Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=2)[C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:28])=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:28])=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:29]=[CH:30][CH:31]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Oc2ccc(N)cc2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 80 °C
Yield: 81.1 %

Procedure:
A suspension of 3-(1-cyanocyclopropyl)-N-[2-methyl-5-(4-nitrophenoxy)phenyl]benzamide (3.19 g, 22.5 mmol), calcium chloride (5.55 g, 50 mmol) and reduced iron (14.5 g, 260 mmol) in ethanol (540 mL)/water (60 mL) was stirred with heating at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, passed through a pad filled with celite to separate insoluble material, and the insoluble material was washed with ethanol. The filtrate and the washing were combined and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (400 mL), washed with 5% aqueous ammonium chloride solution (200 mL), water (200 mL×2), 5% aqueous sodium hydrogencarbonate solution (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (7.0 g, 84%) as a pale-yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].Br[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccncc1
Reactant: Fc1ccccc1CCCBr
Product: CC(CCCc1ccccc1F)c1ccncc1
Yield: 71.9 %

Procedure:
1.62 g (15.1 mmol) of 4-ethylpyridine and 3.3 g (15.1 mmol) of 1-bromo-3-(2-fluorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.64 g of the desired compound (yield: 71.6%). The resulting compound was identified as 1-(2-fluorophenyl)-4-(4-pyridyl)-pentane (hereinafter referred to as compound 40) by the following analytical results.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31](OC1C=CC=CC=1)=[O:32])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:43]([NH2:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(OCC)(=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:51][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:32])(=[O:28])=[O:29])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)Oc1ccccc1
Reactant: CCCCCCCCN
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCCNC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Yield: 97.6 %

Procedure:
A benzene (10 ml) solution containing 200 mg (0.40 mmol) of 3-benzyloxy-N-[2-[(phenyloxycarbonylamino)sufonyl]phenyl]benzamide produced in Example 45 and 0.15 mol (0.88 mmol) of octylamine was heated under reflux for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel chromatography to obtain 210 mg (yield: 98.0%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[CH3:22][C:23]([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])([CH3:26])[C:24]#[CH:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>N1C=CC=CC=1>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][C:23]([CH3:22])([CH3:26])[C:24]#[CH:25])[CH:29]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Reactant: C#CC(C)(C)Oc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: C#CC(C)(C)Oc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(C)=O)sc4c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 3-[(1,1-dimethylprop-2-yn-1-yl)oxy]benzoic acid (215 mg, 1.07 mmol) in pyridine (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (407 mg, 1.07 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100), and crystallized from ethyl acetate to give the title compound (181 mg, 70%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[S:6][C:5]([CH:7]([O:13][Si:18]([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)c1ccc(Br)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-(5-bromothiophen-2-yl)-2-hydroxyacetate (2.5 g, 9.43 mmol, 1.0 eq), DMAP (115 mg, 0.94 mmol, 0.1 eq) in dichloromethane (30 mL) was added TBDMSCl (2.85 g, 18.91 mmol, 2.0 eq) and triethylamine (5.0 mL, 35.97 mmol, 3.8 eq) at 0° C. After addition, the ice-water bath is removed and the mixture is allowed to reach room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE:EA=50:1) to produce ethyl 2-(5-bromothiophen-2-yl)-2-(tert-butyldimethylsilyloxy)acetate (2.5 g, 69.9%). 1H NMR (400 MHz, DMSO-d6): δ 0.03 (s, 3H), 0.07 (s, 3H), 0.85 (s, 9H), 1.16 (t, J=7.0 Hz, 3H), 4.09-4.15 (m, 2H), 5.56 (d, J=0.8 Hz, 1H), 6.91-6.92 (m, 1H), 7.08 (d, J=4.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:30]2>COC(O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[CH2:32][N:31]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:30]4)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: NC(=O)CN1Cc2ccc(N)cc2C1
Agent: CCC(O)OC
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)CN(CC(N)=O)C4)nn12

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (0.111 g, 0.298 mmol) and 2-(5-Amino-1,3-dihydro-isoindol-2-yl)-acetamide (0.077 g, 0.40 mmol) were reacted in an analogous manner to Example 908D at 50° C. for 16 h in methoxypropanol. Pale yellow solid was filtered off, washed with water. Found to be pure product (35 mg, 28%). LCMS=414.9 (M+H), HPLC rt=2.256 min, purity=99%. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.40 (s, 1H), 8.95 (s, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.75 (s, 1H), 7.47 (dd, J=7.6 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.32 (s, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.13-7.05 (m, 3H), 6.94 (d, J=4.6 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 3.89 (s, 4H0, 3.78 (s, 3H), 3.27 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCC2)c1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C2CCCC2)c1Cl
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To a stirred solution of methyl 5-bromo-2-chloro-3-(cyclopentylamino)benzoate (0.550 g, 1.65 mmol) in acetonitrile (20 mL) was added cesium carbonate (1.08 g, 3.31 mmol) and methyl iodide (1.17 g, 8.25 mmol). The reaction mixture was heated at 80° C. for 12 h. On completion, the reaction mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated and purified by column chromatography to afford methyl 5-bromo-2-chloro-3-(cyclopentyl(methyl)amino)benzoate (0.350 g, 61%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(CCN)c1
Yield: 71 %

