Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:12])[CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]1=[O:11].[NH2:13][CH2:14][C:15]([OH:17])=[O:16].O>C(O)(=O)C>[CH3:12][C:2]1[N:13]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:11])[C:4]=2[CH:3]=1
Reactant: NCC(=O)O
Reactant: CC(=O)CC1C(=O)CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(n1CC(=O)O)CCCC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred mixture of 2-(2-oxopropyl)cyclohexane-1,3-dione (prepared by evaporation of an ethanolic solution to dryness under vacuum) (20.0 g, 119 mmol) and glycine (17.9 g, 238 mmol) in acetic acid (100 mL) was heated under reflux for 1.5 h then allowed to cool to r.t. Water (100 mL) was then added and the mixture evaporated to a thick oil in vacuo. Acetone (200 mL) and water (40 mL) were added to the residue and the mixture stirred for 30 mins at r.t., after which the solid was collected by filtration and the filtrates retained. The solid was slurried with further acetone (100 mL) and water (20 mL) at r.t. then removed by filtration. The combined filtrates were concentrated in vacuo then dissolved in aqueous sodium hydroxide (1M, 200 mL), adding a small amount of 10M sodium hydroxide to bring the pH to 14. After washing with ethyl acetate (2×100 mL), the mixture was acidified by the addition of aqueous hydrochloric acid (5M, 60 mL) then sodium chloride (50 g) was added. After stiffing for 4 h, the solid product was collected by filtration, washed with acetone (2×25 mL) then dried under vacuum at 40° C. to afford the title compound as an orange-brown solid; 7.45 g (30%); purity 99.1 area % by HPLC; m/z: 208 (MH+); 1H-NMR: 13.2 (1H, br s), 6.02 (1H, s), 4.67 (2H, s), 2.65 (2H, t, J=6.2 Hz), 2.29-2.24 (2H, m), 2.10 (3H, s), 2.02-1.95 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:10])[Cl:11])[CH:7]=1)[CH2:13][Br:32]
Reactant: Cc1cc(Cl)cc(C(Cl)=C(Cl)Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClC(Cl)=C(Cl)c1cc(Cl)cc(CBr)c1
Yield: 66.4 %

Procedure:
A solution of 3-chloro-5-(trichlorovinyl)toluene (7.56 g) and dibenzoyl peroxide (0.5 g) in 250 ml of benzene was heated at reflux. N-Bromosuccinimide (6.04 g) was added in portions and the reaction mixture stirred at reflux for 3 hours. The mixture was then evaporated and the residue titurated with hexane (200 ml). The precipitated succinimide was removed by filtration and washed with hexane (2 x 25 ml). The hexane was concentrated and the residual oil (10.1 g) chromatographed on silica with petroleum ether as eluant. The column afforded 1.39 g of starting toluene, 1.18 g of dibromide, and 6.57 g of the desired benzyl bromide.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:53][CH2:54][C:55]1[C:56]([OH:63])=[N:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>ClCCl.O>[OH:63][C:56]1[C:55]([CH2:54][NH:53][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([CH:4]([O:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:3][CH:2]([CH3:1])[CH3:21])=[CH:20][CH:19]=2)=[C:60]([CH3:61])[CH:59]=[C:58]([CH3:62])[N:57]=1
Reactant: CC(C)CC(Oc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(CC(C)C)Oc3ccccc3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of 4-(3-Methyl-1-phenoxybutyl)benzoic acid (20 mg, 0.07 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) and triethylamine (2 mL) was dissolved in dichloromethane (20 mL). The mixture was stirred for 0.5 hour. And then added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (100 mg, 0.66 mmol) was added to the mixture and the resultant mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the reaction mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(3-methyl-1-phenoxybutyl)benzamide (Compound I-49) (15 mg, 52%). LRMS (M+H+) m/z: calcd 418.23. found 418. HPLC purity (214 nm): 95%. 1H NMR (300 MHz, CD3OD): δ 7.73 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.13 (t, J=7.5 Hz, 2H), 6.83-6.79 (m, 3H), 6.09 (s, 1H), 5.26-5.21 (m, 1H), 4.47 (s, 2H) 2.34 (s, 3H), 2.23 (s, 3H), 1.95-1.82 (m, 2H), 1.61-1.56 (m, 1H), 1.02-0.95 (m, 6H).
