Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:13][CH:12]=1.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][CH:12]=1
Reactant: CCCc1ccc(F)c(-c2cccc(C(=O)OC)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1ccc(F)c(-c2cccc(C(=O)O)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of methyl 6-(2-fluoro-5-propylphenyl)picolinate (1.0 equiv.) in THF was added lithium hydroxide (10 equiv.) and the reaction was stirred at room temperature for 1 hour. The THF solvent was removed in vacuo and the remaining basic phase was acidified with concentrated HCl. The aqueous layer was extracted with ethyl acetate (2×), the organic phase was dried with sodium sulfate, filtered and concentrated to give 6-(2-fluoro-5-propylphenyl)picolinic acid in 35% yield. LC/MS=260.2 (M+H), Rt=0.36 min.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C:12]([C:21]#[N:22])([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[OH-].[Na+].C([OH:27])C.OO>O>[N:18]1[CH:19]=[CH:20][C:15]([C:12]2([C:21]([NH2:22])=[O:27])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:16][CH:17]=1
Reactant: N#CC1(c2ccncc2)CCN(Cc2ccccc2)CC1
Reactant: CCO
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: NC(=O)C1(c2ccncc2)CCNCC1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Combine 1-benzyl-4-cyano-4-(pyridin-4-yl)-piperidine hydrochloride (1.6 g, 4.5 mmol), a concentrated aqueous sodium hydroxide solution (1.5 mL, 50%, 9 mmol) and ethanol (30 mL). Heat to about 55° C. Add an aqueous solution of hydrogen peroxide (3.0 mL, 30%, 26 mmol) over about 10 minutes. After 3 hours, add an aqueous solution of hydrogen peroxide (2.0 mL). After 1 hour, cool to ambient temperature and dilute with water (20 mL), concentrate in vacuo, add water (40 mL), and again concentrate in vacuo to give a solid. Collect the solid by filtration, rinse with water, and dry to give 1-benzyl-(4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide: Rf =0.20 (silica gel, 9/1 dichloromethane/methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([N+:19]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[C:12]([CH:22]=[CH2:23])=[N:11]2)=[CH:7][CH:6]=[C:5]([CH3:24])[N:4]=1.CO>[OH-].[OH-].[Pd+2].ClCCl>[CH2:22]([C:12]1[C:13]2[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][C:18]=2[N:10]([CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([CH3:24])=[CH:6][CH:7]=2)[N:11]=1)[CH3:23]
Reactant: C=Cc1nn(Cc2ccc(C)nc2OC)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1nn(Cc2ccc(C)nc2OC)c2cccc(N)c12
Reaction time: 7 h
Yield: 29.9 %

Procedure:
1-((2-M ethoxy-6-methylpyridin-3-yl)methyl)-4-nitro-3-vinyl-1H-indazole (395 mg, 1.22 mmol) and palladium hydroxide on carbon (171 mg, 0.244 mmol; 20%) were added to a hydrogenation flask. Methanol (6 mL) was added along with a small amount of dichloromethane. The reaction flask was evacuated and purged with nitrogen prior to being shaken on a Parr apparatus under an atmosphere of hydrogen at 40 psi for 7 hours. The mixture was filtered through Celite, rinsing with methanol and the filtrated was concentrated under reduced pressure. The material was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide solution. Further purification was carried out using column chromatography on silica, eluting with 1% methanol in dichloromethane containing 0.5% ammonium hydroxide solution to provide 3-ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine (108 mg). Some material was isolated where the nitro group had not been completely reduced (186 mg). This material was dissolved in ethanol (3 mL). Iron powder (318 mg; 5.70 mmol) and ammonium chloride (15.2 mg; 0.285 mmol) were added and the mixture was heated at reflux for 1 hour. The mixture was allowed to cool and filtered through glass fiber filter paper rinsing with ethanol. The solution was concentrated under reduced pressure and purified using preparative thin layer chromatography, eluting with 2% methanol in dichloromethane containing 0.25% ammonium hydroxide solution to provide an additional 108 mg of 3-ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
By alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(p-tolyl)-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-p-tolyl-piperidine-1-carboxylate as a colourless oil; MS: 431 (M)+.
Reaction SMILES: [OH:1][C:2]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22](C=O)=[CH:21][C:20]=2[Cl:27])=[O:17])[CH3:13])[CH2:8][CH2:7]1)=[O:4].C([O-])(=O)C.C([Si](C)(C)O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)C[NH3+])(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:79]([Si:83]([CH3:135])([CH3:134])[O:84][C@H:85]([C:122]1[CH:131]=[CH:130][C:129]([OH:132])=[C:128]2[C:123]=1[CH:124]=[CH:125][C:126](=[O:133])[NH:127]2)[CH2:86][NH:87][CH2:88]C1C=CC(OCCCN(C)[C@H]2CC[C@H](OC(C3SC=CC=3)(C3SC=CC=3)C([O-])=O)CC2)=CC=1)([CH3:82])([CH3:81])[CH3:80]>>[OH:1][C:2]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)[C:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:88][NH:87][CH2:86][C@H:85]([O:84][Si:83]([C:79]([CH3:82])([CH3:81])[CH3:80])([CH3:135])[CH3:134])[C:122]3[CH:131]=[CH:130][C:129]([OH:132])=[C:128]4[C:123]=3[CH:124]=[CH:125][C:126](=[O:133])[NH:127]4)=[CH:21][C:20]=2[Cl:27])=[O:17])[CH3:13])[CH2:8][CH2:7]1)=[O:4]
Reactant: CN(CCCOc1ccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1)[C@H]1CC[C@H](OC(C(=O)[O-])(c2cccs2)c2cccs2)CC1
Reactant: CN(CCC(=O)Nc1ccc(C=O)cc1Cl)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: CC(C)(C)[Si](C)(C)O[C@@H](C[NH3+])c1ccc(O)c2[nH]c(=O)ccc12
Product: CN(CCC(=O)Nc1ccc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c3[nH]c(=O)ccc23)cc1Cl)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1

