Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:6]2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:7]([CH2:33][CH2:34][C:35]([F:36])([F:38])[F:37])=[CH:6]2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(CCC(F)(F)F)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(CCC(F)(F)F)cc2c1
Yield: 87.5 %

Procedure:
Ethyl ester (127) (0.34 g, 0.65 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.28 g (88%) of the title compound (128) as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.10-2.25 (m, 2H), 2.80-2.90 (m, 2H), 3.94 (s, 3H), 6.22 (d, J=15.9 Hz, 1H), 6.57 (d, J=8.6 Hz, 2H), 7.06-7.14 (m, 3H), 7.17 (d, J=2.4 Hz, 1H), 7.22-7.30 (m, 5H), 7.59 (s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 493 (M+H)+, m/z 491 (M−H)−.
Reaction SMILES: [CH3:1][C:2](/[CH:7]=[CH:8]\[CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=O.[CH3:18][CH2:19]OCC.C([Li])C.[Cl-].[NH4+]>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4](=[O:6])[CH2:18][CH3:19]
Reactant: CCOCC
Reactant: CC(=CC(=O)O)/C=C\CC(C)CCCC(C)C
Agent: [Cl-]
Agent: [Li]CC
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 3.00 g. of trans/cis 3,7,11-trimethyldodeca-2,4-dienoic acid in 50 ml. ether at 0° under nitrogen is added 28.00 ml. of 0.9 M solution of ethyllithium in benzene. The solution is stirred for 1/2 hour at 0° and then overnight at room temperature. To the reaction mixture is added 50 ml. of ether and the resultant solution is added dropwise with stirring to 300 ml. saturated aqueous ammonium chloride. The organic layer is separated and is washed in turn with 50 ml. saturated aqueous ammonium chloride, 35 ml. water, and 35 ml. saturated aqueous sodium chloride. The solution is dried over calcium sulfate, is concentrated and is then purified by preparative thin layer chromatography (1:3 ether/hexane) and short path distillation (boiling point 100° at .18 mm.) to give 5,9,13-trimethyltetradeca-4,6-dien-3-one (85.4% trans-4, trans-6; 14.6% cis-4, trans-6.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([CH2:25][CH2:26][OH:27])=[C:12]([CH2:23][OH:24])[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]45[CH2:25][CH2:26][O:27][C:23](=[O:24])[CH:12]4[CH:13]=[CH:14][CH:15]=[C:16]5[C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCc1c(CO)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C1OCCC23C(=CC=CC12)C1=C(C=C3c2ccc3c(c2)OCO3)OCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.7 %

Procedure:
To a chloroform (3 ml) solution of 9-(1,3-benzodioxol-5-yl)-8-(2-hydroxyethyl)-7-hydroxymethylnaphtho[1,2-d]-1,3-dioxole (36 mg) was added manganese dioxide (360 mg) and stirred for 4 hours, at room temperature. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the entitled compound (16 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:41][C@H:42]([C:47]([OH:49])=O)[CH2:43][CH:44]([CH3:46])[CH3:45])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[OH-].[Na+].[Cl-].[Na+]>CO.ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:41][C@H:42]([C:47]([NH2:1])=[O:49])[CH2:43][CH:44]([CH3:46])[CH3:45]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(N)=O
Reaction time: 3 h

