Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[Mg+2].[Cl-].[CH2:24]=[O:25]>C1COCC1.CCOC(C)=O.Cl>[OH:20][C:15]1[C:16]([CH:24]=[O:25])=[CH:17][CH:18]=[CH:19][C:14]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=O
Reactant: Oc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccc2)c1O
Temperature: 31.5 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (20.2 g, 27.8 mL, 0.20 mol, 2.0 equiv) was added to a solution of 2-phenylphenol (13) (17.0 g, 0.10 mol, 1.0 equiv) in THF (200 mL) followed by solid magnesium chloride (14.3 g, 0.15 mol, 1.5 equiv). The reaction temperature increased from 23 to 40° C. over ˜10 min. The reaction mixture was stirred an additional 10 min during which time a light tan suspension formed. Paraformaldehyde (15.0 g, 0.5 mol, 5.0 equiv) was added and the mixture heated to reflux with formation of a yellow suspension. The mixture was refluxed for 2.5 hr, allowed to slowly cool to room temperature and stirred overnight. The mixture was diluted with EtOAc and 1N HCl (300 mL) with mild cooling to keep the reaction temperature at <25° C. The mixture was transferred to a separatory funnel and shaken with an additional 1N HCl (200 mL). The organic phase was washed with brine (300 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure giving a yellow oil that partially crystallized. The oily crystalline material was pumped on high vacuum for 1 hr to give 20.6 g (104%) of crude 14 that was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5].C(N(CC)CC)C.[N:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>C(Cl)Cl>[OH:5][CH2:4][CH:3]([NH:2][S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)(=[O:31])=[O:32])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled mixture of 6.84 g (44 mmol) of D, L-serine, methyl ester hydrochloride and 21.4 (144 mmol) of triethylamine in 90 ml of CH2Cl2 was added a solution of 10.78 g (40 mmol) of 4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH2Cl2. The mixture was stirred at room temperature overnight, diluted with 50 ml of CH2Cl2 and the solution washed with H2O, 1N NaHCO3, 2N citric acid, brine and dried (with Na2SO4). The solvent was removed under vacuum to give a solid. The aqueous 2N citric acid wash was made basic with saturated NaHCO3 and then extracted with CH2Cl2. The solvent was removed to give a solid. The two crops of solid were combined, washed with H2O and then hexane. The solid was dried at 80° C. to give 10.95 g of methyl 3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino]propionate as white crystals, mp. 137-139° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:24][C:25]4[CH:29]=[CH:28][N:27]([CH2:30][CH2:31][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:26]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1ccn(CCc2ccccc2)n1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccn(CCc5ccccc5)n4)ncnc3[nH]2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (110 mg, 0.33 mmol) and 3-amino-1-phenethyl-1H-pyrazole (74 mg, 0.39 mmol) in 1-butanol (3 mL) was heated at 120° C. overnight, LC-MS showed the reaction was complete. The mixture was concentrated, then dissolved in MeOH-DMSO, and purified by MSDP (using water/acetonitrile/HCOOH mixtures) to give the title compound as a brown solid. LC-MS (ES, Pos.): 486 [MH+]. 1H NMR (CD3OD, 400 MHz): δ=1.49 (s, 9H), 2.54 (m, 2H), 3.16 (t, J=7.1 Hz, 2H), 3.65 (m, 2H), 4.12 (m, 2H), 4.32 (t, J=7.1 Hz, 2H), 6.27 (s, 1H), 6.48 (d, J=2.3 Hz, 1H), 6.53 (s, 1H), 7.14-7.28 (m, 5H), 7.36 (d, J=2.3 Hz, 1H), 8.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[C:17](=[O:18])[CH2:16][CH:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:14]2[CH:27]=[CH:28][CH:29]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:30]([CH3:35])[CH2:31][C:32]#[C:33][CH3:34])[C:8]=1[O:44][CH2:45][O:46][CH3:47].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].OO>C1COCC1>[CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]2[CH:17]([OH:18])[CH2:16][CH:15]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:14]2[CH:27]=[CH:28][CH:29]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:30]([CH3:35])[CH2:31][C:32]#[C:33][CH3:34])[C:8]=1[O:44][CH2:45][O:46][CH3:47]