Procedure:
tert-Butyl [2-(3-cyanophenyl)ethyl]carbamate (0.949 g, 3.853 mmol) was dissolved in DCM (5 mL) and TFA (4 mL) and stirred at rt for 2 h. The mixture was concentrated and redissolved in EtOAc. The mixture was washed with saturated aqueous K2CO3, dried over Na2SO4, filtered and evaporated affording the title compound (0.40 g, 71.7%). 1H NMR (500 MHz, CDCl3): δ 1.18 (bs, 2H), 2.79 (t, 2H), 3.00 (t, 2H), 7.39-7.47 (m, 2H), 7.50-7.53 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 39.81, 43.42, 112.74, 119.17, 129.47, 130.24, 132.57, 133.66, 141.67.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1ncnc2ccccc12
Reactant: NCCCCCOc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(OCCCCCNc2ncnc3ccccc23)cc1
Yield: 19.5 %

Procedure:
To a solution of 1.7 g (0.01 mol) of 4-chloroquinazoline in 50 ml of benzene were added 1.0 g (0.01 mol) of triethylamine and 1.8 g (0.01 mol) of 5-phenoxypentylamine, and the mixture was refluxed for 3 hours. After completion of the reaction, the benzene was evaporated under reduced pressure to leave crystals, which were washed with water, collected by filtration and recrystallized from aqueous ethanol, giving 0.6 g of 4-(5-phenoxypentyl)aminoquinazoline in the form of colorless flakes.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH:47]([CH:58]([CH3:60])[CH3:59])[C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH:47]([CH:58]([CH3:60])[CH3:59])[C@@H:48]([NH:50][C:51]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:57])[CH3:49])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: CC(C)C(O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.6 %

Procedure:
p-Nitrobenzoic acid (10.6 g), triphenylphosphine (20.8 g), and DIAD (42 ml) were added to a THF (50 ml) solution containing tert-butyl ((2S)-3-hydroxy-4-methylpentan-2-yl)carbamate (11.5 g) obtained in the 2nd step, followed by stirring at room temperature for 15 hours. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0 to 5:1). Yellow oily matter of (2S)-2-((tert-butoxycarbonyl)amino)-4-methylpentan-3-yl 4-nitrobenzoate (10 g) was thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:22][C:23]#[N:24]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:22][C:23]#[N:24])#[N:2]
Reactant: N#CCCl
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cccc(C#N)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The compound 3-cyanophenoxyacetonitrile was prepared by heating 20.0 g of 3-cyanophenol, 30.1 g of anhydrous potassium carbonate and 30 ml of dimethylformamide with stirring in a 250 ml round-bottomed three-necked flask to 70° C. and then 12.7 g of chloroacetonitrile was added dropwise over a 15 minute period with cooling. The temperature of the mixture was held at 70°-80° C. for three hours, after which time the reaction mixture was poured into approximately 700 ml of ice and water which resulted in crystal formation. The crystals were separated by filtering and then washed thoroughly with water. After drying in a vacuum oven, a tan solid 3-cyanophenoxyacetonitrile was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[C:10]#[N:11].[H][H].C([O-])(=O)C.[K+].CO>[Pd].O1CCCC1>[NH2:8][C:6]1[CH:5]=[C:4]([NH2:9])[C:3]([C:10]#[N:11])=[CH:2][N:7]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cnc(N)cc1N
Reaction time: 2 h

Procedure:
A suspension of 21.3 g of 6-bromo-2,4-diamino-5-cyanopyridine (JACS, 80:2838-2840 (1958)) and 1 g of 20% palladium on charcoal in 250 mL of tetrahydrofuran was shaken in a Parr apparatus under an atmosphere hydrogen. After 2 hours, the reaction was stopped and 10 g of potassium acetate and 50 mL of methanol added. The reaction was recharged with hydrogen and shaken for 18 hours. The solvents were removed under reduced pressure and the residue crystallized from isopropyl alcohol to afford the title compound 2,4-diamino-5-cyanopyridine, mp 201°-202° C.
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[N:4][C:3]1=[O:17].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1.CC1(C2C=CC(C#N)=CC=2)SC(N[C@H](C2C=CC=CC=2C(F)(F)F)C)=NC1=O.[Li]N([Si](C)(C)C)[Si](C)(C)C>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:5]2[S:6][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([O:19][CH3:18])=[O:28])=[CH:22][CH:23]=3)([CH3:1])[C:3](=[O:17])[N:4]=2)[CH3:9])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC1SC(N[C@@H](C)c2ccc(F)cc2)=NC1=O
Agent: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: COC(=O)c1ccc(C2(C)SC(N[C@@H](C)c3ccc(F)cc3)=NC2=O)cc1