Procedure:
One gram (1.54 mmols) of (Z)-1-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethene-Fmoc-L-leucine was dissolved in 10 ml of methanol and 10 ml of dichloromethane, and 0.9 ml (1.7 mmols) of an aqueous solution of 2-N sodium hydroxide were added thereto. The mixture was stirred for 3 hours. A saturated aqueous solution of sodium chloride was added thereto, and the resulting mixture was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The product was purified using a silica-gel column (mixture of 10-% by volume methanol and dichloromethane) to produce 560 mg of the final compound in a yield of 84.9%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[C:13]4([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccnc(Cl)n2)C2(CCCC2)C1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2nccc(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution of tert-butyl 4-((2-chloropyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (528 mg, 1.50 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (240.52 mg, 1.8 mmol) in n-BuOH (8 mL) was added DIPEA (581.60 mg, 4.5 mmol). After addition, the reaction mixture was stirred at 150° C. overnight. The resulting mixture was concentrated in vacuo and purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 20/1) to give the product as a yellow oil (550 mg, 88.9%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[Cl:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[Cl:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:3]([OH:2])=[O:4]
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1[nH]c2ccccc2c1Cl
Product: O=C(O)c1c(Cl)c2ccccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 3-chloro-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 334.3 ([M−H]−).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:35]=[CH:34][C:9](/[CH:10]=[C:11]2\[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[CH:19][CH:18]=3)[O:14][C:15]\2=[O:16])=[CH:8][CH:7]=1>C(O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9](/[CH:10]=[C:11](\[NH:12][C:13](=[O:14])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[CH:19][CH:18]=2)/[C:15]([NH:1][CH2:2][CH2:3][OH:4])=[O:16])=[CH:34][CH:35]=1
Reactant: COc1ccc(CCOc2ccc(C3=N/C(=C\c4ccc(Cl)cc4)C(=O)O3)cc2)cc1
Reactant: NCCO
Solvent: CCO
Product: COc1ccc(CCOc2ccc(C(=O)N/C(=C\c3ccc(Cl)cc3)C(=O)NCCO)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
2-Aminoethanol (18 μL, 0.30 mmol) was added to a solution of ethanol (0.7 mL) containing (4Z)-4-(4-chlorobenzylidene)-2-{4-[2-(4-methoxyphenyl)ethoxy]phenyl}-1,3-oxazol-5(4H)-one prepared in Example 1 (1c) (108 mg, 0.25 mmol). The mixture was stirred at 60° C. for 3 hours. The solvent was evaporated, and the residue was purified by thin layer chromatography for separation (ethyl acetate:methanol, 30:1, v/v, developed three times) to give 88 mg of the title compound (white amorphous solid, yield: 71%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:13]1[NH:14][N:15]=[N:16][C:17]=1[CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.ClC1C=CC(CN2N=NC(C3CCNCC3)=N2)=CC=1>>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:14]2[N:15]=[N:16][C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:13]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nn[nH]n2)CC1
Agent: Clc1ccc(Cn2nnc(C3CCNCC3)n2)cc1
Product: CS(=O)(=O)c1ccc(Cn2nnc(C3CCNCC3)n2)cc1

Procedure:
This was prepared from 4-methanesulphonylbenzyl bromide and tert-butyl 4-(2H-tetrazol-5-yl)piperidine-1-carboxylate using a similar method to that used to prepare 4-[2-(4-chloro-benzyl)-2H-tetrazol-5-yl]-piperidine (Method G, Steps 4 and 5); NMR (CDCl3): 1.8 (m, 2H), 2.05 (m, 2H), 2.8 (m, 2H), 3.05 (s, 3H), 3.1 (m, 1H), 3.2 (m, 2H), 5.89 (s, 2H), 7.55 (d, 2H), 7.95 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][C:14]=2[O:27]CC2C=CC=CC=2)(O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:27])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(c2ccc(O)cc2O)C1
Reaction time: 24 h
Yield: 27.8 %

Procedure:
1 g of 3-(2,4-bis(benzyloxy)phenyl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester are dissolved in a mixture of 20 ml of ethyl acetate/10 ml of methanol, and then 0.2 g of palladium-on-charcoal at 10% is added. The reaction mixture is stirred for 24 hours under a hydrogen atmosphere. The reaction mixture is filtered and then the residue is chromatographed on silica gel (7/3 heptane/ethyl acetate). 0.16 g of 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester is obtained. Yield=28%.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[N:15]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[N:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>C1(C)C=CC=CC=1>[CH:20]([O:19][C:17]([N:16]([C@:3]([C:1]#[N:2])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:15][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[O:18])([CH3:22])[CH3:21]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CCOC(=O)C(C#N)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@](C#N)(c1ccccc1)N(NC(=O)OC(C)C)C(=O)OC(C)C
Reaction time: 0.25 h
Yield: 105.8 %

