Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)(=[O:3])[CH3:2].[OH2:15].[CH2:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>[Mo]=O>[CH:16]1([O:15][N:8]2[C:7]([CH3:14])([CH3:13])[CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][C:9]2([CH3:12])[CH3:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCCCC1
Reactant: CC(=O)OC1CC(C)(C)NC(C)(C)C1
Reactant: O
Agent: O=[Mo]
Product: CC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
60 g (301 mmol) of 4-acetoxy-2,2,6,6-tetramethylpiperidine are dissolved in 300 ml of cyclohexane under nitrogen in a 1.5 l sulfonation flask fitted with magnetic stirrer, water separator, thermometer and dropping funnel. 4.3 g (30 mmol) of molybdenum oxide are added. 154 g (1.2 mol) of an aqueous 70% solution of t-butyl hydroperoxide are extracted three times with 35 ml of cyclohexane in each case, and the organic phase is dried over sodium sulfate and transferred into the dropping funnel. The reaction mixture is warmed to reflux, and the t-butyl hydroperoxide solution is added dropwise over the course of 2 hours. After a further 2 hours, the elimination of water is complete. The mixture is held at the reflux temperature overnight and is then cooled to 25° C., and the catalyst is filtered off. Ice is added, a little sodium sulfite is added in order to destroy the excess hydroperoxide, and the organic phase is then separated off, washed with water and dried over sodium sulfate, and the solvent is removed on a Rotavap.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C@@:7]([C:17]([O:19][C:20](C)(C)C)=[O:18])([CH3:16])[NH:8]C(OC(C)(C)C)=O)=[CH:3][CH:2]=1>C(Cl)Cl.Cl>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:5][C:4]([C@@:7]([C:17]([O:19][CH3:20])=[O:18])([CH3:16])[NH2:8])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C(=O)OC(C)(C)C)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@](C)(N)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HCl (7.2 ml, 4M in dioxane) was added dropwise to a solution of 1,1-dimethylethyl 2-(4-biphenylyl)-N-{[(1,1-dimethylethyl)oxy]carbonyl}alaninate (1.14 g, 2.87 mmol) in CH2Cl2 (10 ml) at 0° C. under argon. The resulting mix was stirred at room temperature for 16 h. The reaction mixture was concentrated leaving a white solid which was refluxed in methanolic HCl (30 mL) for 16 h. The reaction mixture was concentrated and the residue was taken into Na2CO3 (10%, 100 ml) and the product was extracted by EtOAc (3×20 ml). The combined extracts were washed by water then brine, dried and concentrated left 830 mg as a clear oil. MS (ES) m/e 256.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([F:18])[CH:17]=1)[CH2:13][OH:14].[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:14][CH2:13][C:12]2[CH:11]=[C:10]([F:9])[CH:17]=[C:16]([F:18])[CH:15]=2)[N:3]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Fc1cc(F)cc(COc2cncc(Cl)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol), 3,5-difluorobenzyl alcohol (475 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). The solid product was collected, washed with water, and dried to give 0.77 g (100%) of the crude product that was used directly in the next step. An analytical sample was recrystallized from diethyl ether/hexane: mp 70-71° C. MS m/z 257 (M+H)+. Anal. (C11H7ClFN2O) C, H, N.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[S:5][CH:6]=[CH:7][N:8]=1.[S:9]([O-:13])([O-:12])(=[O:11])=[O:10].CS[C:16]([NH2:18])=[NH2+:17].CS[C:21]([NH2:23])=[NH2+:22]>>[S:9]([OH:13])([OH:12])(=[O:11])=[O:10].[S:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][CH2:2][NH:1][C:16]([NH2:18])=[NH:17].[S:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][CH2:2][NH:1][C:21]([NH2:23])=[NH:22]
Reactant: NCCc1nccs1
Reactant: O=S(=O)([O-])[O-]
Reactant: CSC(N)=[NH2+]
Product: N=C(N)NCCc1nccs1
Product: O=S(=O)(O)O