Procedure:
Obtained as a white solid (65%) starting from trans-4-((3-(2-chloro-4-formylphenylamino)-3-oxopropyl)(methyl)amino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 50; 54 mg, 0.10 mmol), (2R)-2-{[tert-butyl(dimethyl)-silyl]oxy}-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethanaminium acetate (prepared according to preparation 8 from US20060035931) (57 mg, 0.14 mmol) and sodium triacetoxyborohydride (77 mg, 0.35 mmol) following the experimental procedure as described in intermediate 30 followed by a purification by preparative reversed-phase HPLC (CHCl3 to CHCl3/MeOH 95:5).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[CH3:15][N+:16]([O-])([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH2:28][CH2:29][N+:30]([O-])([CH3:32])[CH3:31])=[C:23]2[C:34]([C:36]3[C:41]([C:42](=[O:43])[C:22]=12)=[C:40]([OH:44])[CH:39]=[CH:38][C:37]=3[OH:45])=[O:35])[CH3:17]>>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][NH:27][C:24]1[C:23]2[C:34](=[O:35])[C:36]3[C:41](=[C:40]([OH:44])[CH:39]=[CH:38][C:37]=3[OH:45])[C:42](=[O:43])[C:22]=2[C:21]([NH:20][CH2:19][CH2:18][N:16]([CH3:17])[CH3:15])=[CH:26][CH:25]=1
Reactant: C[N+](C)([O-])CCNc1ccc(NCC[N+](C)(C)[O-])c2c1C(=O)c1c(O)ccc(O)c1C2=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)CCNc1ccc(NCCN(C)C)c2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
The solid dihydrochloride should be stored in a sealed container in a cold dark place (preferably a freezer). Before opening such containers they should be allowed to warm to room temperature, since the dihydrochloride (and AQ4N) absorb moisture particularly rapidly when cold.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[CH:10]=[C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:8])([O-])=O.[H][H]>O1CCOCC1CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[CH:10]=[C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:8]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccn12
Reactant: [H][H]
Agent: [Pd]
Agent: OCCC1COCCO1
Product: CCOC(=O)CCCc1cc(C(=O)c2cccc(N)c2)c2ccccn12
Yield: 100.8 %