Reactant: CC#CCC(C)C(C=CC1C(O[Si](C)(C)C(C)(C)C)CC(=O)C1c1cccc(CCCC(=O)OC)c1OCOC)O[Si](C)(C)C(C)(C)C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: CC#CCC(C)C(C=CC1C(O[Si](C)(C)C(C)(C)C)CC(O)C1c1cccc(CCCC(=O)OC)c1OCOC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-(3-{3-(tert-Butyl-dimethyl-silanyloxy)-2-[3-(tert-butyl-dimethyl-silanyloxy)-4-methyl-oct-1-en-6-ynyl]-5-oxo-cyclopentyl}-2-methoxymethoxy-phenyl)-butyric acid methyl ester of 2.6 g (3.67 mmol) was dissolved in THF (40 ml). The solution was cooled to −78° C., and then, L-selectride (1 M.THF solution, 7.35 mmol) was slowly added thereto dropwise. The mixture was stirred at the above temperature for 2 hours, and the reaction was stopped with hydrogen peroxide (30% aqueous solution, 16 mmol). The reaction solution was stirred at 0° C. for 30 minutes, and then, extracted with diethyl ether. The combined organic layer was washed with water and brine, and then, dried over magnesium sulfate, filtered off, and concentrated under reduced pressure. The concentrate was subjected to column chromatography on a silica gel (hexane:ethyl acetate=4:1) to obtain 4-(3-{3-(tert-butyl-dimethyl-silanyloxy)-2-[3-(tert-butyl-dimethyl-silanyloxy)-4-methyl-oct-1-en-6-ynyl]-5-hydroxy-cyclopentyl}-2-methoxymethoxy-phenyl)-butyric acid methyl ester (2.3 g, yield: 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.[CH2:38]([CH2:40][NH2:41])[OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([NH:41][CH2:40][CH2:38][OH:39])=[O:37])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(O)/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Product: O=C(/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1)NCCO
Yield: 60 %

Procedure:
The title compound was prepared as described in Example 34.B using (2E)-3-(4-{[2-(4-fluorophenyl)-6-(phenylmethoxy)( 1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)prop-2-enoic acid (0.494 g, 1.0 mmol) and ethanolamine (0.122 g, 2.0 mmol) to provide the title compound (0.322 g, 60% yield): 1H NMR (CDCl3) 8.02 (br, 1H), 7.61 (d, 1H), 7.32-7.41 (m, 7H), 7.00 (d, 2H), 6.91 (m, 2H), 6.69-6.77 (m, 5H), 6.37 (d, 1H), 6.12 (t, 1H), 5.03 (s, 2H), 4.75 (t, 1H), 3.80 (t, 2H), 3.57 (t, 2H), 3.45-3.56 (m 2H), 3.15 (dd, 1H), 2.89 (m, 2H), 2.66 (dt, 1H); ES-MS m/z 537 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]1=[O:16]>C(N)CCC>[CH2:3]([NH:2][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][C:3](=[O:16])[N:2]([CH3:1])[C:7]=2[N:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: Cn1c(=O)ccc2cnc(S(C)(=O)=O)nc21
Solvent: CCCCN
Product: CCCCNc1ncc2ccc(=O)n(C)c2n1
Yield: 159.8 %

Procedure:
A solution of 8-methyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (200 mg, 0.83 mmol) in 2 mL of n-butylamine was stirred at room temperature for 10 minutes. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated in vacuo. A 4:1 mixture of hexane:ethyl acetate was added to the residue and the resultant solid collected by filtration to give 154 mg (79%) of 2-butylamino-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 146-147° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C:15](=[CH2:16])[C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH:18]=2)[C@H:13]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:12]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:11]1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:57][Zn]C.ICI.[NH4+].[Cl-]>C1(C)C=CC=CC=1.O>[CH2:50]([O:49][C@H:11]1[C@H:12]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:13]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH:18]=2)[C:15]2([CH2:57][CH2:16]2)[C@@H:10]1[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: C=C1[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1c1ccc(Cl)c(Cc2ccc(CC)cc2)c1
Reactant: C[Zn]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(Cc2cc([C@H]3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@@H](COCc4ccccc4)C34CC4)ccc2Cl)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a vigorously stirred solution of ((1S,2R,3R,4R,6S)-4-(benzyloxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)-5-methylenecyclohexane-1,2,3-triyl)tris(oxy)tris(methylene)-tribenzene (34, 25 mg, 32.7 μmol) in anhydrous toluene (2 mL) under nitrogen at −10° C. was added 2M solution of dimethyl zinc (146 μL, 291 μmol) dropwise and stirred for 15 minutes. Diiodomethane (47 μL, 583 μmol) was added drop-wise and the resulting mixture was stirred over night. 40% product fonnation was observed. More dimethyl zinc (18 more equivalent in two batches over 48 hour period) and diiodomethane (35 equivalent in two batches over 48 hour period) were added and the reaction was 80% complete after 96 hours of reaction. Saturated solution of NH4Cl (1 mL) was added and the mixture was stirred for 30 minutes. The mixture was diluted with water (1 mL) and extracted into ethyl acetate (3×1 mL). The combined organic extracts were washed with 10% sulfuric acid (1.5 mL), saturated NaHCO3 (1.5 mL) and brine (1.5 mL), dried (Na2SO4), filtered and evaporated. Preparative TLC (9:1 hexane:ethyl acetate) afforded 85% compound 36 which was used directly in the next reaction.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH:9]2[C:21]2([OH:32])[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)C=CC=CC=1.[H][H]>CO.[Pd]>[OH:32][C:21]1([CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CN(Cc3ccccc3)CCN2Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(O)(C2CNCCN2)C1