Procedure:
An intimate mixture of 2-(2-aminoethyl)thiazole (4.5 g) and S-methylthiouronium sulphate (9.8 g) is heated at 140°-150° C for one hour. Extraction with ethanol and cooling affords the crude product, m.p. 130°-135° C. Recrystallization from ethanol gives 2-(2-thiazolyl)ethylguanidine hemisulphate, m.p. 143°-145° C.
Reaction SMILES: [Li+].[Cl-].[CH2:3]([C:10]1[CH:11]=[C:12]([O:24][CH3:25])[CH:13]=[CH:14][C:15]=1OS(C(F)(F)F)(=O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26]([Sn](CCCC)(CCCC)CCCC)[CH:27]=[CH2:28]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:28]([C:15]1[CH:14]=[CH:13][C:12]([O:24][CH3:25])=[CH:11][C:10]=1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:27]=[CH2:26]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCc1ccc(OC)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
LiCl (3.08 g, 72.8 mmol) in a roundbottom flask was flame-dried in high vacuum, and the system was allowed to cool to RT under argon. 3-Benzyl-4-(trifluoromethanesulfonyloxy)anisole (21.0 g, 60.6 mmol), bis(triphenylphosphine)palladium(II) chloride (2.13 g, 3.0 mmol), anhydrous DMF (150 mL), and allyltributyltin (22.6 mL, 72.8 mmol) were added, and the mixture was purged with argon through three evacuation/argon flush cycles. The mixture was heated in an oil bath preset at 95° C., affording a yellow, homogeneous solution. After 1.5 h, the dark mixture was concentrated on the rotavap (high vacuum), and the residue was reconcerntrated from xylenes. The resulting residue was taken up in Et2O (120 mL) and stirred briskly with 10% KF (120 mL) for 0.5 h. The layers were separated, and the aqueous layer was extracted with Et2O (2×120 mL). The combined organics were filtered through celite® to remove the insoluble solids, and the filtrate was washed sequentially with H2O (60 mL) and brine (60 mL). Drying (MgSO4) and concentration left a cloudy, yellow oil. Chromatography (silica gel, 5% EtOAc/hexanes) gave the title compound as a light yellow oil (14.21 g, 98%): TLC Rf (5% EtOAc/hexanes) 0.51; 1H NMR (250 MHz, CDCl3) δ 7.03-7.31 (m, 6H), 6.74 (dd, J=8.3, 2.7 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 5.79-5.98 (m, 1H), 4.89-5.07 (m, 2H), 3.97 (s, 2H), 3.75 (s, 3H), 3.21-3.33 (m, 2H); FTIR (CCl4) 1610, 1496, 1256, 1046, 914 cm-1 ; MS (ES) m/e 239.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:17]=[C:16]([CH3:18])[S:15][C:10]=2[NH:11][C:12](=[O:14])[N:13]=1.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:21][N:11]1[C:10]2[S:15][C:16]([CH3:18])=[CH:17][C:9]=2[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][C:12]1=[O:14]
Reactant: Cc1cc2c(-c3ccccc3F)nc(=O)[nH]c2s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(-c3ccccc3F)nc(=O)n(C)c2s1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 12.4 g of 4-(o-fluorophenyl)-6-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 248 ml of dimethylformamide is added 2.58 g of 67% sodium hydride. After stirring at 50°C for 1 hour and cooling to room temperature, 20.45 g of methyl iodide in 61.4 ml of dimethylformamide is added dropwise thereto. The mixture is stirred at room temperature for 1 hour, then poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-(o-fluorophenyl)-6-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 119° - 121°C (after recrystallization from chloroform-ethanol), and 3-methyl-4-(o-fluorophenyl)-6-methyl-3H-thieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 239° - 241°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]([C:15](O)=O)[O:7][CH2:8]2.C(N1[CH:29]=[CH:28]N=C1)(N1C=CN=C1)=O.C([SH:32])C>C1COCC1>[CH2:28]([C:15]([CH:6]1[CH2:5][C:4]2[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8][O:7]1)=[S:32])[CH3:29]
Reactant: COc1ccc(OC)c2c1COC(C(=O)O)C2
Reactant: CCS
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC(=S)C1Cc2c(OC)ccc(OC)c2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
5,8-dimethoxy-3-carboxyisochroman (300 mg, 1.26 mmol) in THF (6 ml) was stirred with 1,1'-carbonyldiimidazole (225 mg, 1.386 mmol) at room temperature for 30 minutes. More THF (6 ml) was added to dilute the forming suspension. After one hour, ethanethiol (103 μl, 1.40 mmol) was added and the mixture was stirred for 18 hours at room temperature. Solvent was evaporated and the crude titled product was chromatographed (hex:EtOAc=4:1) to give desired product as a solid (200 mg, m.p. 99.2° C).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:22].[K+].[K+].[CH:32]1[C:45]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>C(O)(=O)C.C(O)(C)(C)C.O>[CH:32]1[C:45]2[C:44](=[O:22])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:37][C:36]=2[CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2ccccc2oc2ccccc12