Procedure:
To a solution of ethyl 4-[1-(3-nitrobenzoyl)-indolizin-3-yl]butyrate (350 mg) in dioxane-ethanol (1:1; ml) was added 10% palladium on carbon (210 mg) and hydrogenated under 4 atm of hydrogen for 4 hours, and then filtered through a celite. Removal of the solvent gave ethyl 4-[1-(3-aminobenzoyl)indolizin-3-yl]butyrate (325 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([N:31]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]>>[C:28]([N:31]([C:32]1[CH:37]=[CH:36][C:35]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:34][CH:33]=1)[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])(=[O:30])[CH3:29]
Reactant: CC(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(CCN(C)C)C(C)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-acetyl-N-(2-dimethylamino-ethyl)-p-phenylenediamine
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]=[C:12]1[C@H:18]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]([NH:31][CH:32]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[C:33](OCC)=O)=[O:30])[CH2:24][CH2:23]2)=[O:21])[N:17]=[C:16]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:15]2[CH:50]=[CH:51][CH:52]=[CH:53][C:14]=2[N:13]1[CH2:54][C:55]([F:58])([F:57])[F:56]>C1(C)C=CC=CC=1.ClCCl>[O:11]=[C:12]1[C@H:18]([NH:19][C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[CH:33]=[C:32]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[NH:31][C:29]3=[O:30])[CH2:26][CH2:27]2)=[O:21])[N:17]=[C:16]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:15]2[CH:50]=[CH:51][CH:52]=[CH:53][C:14]=2[N:13]1[CH2:54][C:55]([F:58])([F:56])[F:57]
Reactant: CCOC(=O)C(NC(=O)NC1CCN(C(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(CC(F)(F)F)C2=O)CC1)c1ccccn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2cc(-c3ccccn3)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminum hydride (1M, 0.108 mL, 0.108 mmol) was added to a solution of ethyl [({[1-({[(3R)-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]amino}carbonyl)piperidin-4-yl]amino}carbonyl)amino](pyridin-2-yl)acetate (60 mg, 0.090 mmol) in toluene (4 mL) and dichloromethane (4 mL) at −78° C. and stirred for 30 min and then warmed to ambient temperature. After 4 h, the reaction was quenched with 1 N saturated potassium sodium tartrate solution and extracted with dichloromethane (2×). The combined organic extracts were dried over sodium sulfate, filtered, concentrated. Purification by silica gel chromatography (100% dichloromethane→10% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound. MS 604.2 (M+1)
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]([CH3:19])=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C.N1CCCCC1>[CH3:19][C:12]1[NH:11][CH:9]=[CH:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C=C(C)N
Reactant: O=C/C=C/c1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(C)NC=CC1c1ccccc1
Yield: 72.3 %

Procedure:
(E)-3-Phenyl-2-propenal (13.8 ml, 0.11 mol) and ethyl 3-amino-2-butenoate (12.9 g, 0.1 mol) were dissolved in 150 ml of absolute ethanol containing 0.5 ml of piperidine. The mixture was heated under reflux for 18 hours followed by removal of the solvent under vacuum to yield 17.6 g of ethyl 1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate as a brown viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH2:26][CH2:27][C:28]([O:30][CH2:31]C)=[O:29])=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH2:33]1N2CCN(CC2)C1.C(=O)(OC)OC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:33])[C:21]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Reactant: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: COC(=O)OC
Product: COC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2n1C
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A solution of ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D33) (114 mg), DABCO (56 mg) and dimethyl carbonate (2 mL) in N,N-dimethylformamide (DMF, 2 mL) was stirred at 90° C. for 2 days. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford methyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoate (D113) (67 mg). MS (ES): C24H24ClN3O4 requires 453; found 454.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCOC(C)=O>[Pd].CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1OC
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Reaction time: 3 h
Yield: 7.8 %