Procedure:
To a solution of ethyl 2-cyano-2-phenylacetate (23.0 mg, 0.11 mmol) and (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (4.1 mg, 0.01 mmol) in toluene (1 mL) was added diisopropyl azodicarboxylate (21.5 μL, 0.10 mmol) at −78° C. After stirring for 15 min, the reaction mixture was concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=3/1) to give the title compound (41.4 mg, yield: 100%, optical purity: 76% ee). Colorless amorphous
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:11](=[O:12])[O:10][C:8](=[O:9])[CH2:7][C:6]2=[CH:13][C:14]=1[O:15][CH3:16].[CH3:17][N:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:30])[O:28][CH3:29]>C(Cl)(Cl)Cl>[CH3:29][O:28][C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C@H:19]1[C@@H:7]([C:8]([OH:10])=[O:9])[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:14]([O:15][CH3:16])[CH:13]=2)[C:11](=[O:12])[N:18]1[CH3:17])=[O:30]
Reactant: CN=Cc1ccccc1NC(=O)OC
Reactant: COc1cc2c(cc1OC)C(=O)OC(=O)C2
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1ccccc1[C@H]1[C@@H](C(=O)O)c2cc(OC)c(OC)cc2C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
4,5-Dimethoxyhomophthalic anhydride (9, 1.16 g, 5.2 mmol) was added to a solution of 8 (1 g, 5.2 mmol) in chloroform (10 mL) and the mixture was stirred for 2 h at room temperature. The precipitate was filtered, washed with chloroform (2×10 mL) and dried to yield acid cis 10 (750 mg, 35%): mp 212-213° C. (dec). IR (KBr) 1737, 1626, 1599, 1578 cm−1; 1H NMR (300 MHz, methanol-d4) δ 7.80 (s, 1 H), 7.51 (s, 1 H), 7.29 (m, 2 H), 7.11 (t, J=7.0 Hz, 1 H), 6.83 (m, 2 H), 5.33 (d, J=6.60 Hz, 1 H), 4.45 (d, J=6.60 Hz, 1 H), 3.80 (s, 3 H), 3.74 (s, 3 H), 3.65 (s, 3 H), 2.80 (s, 3 H); ESIMS m/z (rel intensity) 851 (35), 459 (13), 436 (100), 415 (6), 215 (15); ESIHRMS m/z MNa+ calcd. for C21H22N2O7, 437.1325; found, 437.1333.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([N:29]1CCN(CCCCl)CC1)=[O:28])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:24]([O:26][C:27]([N:29]1[CH2:4][CH2:5][N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:2][CH2:3]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)N1CCN(CCCCl)CC1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(CCCOc2ccc(C3(C#N)CCOCC3)cc2)CC1
Yield: 28.7 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (500 mg, 2.46 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid ethyl ester (570 mg, 2.43 mmol), DMF (10 ml) and K2CO3 (1.36 g, 9.84 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. The crude product was subjected to chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to provide the title compound (280 mg, 28%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.14 (q, 2H), 4.11-4.05 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.55-3.42 (m, 4H), 2.53 (t, 2H), 2.47-2.36 (m, 4H), 2.15-1.92 (m, 6H), 1.26 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][O:14][CH3:15])=[N:7][C:6]=12.[NH:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)=[N:19][N:18]=[N:17]1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.CO.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].O>[CH3:15][O:14][CH2:13][CH2:12][NH:11][C:8]1[CH:9]=[CH:10][N:5]2[N:4]=[CH:3][C:2]([C:24]3[CH:23]=[CH:22][C:21]([C:20]4[NH:19][N:18]=[N:17][N:16]=4)=[CH:26][CH:25]=3)=[C:6]2[N:7]=1
Reactant: COCCNc1ccn2ncc(Br)c2n1
Reactant: OB(O)c1ccc(-c2nnn[nH]2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COCCNc1ccn2ncc(-c3ccc(-c4nnn[nH]4)cc3)c2n1
Temperature: 85 °C