Procedure:
The above oxidation reaction may be carried out using dichromate anion such as sodium dichromate or potassium dichromate as the oxidizing agent. The reaction will proceed in from 15 minutes to 6 hours at a temperature of from 80° to 120°C. The amount of oxidizing agent is limited to the stoichiometric quantity required for oxidation of the 9-methylene group of the xanthene derivative. Suitable solvents for this conversion are, for example, water, acetic acid, tert-butyl alcohol, and the like, or combinations of these solvents. For example, by combining three moles of the xanthene derivative, Formula II, dissolved in acetic acid with four moles of sodium dichromate and refluxing the mixture for 1 to 3 hours, the corresponding xanthen-9-one derivative, Formula III, can be obtained.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C.O>[CH3:3][C:4]([CH3:26])=[CH:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12](=[O:25])[C:13]3[C:18]([O:19][C:20]=2[C:21]=1[C:22](=[O:24])[CH:23]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c3ccccc3oc12
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CCOc1ccc2c(=O)c3ccccc3oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 3-(3-methylbut -2-enyloxy)-4-acetylxanthen-9-one (2.4 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.1 g of product m.p. 116-118° C., 1H-NMR (CDCl3)δ:1.69 (s, 3H); 1.72 (s, 3H); 4.71 (d, 2H, J=6.5); 5.38-5.40 (m, 1H); 7.05-7.10 (m, 2H); 7.08 (d, 1H, J=8.8 Hz); 7.10 (d, 1H, J=16 Hz); 7.30-7.48 (m, 6H); 7.50-7.58 (m, 2H); 7.65-7.60 (m, 1 H) 8.30-8.33(m, 1H); 8.42 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[NH4+:17].[OH-]>O=S(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:17])=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C

Procedure:
A suspension of 4,5-dimethoxy-2-nitrobenzoic acid 1 (2 g; 8.8 mmol) in SOCl2 (10 mL) was stirred under reflux for 50 minutes. After cooling, the reaction mixture was poured into a mixture of concentrated NH4OH (50 mL) and ice (30 g). The precipitate were collected by filtration, washed with water, and dried to give 1.85 g crude crystals. After recrystallization from DMF, 1.76 g pure product was obtained (88.5%). 1H NMR(DMSO-d6) : δ 7.60(s, 2H, —NH2), 7.57(s, 1H, 6-H), 7.12(s, 1H , 3-H), 3.90, 3.87(s, s, 6H, —OCH3); IR(KBr) υmax: 3454, 2840, 1670, 1512, 1274, 1227 cm−1; GC/MS m/z 226(M+, 10.0), 178(98.5), 163(100.0), 135(51.0).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[F:29])[N:16]=1>O1CCCC1>[F:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:17]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Reaction time: 12 h
Yield: 94.8 %

Procedure:
To a solution of morpholine (3.2 g, 36.7 mmol) and triethylamine (10.2 g, 101 mmol) in tetrahydrofuran (80 ml) was added 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (8.0 g, 32.4 mmol) portionwise and stirred for 12 hours. The resulting suspension was partitioned between chloroform and 1N sodium hydroxide and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 6-(3-fluoropyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one (8.9 g, 30.7 mmol, 92%) as white crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17](Cl)=[O:18].[CH3:20][NH2:21]>O1CCCC1.O>[CH3:20][NH:21][C:17]([N:3]1[CH2:4][C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C@@H:2]1[CH3:1])=[O:18]
Reactant: CC1C(Oc2cccc(C(F)(F)F)c2)CN1C(=O)Cl
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1C[C@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 6 h
Yield: 90.3 %

Procedure:
A solution of 4.02 g (0.01 mole) of crude (73%) 2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cis isomer in 20 ml of tetrahydrofuran was treated while stirring with 1.6 g (0.02 mole) of 40% aqueous monomethylamine. After stirring for 6 hr, the reaction mixture was diluted with 100 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo (4.2 g). The oil solidified on standing and was recrystallized from isooctane with a trace of benzene to give 2.6 g (90.3%) of white crystalline product, m.p. 89°-91° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[NH2:20])([CH3:10])[CH3:9].[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([NH:20][C:12]1[C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:17]([CH3:19])[CH3:18])=[O:24]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
222 mL (1.59 mol) of triethylamine are added to a solution of 300 mL (1.59 mol) of 2,6-diisopropyl-phenylamine (Starting material 3) in 1 litre of dichloromethane. The reaction mixture is cooled to 0° C., and 127 mL (1.59 mol) of chloroacetyl chloride are then added dropwise. Once the addition is complete, the ice bath is removed and the medium is stirred for 20 minutes. It is then poured into water and extracted with dichloromethane. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is filtered through silica gel (eluent: dichloromethane). The filtrate is evaporated and then triturated in heptane. 2-Chloro-N-(2,6-diisopropyl-phenyl)acetamide is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]3[N:16]([CH3:20])[C:17](=[O:19])[NH:18][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH:21](=O)[CH2:22][CH2:23][CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C.C(OCC)(=O)C>[CH2:21]([N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10]1[C:15]2[N:16]([CH3:20])[C:17](=[O:19])[NH:18][C:14]=2[CH:13]=[CH:12][CH:11]=1)[CH2:22][CH2:23][CH3:24]
Reactant: COc1ccc(Nc2cccc3[nH]c(=O)n(C)c23)cc1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCCCN(c1ccc(OC)cc1)c1cccc2[nH]c(=O)n(C)c12
Temperature: 70 °C
Yield: 581.4 %