Procedure:
The title compound was prepared from the reaction of 5-methyl-2-((S)-1-(4-fluorophenyl)ethylamino)thiazol-4(5H)-one with methyl-4-bromobenzoate using the procedure described for 2a. 2.0 equivalent of NaN(SiMe3)2 or LiN(SiMe3)2 with reaction temperature of 50° C. was used. MS (ESI, pos. ion) m/z: 387 (M+1).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[ClH:1].[CH3:2][N:3]1[CH2:4][CH2:5][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][C:23](=[O:25])[CH3:24])[C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:8]1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC2(CC1)c1ccccc1Oc1c(O)cccc12
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc2c1Oc1ccccc1C21CCN(C)CC1

Procedure:
1'-Methyl-4-hydroxyxanthene-9-spiro-4'-piperidine hydrochloride (0.3 g.) in dry pyridine (10 ml.) is treated with excess acetic anhydride for 12 hours at room temperature. Pyridine and acetic anhydride are removed in vacuo and the residue dissolved in chloroform and treated with ethereal hydrochloric acid. The solvent is removed and the residue recrystallised from isopropanol-light petroleum to give 1'-methyl-4-acetoxyxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 216°-220° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.O.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]2)[CH2:27][CH2:26]1>CO>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[CH:35]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: CN1CCC(n2cc(N)cn2)CC1
Solvent: O
Solvent: CO
Product: CN1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 70 °C
Yield: 17 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.060 g, 0.21 mmol) in MeOH (1.0 mL) and water (0.1 mL) containing 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.039 g, 0.21 mmol) was heated at 70° C. for 48 hours. The mixture was adsorbed onto silica gel and purified by silica column chromatography (Combiflash Rf, 4 g SiO2 Cartridge, 0-50% MeOH in DCM). Further purification by HPLC (eluting with 30-100% gradient in acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid, flow rate 4.0 mL/min) gave the title compound 18 as a light yellow solid (0.015 g, 17%). LCMS-C: rt 4.31 min; m/z 480 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:20]([C:26]([C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:27])[CH:19]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.1 %

Procedure:
To a solution of 4-(4-methoxy-phenoxy)-3,5-dimethyl-nitrobenzene (2.7 g, 10 mmol) and p-fluorobenzoyl chloride (4.0 g, 3.0 mL, 25 mmol) in methylene chloride (10 mL) was added titanium tetrachloride (1M in methylene chloride, 50 mL, 50 mmol). The reaction mixture was stirred at room temperature for 3 d, poured into ice (100 g), and stirred 1 h. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with 5% sodium carbonate (200 mL), brine (150 mL), dried and concentrated. The residue was triturated with ether-petroleum ether. The solid was collected by filtration to give the title compound of Step A (2.1 g) as a tan solid. MS (APCl−Calc.: 395.2, Found: 394.2 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2Br)[N:8]=1)=[O:6].[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=C(OC)C=CC=2C2C=CC=CC=2)N=1)=O)(C)(C)C>>[OH:1][CH2:2][CH2:3][N:4]([CH:30]([CH3:32])[CH3:31])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:36]2[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=2)[N:8]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2Br)nc(O)c1OCc1ccccc1
Reactant: OB(O)c1ccncc1
Agent: COc1ccc(-c2ccccc2)c(Cc2nc(O)c(OCc3ccccc3)c(C(=O)OC(C)(C)C)n2)c1
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2-c2ccncc2)nc(O)c1OCc1ccccc1
Yield: 56.6 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(2-pyridin-4-yl-benzyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (152) (251 mg, 56.02%) as an off-white solid was synthesized from 5-benzyloxy-2-(2-bromobenzyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (151) (450 mg, 0.89 mmol) and pyridine-4-boronic acid (165.78 mg, 1.34 mmol) following the procedure as described for 5-benzyloxy-6-hydroxy-2-(4-methoxybiphenyl-2-ylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (139).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17](O)=[O:18])[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([CH2:17][OH:18])[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(CO)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Hydroborane tetrahydrofuran complex (1.0M in tetrahydrofuran solution; 1 ml, 1.0 mmol) was added at 0° C. to a solution of 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (20 mg, 0.05 mmol) prepared in Example 733 in anhydrous tetrahydrofuran (1 ml). The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 19 mg of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH2:6])[CH3:2].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
(2-Ethoxyethyl)amine (0.178 g, 2.0 mmol) was added to a stirred solution of 4-bromobenzenesulfonyl chloride (0.256 g, 1.0 mmol) in tetrahydrofuran (10 mL) at 0 C, followed by addition of N-ethyl-N,N-diisopropylamine (0.260 g, 2.0 mmol). The resulting mixture was stirred at 0° C. for 10 min, and was then allowed to return to room temperature. A saturated solution of NaHCO3 (aq) was added and the phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, and the solvent was evaporated to give the crude product. Purification by column chromatography using ethyl acetate/heptane (1:10 to 1:1) as the eluent gave 0.278 g (90% yield) of the title compound: MS (ES) m/z 294 and 296 (M++1).