Procedure:
A solution of 3,4-Dimethoxy-3′-hydroxy chalcone (4) (10 g, 352 mmol) in a 1:1 mixture of EtOAc:Acetone (40 mL) was treated with 10% Pd on Carbon (500 mg) and the mixture hydrogenated at 40-50 psi pressure of H2 for 3 h. The reaction mixture was filtered through a pad of Celite with the aid of acetone and the filtrate concentrated to afford a crude solid. The crude solid was triturated with EtOAc and filtered to afford 7.83 g (78%) of white solids which proved to be of −90% purity by 1H NMR analysis: 1H NMR (CDCl3, 300 MHz) 7.56 (s, 1H), 7.55, (d, J=2.2 Hz, 1H), 753-733 (m, 1H), 7.10 (dd, J=7.9, 2.4 Hz, 1H), 6.80-7.79 (m, 3H), 6.61 (s, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.28 (t, J=7.9 Hz, 2H), 3.02 (t, J=7.9 Hz, 2H); 13C NMR (CDCl3, 75 MHz) 200.6, 156.9, 149.3, 147.8, 138.6, 134.2, 130.3, 121.1, 120.6, 115.0, 112.4, 111.8, 56.3, 41.2, 30.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Br:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:17][CH:18]=2)=[S:10])=[CH:4][CH:3]=1)=[O:29]
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Reactant: O=C(Cl)CCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
Thiourea 4 (200 mg, 0.61 mmol, 1 equiv.) was stirred in CH2Cl2 (10 mL) under N2 atmosphere. 4-Bromobutyryl chloride (169 mg, 0.92 mmol, 1.5 equiv.) was added, followed by triethylamine (85 μL, 0.61 mmol, 1 equiv.). The orange solution was stirred at rt for 1.5 h and diluted with CH2Cl2 (10 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×10 mL), 10% aqueous sodium hydroxide (1×50 mL), and saturated brine (1×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting pale yellow foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 4-bromo-N-{4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-butyramide (138 mg, 48%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:3].C([Li])CCC.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>O1CCCC1.CCOCC>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])=[CH:9][CH:8]=1)[CH3:3]
Reactant: CN(C)CCOc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
To a solution of N,N-dimethyl-2-(4bromophenoxy)ethylamine (1.0 g, 4.1 mmol) in tetrahydrofuran (10 ml) at −78° C. was added dropwise n-butyllithium (1.5M in hexane, 2.7 ml, 4.1 mmol). The mixture was stirred at this temperature for 15 min. and then transferred via a cannula into a pre-cooled solution of ethyl trifluoroacetate (0.64 g, 4.5 mmol) in ether (8 ml) at −78° C. The resulting mixture was stirred and the temperature allowed to rise gradually to r.t. over a period of 1.5 h. The reaction mixture was then quenched with water (5 ml) and diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Bulb-to-bulb distillation (82-84° C./0.01 mmHg) afforded the title compound (423 mg, 39%) as a pale yellow oil. Analysis for C12H14F3NO2.0.3H2O calcd. C 54.05%, H 5.52%, N 5.25%; Found: C 54.12%, H 5.39%, N 5.28%.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=[CH:21]5)[CH:14]=[CH:15][C:16]=3[OH:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:34]I.O>CN(C=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=[CH:21]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:34])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2cc(-c3ccc(OC)c(C45CC6CC(CC(C6)C4)C5)c3)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Methyl 6-(3-adamantyl-4-hydroxyphenyl)naphtoate (506 mg, 1.23 mmol) was added to an ice-cooled suspension of NaH (80 mg, 60%) in dry DMF, the mixture stirred 1 h at 0° C., then added with 245 mg (1.7 mmol) of CH3I, and left 90 min at r.t. Taking up with 80 ml of cold water, repeated extraction with CH2Cl2, then with EtOAc, drying and evaporating the joined organic phases, and chromatography (silicagel, hexane/EtOAc 9/1) gave 300 mg of methyl 6-(3-adamantyl-4-methoxyphenyl)naphtoate. This compound (235 mg) was suspended in a 1M solution of NaOH in MeOH and the mixture was refluxed 8 h. Evaporation, taking up with water, addition of HCl and filtration gave 227 mg of 6-(3-adamantyl-4-methoxyphenyl)naphtoic acid, mp >300° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>Cl.O1CCOCC1>[NH2:21][C@@H:19]([CH3:20])[C:18]([NH:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[O:29]
Reactant: CCOP(=O)(CCOCCOCCNC(=O)[C@H](C)NC(=O)OC(C)(C)C)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(=O)(CCOCCOCCNC(=O)[C@H](C)N)OCC

Procedure:
A solution of (S)-tert-butyl (1-((2-(2-(2-(diethoxyphosphoryl)ethoxy)ethoxy)ethyl)amino)-1-oxopropan-2-yl)carbamate (1 eq) in 4N HCl/dioxane (0.4 M) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated en vaccuo to give the title product as a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([OH:8])[C:6](=[NH:9])[N:5]=[C:4](Cl)[CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>CN(C)C=O>[NH2:1][C:2]1[N:7]([OH:8])[C:6](=[NH:9])[N:5]=[C:4]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: N=c1nc(Cl)cc(N)n1O
Reactant: C1CSCCN1
Solvent: CN(C)C=O
Product: N=c1nc(N2CCSCC2)cc(N)n1O
Temperature: 110 °C

Procedure:
A mixture of 16.1 g of 6-amino-4-chloro-1,2-dihydro-2-imino-1-pyrimidinol, 32.1 g of thiomorphline, and 75 ml of dimethyl formamide is heated at 110° C in a nitrogen atmosphere for 17 hours. The solvent is removed under high vacuum. The residue is dissolved in 2 normal hydrochloric acid, and the resulting solution made basic with 5% ammonium hydroxide. There is deposited 13.0 g (57%) of a crystalline solid mp 242° (dec). Recrystallization from methanol-ethanol gives an off-white crystalline solid, mp 246° C(dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[O:19])[CH3:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[O:19])[CH3:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCCO1
Agent: Cl
Solvent: CO
Product: CC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Yield: 108.8 %

Procedure:
To a solution of 1-[3-(4-fluorophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazol-5-yl]ethan-1-one (100 mg, 0.30 mmol) in methanol (30 mL) was added 6 N HCl (30 mL). The solution was stirred at room temperature for 4.5 hours when the methanol was removed under vacuo and the solution made basic with saturated Na2CO3. The suspension was then filtered and the product dried to give the title compound (83 mg, 100% yield). 1H NMR (DMSO-d6) δ 8.64 (s, 1H), 8.1 (m, 2H), 7.97 (d, 1H), 7.67 (d, 1H), 7.40 (t, 2H), 2.69 20 (s, 3H); ES-MS (m/z) 255 [M+1]+.