aqueous solution).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>ClCCl.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:10]=2)[C:6]([CH3:14])([CH3:13])[C:7]1=[O:12]
Reactant: O=C(Cl)c1ccncc1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-amino-1,3,3-trimethylindolin-2-one (W. von der Saal et al., J. Med. Chem. 1989, 32(7), 1481-1491; 500 mg, 2.63 mmol) in dry dichloromethane (13 ml) were added triethylamine (798 mg, 1.1 ml, 7.88 mmol) and isonicotinoyl chloride hydrochloride (724 mg, 3.94 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, water and 1 M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1 M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as brown solid (661 mg).