Procedure:
To a mixture of (3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-(2-methoxy-ethyl)-amine (307.7 mg, 1.1 mmol), (4-(1H-tetrazol-5-yl)phenyl)boronic acid [179942-55-3] (259.6 mg, 1.4 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (522.4 mg, 2.3 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with dichloromethane [95464-05-4] (106.3 mg, 0.1 mmol) contained in a 50 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (12 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 4 h then cooled, diluted with methanol, and gravity filtered. The filtrate was preabsorbed on silica gel and flash chromatographed (silica gel eluted with 1% NH4OH in 10% (v/v) methanol/ethyl acetate). Desired chromatography fractions were combined, evaporated, redissolved in 2-propanol and gravity filtered into stirring heptane to precipitate purified product. (2-Methoxy-ethyl)-[3-[4-(1H-tetrazol-5-yl)-phenyl]-pyrazolo[1,5-a]pyrimidin-5-yl]-amine was isolated by filtration as 96.3 mg of solid material, mp. 264-265° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.63 (t, J=4.29 Hz, 5 H) 6.41 (d, J=7.58 Hz, 1 H) 7.88 (br. s., 1 H) 8.04 (m, J=8.59 Hz, 2 H) 8.31 (m, J=8.34 Hz, 2 H) 8.47 (s, 1 H) 8.53 (d, J=7.58 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 40.69, 58.48, 70.48, 100.86, 103.75, 119.86, 125.23, 127.61, 135.97, 137.08, 142.42, 145.63, 156.60, LRMS (ESI) m/z 337.2 [(M+H)]+, calc'd for C16H16N8O: 336.36.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=2)[CH:4]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].Cl>>[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[C:17]([F:25])[CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-fluoro-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.16) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Light brown solid. MS (ISP) 527.0 [(M+H)+]; mp 238° C.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8](Br)=[N:7][N:6]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[C:5]1=[O:22])[CH:2]=[CH2:3].[Na].[CH3:24][OH:25]>>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([O:25][CH3:24])=[N:7][N:6]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[C:5]1=[O:22])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)c(Br)nn(-c2cccc(NC(C)=O)c2)c1=O
Reactant: CO
Agent: [Na]
Product: C=CCn1c(=O)c(OC)nn(-c2cccc(NC(C)=O)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
According to Scheme 3 Step 3: To a solution of compound 6(B) (800 mg, 2.19 mmol) in MeOH (10 mL) was added. a solution of sodium methoxyde 2M in methanol (1.1 mL, 2.19 mol). After 1 h of stirring at room temperature, the mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layers were successively washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 10 g SiO2) using CH2Cl2/MeOH 98/2 as eluant to afford N-(3-(4-allyl-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 6(C) (600 mg, 86%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[S:13][C:12]([C:14]#[N:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[S:13][C:12]([CH2:14][NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)s1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1ccc(OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-benzyloxy-thiophene-2-carbonitrile described in Preparation Example 81 (30 mg, 0.14 mmol) in tetrahydrofuran (3 mL) was added lithium aluminum hydride (21 mg, 0.557 mmol), which was then stirred for 1.5 hours at room temperature. Sodium fluoride (240 mg, 5.72 mmol) was added to the reaction mixture, which was stirred for 2 hours, then, on an ice bath, 10% hydrous tetrahydrofuran (2 mL) was added. The reaction mixture was filtered through Celite pad, the filtrate was concentrated and C-(5-benzyloxy-thiophen-2-yl)methylamine (32 mg, 0.147 mmol) was obtained as a crude product. The title compound (3 mg, 0.008 mmol, 5.4%) was obtained from this and quinoline-6-carboxylic acid (26 mg, 0.15 mmol) according to an analogous method to Example H-1.
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:23]([CH2:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)=[C:22]([CH2:33][CH3:34])[C:20](=[O:21])[NH:19][C:17]1=[O:18])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[CH3:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([CH3:31])[CH:28]=1)[CH2:24][C:23]1[N:16]([CH2:15][O:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:9])[C:17](=[O:18])[NH:19][C:20](=[O:21])[C:22]=1[CH2:33][CH3:34]
Reactant: CCc1c(Cc2cc(C)cc(C)c2)n(COCCCCOC(=O)c2ccccc2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(Cc2cc(C)cc(C)c2)n(COCCCCO)c(=O)[nH]c1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
1-(4-benzoyloxybutyloxymethyl)-6-(3,5-dimethylbenzyl)-5-ethyluracil (500 mg, 1.08 mmol) was added to a solution of sodium hydroxide (360 mg, 9 mmol) in methanol (50 ml) and the mixture was stirred at 20° C. for 3 h. After neutralization (concentrated hydrochloric acid) and concentration, the residue was subjected to a flash column chromatography (dichloromethane/methanol 19:1) which gave the 6-(3,5-dimethyl benzyl)-5-ethyl-1-(4-hydroxybutyloxymethyl)uracil (190 mg, 48%) in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][NH:14][N:13]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C1N2CCN(CC2)C1.[F:29][C:30]1([F:39])[CH2:33][N:32]([C:34](=[O:38])/[CH:35]=[CH:36]\I)[CH2:31]1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:36]=[CH:35]\[C:34]([N:32]3[CH2:33][C:30]([F:39])([F:29])[CH2:31]3)=[O:38])[N:13]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: O=C(/C=C\I)N1CC(F)(F)C1
Reactant: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1Cl
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 2.7 %

Procedure:
3-(4-Chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole (0.1 g, 1.0 eq.) was dissolved in DMF (5 mL). DABCO (0.071 g, 2 eq.) was added and stirred for 30 min. (Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one (0.095 g, 1.1 eq.) was then added. The reaction mixture was stirred at room temperature for 5 h and then poured into iced water (50 mL). Product was extracted with EtOAc (3×15 mL). The combined organic layers was washed with brine, (20 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.150 g of crude product, which was purified by chromatography to obtain (Z)-3-(3-(4-chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)prop-2-en-1-one (0.004 g, 3% yield). 1H NMR (400 MHz, DMSO) δ=9.32 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 7.47-7.49 (d, J=10.4 Hz, 1H), 6.00-5.04 (d, J=10.4 Hz, 1H), 4.55-4.58 (m, 2H), 4.33-4.36 (m, 2H) LCMS calcd for C16H10ClF8N4O [M+H]+: 461.7. Found: 461.14, at 2.99 min retention time.