Yield: 94.6 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate (408 mg, 0.93 mmol) in methanol (15 mL) was added 10% palladium on carbon (wet), and the resulting suspension was subjected to an atmosphere of hydrogen for 21 hours. The catalyst was removed by filtration through celite, and the filter cake was rinsed with methanol. The combined filtrate was concentrated to provide 1,1-dimethylethyl 3-hydroxy-3-piperazin-2-ylazetidine-1-carboxylate as a brown syrup (227 mg, 0.88 mmol, 95% yield). 1H NMR (400 MHz, CDCl3): 3.94-3.76 (m, 5H), 3.12 (m, 1H), 3.01 (m, 1H), 2.94-2.81 (m, 3H), 2.78-2.70 (m, 2H); MS (EI) for C12H23N3O3: 258 (MH+).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[Si](C)(C)[C:20]#[C:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1.[Mg]>O1CCCC1>[C:10]1([C:2]2[N:4]=[C:5]([C:25]3[CH:26]=[CH:27][C:22]([C:21]#[CH:20])=[CH:23][CH:24]=3)[N:7]=[C:8]([C:25]3[CH:26]=[CH:27][C:22]([C:21]#[CH:20])=[CH:23][CH:24]=3)[N:1]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Reactant: Br[Mg]c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C#Cc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(C#C)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
One mole of cyanuric chloride was treated with one mole of phenylmagnesium bromide as described in Step I of Example I. The product of this reaction (2.3 g, 0.01 mole) in 25 ml of tetrahydrofuran (THF) was added slowly to a refluxing solution of the Grignard reagent prepared from 1-(trimethylsilyl)-2-(4-bromophenyl)acetylene (0.03 moles) and magnesium (0.75 g). The solution was stirred overnight, filtered, and the solvent removed. To the residue which remained was added a solution of KOH (10.0 g) in water (5 ml), anhydrous ethanol (100 ml) and dioxane (100 ml). The resulting mixture was heated for 2.5 hours at 60° C., filtered, and the solvent removed. Chromatographic separation of the resulting residue yielded a yellow solid, 6-phenyl-2,4-bis(4-ethynylphenyl)-s-triazine, which melted at approximately 215° C. with rapid polymerization.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[N+](=[CH2:24])=[N-]>ClCCl>[CH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH3:24])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: C=Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A solution of 200 mg of 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate. Likewise but using diazoethane, diazopropane and diazobutane in place of diazomethane there are respectively obtained:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]1[N:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[N:9]=1>O1CCCC1>[Cl:15][C:10]1[CH:11]=[C:12]([Cl:14])[N:13]=[C:8]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:9]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COCCCN
Solvent: C1CCOC1
Product: COCCCNc1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
48 g (0.54 mole) of 3-methoxypropylamine are added dropwise to 50 g (0.27 mole) of 2,4,6-trichloropyrimidine, dissolved in 300 ml of tetrahydrofuran, at -30° C. After the reaction mixture has thawed to room temperature and been stirred for a further six hours, it is poured into ice water and extracted with methylene chloride, the extract is dried over sodium sulphate and the solvent is removed. The resulting residue is subjected to steam distillation in the course of which 10.6 g (16.6% of theory) of the desired pyrimidine pass over as a solid, melting point 48° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1>S(=O)(=O)(O)O>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:9]2[O:8][C:4]3[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:11](=[O:13])[C:10]=2[CH:14]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Oc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: O=c1c2ccc(F)cc2oc2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
700 grams of 2-(3-fluorophenyloxy)-5-trifluoromethylbenzoic acid were dissolved in 3,000 milliliters of concentrated sulfuric acid whereby the temperature rose to 60 degrees Centigrade. The mixture was stirred at 45- 50 degrees Centigrade for one hour and then poured onto 10 liters of crushed ice. The precipitate was filtered off, suspended in 1,000 milliliters of acetone, made alkaline with concentrated aqueous ammonia and reprecipitated with ice and water to a volume of 10 liters. The precipitate was filtered, washed with water and dried in vacuum, whereupon it was recrystallized to yield 167 grams of 2-trifluoromethyl-6-fluoroxanthen-9-one which melts at 140- 142 degrees Centigrade.