Procedure:
A mixture of 0.100 g (0.37 mmol) of 7-[(4-methoxyphenyl)amino]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 0.13 mL (1.5 mmol) of butyraldehyde in 15 mL of dichloroethane was treated with four drops of glacial acetic acid and 0.31 g (1.5 mmol) of sodium triacetoxyborohydride. The mixture was heated to 70° C. for five days. The mixture was diluted with ethyl acetate and was washed successively with saturated sodium bicarbonate and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude oil was purified by flash chromatography eluting with a 97% dichloromethane/methanol mixture to give 0.70 g (45%) of the title compound as a yellow sticky semi-solid that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([NH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:7]2.ClCCl.B(Br)(Br)[Br:25]>CO>[BrH:25].[F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([NH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:7]2
Reactant: BrB(Br)Br
Reactant: COc1ccc(F)c2c1CN(Nc1ccncc1)CC2
Solvent: ClCCl
Solvent: CO
Product: Br
Product: Oc1ccc(F)c2c1CN(Nc1ccncc1)CC2
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of (5-fluoro-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl-amine (4.82 g) and dichloromethane (100 ml) at -78° C., boron tribromide (5.5 ml) was added, with stirring. The reaction mixture was warmed to ambient temperature, stirred for 3 hrs, and methanol (100 ml) was added. The mixture was stirred for 1 hr and concentrated in vacuo. The residue was recrystallized from 2-propanol to yield 4.45 g (74%) of product, mp 266° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[CH:16][CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:21][CH:20]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>ClCCCl>[C:36]1([NH:35][CH2:16][CH2:17][CH2:18][C:19]2[CH:34]=[CH:33][C:22]([O:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCC=O)cc2)nc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCCNc3ccccc3)cc2)nc1
Yield: 8.2 %

Procedure:
Add sodium triacetoxyborohydride (0.1633 g, 0.7705 mmol) to a stirred solution of 6-[4-(3-oxo-propyl)-phenoxy]-nicotinamide (0.1341 g, 0.4962 mmol), aniline (0.047 mL, 0.5158 mmol), and 1,2-dichloroethane (7 mL). Stir the reaction for 18 h at room temperature under nitrogen. Pour the reaction mixture into 1 N sodium hydroxide (50 mL), extract with dichloromethane (3×50 mL), dry the dichloromethane extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.6% concentrated ammonium hydroxide/6% ethanol/chloroform to yield 0.0142 g (8%) of 6-[4-(3-phenylamino-propyl)-phenoxy]-nicotinamide: mass spectrum (ion spray): m/z=348.1 (M+1); 1H NMR (CDCl3): 8.58 (d, 1H), 8.16 (dd, 1H), 7.26-7.18 (m, 7H), 7.10-7.04 (m, 2H), 6.97-6.94 (m, 1H), 6.79-6.51 (m, 2H), 3.19 (t, 2H), 2.76 (t, 2H), 2.04-1.97 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][C:3]=1[O:19][CH3:20].O>O1CCCC1.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(C=CC(=O)c2ccc(O)cc2)ccc1O
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)c2ccc(O)cc2)ccc1O
Yield: 89.3 %

Procedure:
10 g of 3-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)-2-propen-1-one are dissolved in 100 g of tetrahydrofuran, combined with 0.2 g of Pd on activated carbon (Pd content: 5 wt. %, water content approx. 50 wt. %, in each case relative to the total mass of the catalyst) and hydrogenated at standard pressure and room temperature (approx. 20° C.) After removal of the catalyst and the solvent, 9 g of 3-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)-propan-1-one are obtained. Yield: 89% of theoretical
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[CH:30])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:17]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[O:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:30]=1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: Oc1ncc(Cl)cc1I
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2cc(Cl)cnc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.07 g (12 mmol) sample of 5-chloro-3-iodo-2-pyridinol, from step 13a above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.39 g, 0.5 mmol), CuI (0.38 g, 1.98 mmol) and triethylamine (1.7 mL, 12 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.95 g (10 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1c above, dissolved in 5 mL of DMF, was added carefully. The reaction mixture was stirred at 60° C. for 16 hours, cooled to room temperature, diluted with ether and washed with 50% brine. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 1.55 g of title compound: MS m/z: 323 (M+H)+.