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C>C1(C)C=CC=CC=1.Cl>[CH3:12][C:8]1([CH3:13])[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([B:23]([OH:24])[OH:22])[CH:11]=[CH:10][C:9]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC1(C)CCCc2cc(B(O)O)ccc21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of 2.02 g (8.4 mmol) of, 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene in 11.0 mL of toluene, was added 4.6 g (6.8 mL, 10.9 mmol, 1.6 M in hexane) of n-BuLi. The resulting solution was stirred at −78° C. for 45 min. and then 2.40 g (3.0 mL, 12.7 mmol) of triisopropylborate was dropwise added and the reaction stirred at room temperature for 12 h. The reaction was then diluted with 10% HCl, and extracted with ether (2×). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give an oil. Recrystallization from hexane afforded the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]2[C:8]([CH:9]=[C:10]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:11]=[N:12]2)=[C:7]([I:31])[N:6]=1)=[O:4].O1CCCC1.[OH-].[Na+].Cl>CO>[CH2:16]([O:15][C:14]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([I:31])=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[CH:9]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above Compound 8 (20.0 g, 37.86 mmol) was added tetrahydrofuran (100 ml) and methanol (100 ml) to give suspension, followed by addition of 2N sodium hydroxide aqueous solution (24.6 ml, 49.2 mmol) under stirring at room temperature and stirring was continued. After 4 hours, 2N hydrochloric acid (24.6 ml, 49.2 mmol) was added, and the reaction solution was concentrated under reduced pressure and added with chloroform (150 ml) and water (150 ml). Then the solution was shaken for separation, washed with saturated sodium hydrogen carbonate and dried over sodium sulfate, followed by distillation under reduced pressure. The residue (20.8 g) was added with diisopropyl ether (80 ml) and n-hexane (80 ml), warmed on a water bath for crystallization, and then the crystals were collected by filtering and washed with diisopropyl ether:n-hexane (1:1), to give 8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylic acid 9 in a yield of (19.41 g, 99.7%).
Reaction SMILES: C(OCC)(=O)C.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]([OH:44])[CH:31]4[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]4)=[CH:26][CH:25]=3)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]([OH:44])[CH:31]4[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]4)=[CH:26][CH:25]=3)=[O:22])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(O)c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C(O)C2CCCNC2)cc1)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 181.7 %

Procedure:
4N Hydrogen chloride-ethyl acetate (1 ml) was added to tert-butyl 3-[[4-[[(4′-chloro[1,1′-biphenyl]-4-yl)carbonyl]amino]phenyl](hydroxy)methyl]-1-piperidinecarboxylate (100 mg, 0.192 mmol) obtained in Reference Example 78. One hour later, the solvent was distilled out under reduced pressure. Diisopropyl ether was added to the residue, to give the titled compound (79.8 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CC(C)=O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: COC(=O)CBr
Reactant: CCCCCCCCCCCCCCCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)OC)cc1
Yield: 89.4 %

Procedure:
A mixture of 23 g of p-(hexadecyloxy)phenol, 13.35 g of methyl bromoacetate, 10.45 g of potassium carbonate in 200 ml of acetone is refluxed for 24 hours. The mixture is cooled, chloroform added and filtered. The filtrate is evaporated and the residue crystallized from hexane to give 25 g of the desired compound as a gray white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[N:21]S(C(C)(C)C)=O)[CH2:17][CH2:16]2)OCC1>>[NH2:21][C:18]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:19][CH2:20][C:15](=[O:11])[CH2:16][CH2:17]1
Reactant: COc1cccc([Mg]Br)c1
Reactant: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Product: COc1cccc(C2(N)CCC(=O)CC2)c1

Procedure:
The title compound was prepared as a white solid from addition of 3-methoxy-phenyl magnesium bromide (Aldrich) to 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide (as prepared in Example 84, Step A) followed by hydrolysis using the procedure described in Step B of Example 84.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][OH:11].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[CH3:22][N:18]1[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=[C:13]([O:11][CH2:10][C:3]3[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:23]=[C:17]12
Reactant: OCc1cc(F)c(F)cc1F
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(F)cc1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (2,4,5-trifluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.