Reaction SMILES: [Si:1]([CH:8]1[C:12](=[CH:13][O:14][Si](C(C)(C)C)(C)C)[C:11]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:10]=2[O:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl>CO>[Si:1]([C:8]1[O:9][C:10]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:11]=2[C:12]=1[CH:13]=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)OC([Si](C)(C)C(C)(C)C)C2=CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: COc1ccc2c(C=O)c([Si](C)(C)C(C)(C)C)oc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-t-butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy-benzofuran (1.09 g, 2.69 mmol) in methanol (100 mL) was added concentrated hydrochloric acid (200 μL) and the reaction was stirred for 30 minutes (monitored by tlc), quenched with triethylamine (2 mL) and the solvent removed by distillation under vacuum. The residue was dissolved in dichloromethane (20 mL), washed with water (10 mL), dried over magnesium sulfate, concentrated under vacuum and co-distilled with toluene (20 mL); 1H NMR (300 MHz, CDCl3) δ 7.57(d, 1H, J=8.57 Hz), 7.00(d, 1H, J=2.17 Hz), 6.86(dd, 1H, J=8.55, 2.22 Hz), 4.81(s, 2H, CH2), 3.84(s, 3H, OMe), 0.94(s, 9H), 0.37(s, 6H). The crude yellow paste (˜985 mg) was dissolved in dry dichloromethane (4 mL) and added to a stirred solution of Collin's reagent (chromium trioxide (1.01 g), pyridine (1.65 mL) in dry dichloromethane (30 mL)). The suspension was stirred for 10 minutes, filtered and the residue washed with diethyl ether (20 mL). The filtrate was concentrated onto silica (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl-ether/triethylamine (90:9:1) to afford the title compound as a light yellow oil which crystallized on standing (485 mg, 68%); 1H NMR (300 MHz, CDCl3) δ 10.25(s, 1H, CHO), 8.06(d, 1H, J=8.61 Hz), 7.03(d, 1H, J=2.16 Hz), 6.95(dd, 1H, J=8.60, 2.19 Hz), 3.84(s, 3H, OMe), 0.97(s, 9H), 0.46(s, 6H); 13C NMR (75 MHz, CDCl3) δ 186.91(CHO), 174.18, 159.19, 159.17, 132.82, 122.77, 117.34, 113.56, 95.36, 55.60, 27.04, 17.09, −5.24.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=O)=[C:13](OC)[CH:12]=2)[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:24][CH3:23])=[CH:15][C:16]=2[O:31][CH3:30])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1cc(Oc2cc(Cl)ccc2C#N)ccc1C=O
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNCc1ccc(Oc2cc(Cl)ccc2C#N)c(OC)c1
Yield: 109.8 %

Procedure:
4-Chloro-2-(4-formyl-3-methoxy-phenoxy)-benzonitrile (0.93 g, 3.2 mmol), methylamine (2M in methanol, 4.8 ml, 9.6 mmol) and sodium cyanoborohydride (0.22 g, 3.6 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (125 ml) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. Fumaric acid (0.40 g, 3.4 mmol) was added to the separated ethyl acetate layer and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(2-methoxy-4-methylaminomethyl-phenoxy)-benzonitrile fumarate (782 mg, 58%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1.[OH-].[Na+]>CO>[Cl:22][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]2)[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)C(CC1CCC(=O)C1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid methyl ester (1.02 g, 2.84 mmol) in methanol (7.1 mL) was treated with a 1N aqueous sodium hydroxide solution (6.0 mL, 6.0 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo to remove methanol. The resulting aqueous residue was diluted with water (100 mL) and acidified to pH=3 with a 1N aqueous hydrochloric acid solution then extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting yellow oily solid was triturated with ethyl acetate/petroleum ether to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-propionic acid (800.0 mg, 82%) as a white solid: mp 164–167° C.; (ES)+-HRMS m/e calcd for C15H17ClO5S (M+H)+ 345.0558 found 345.0561.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Oc3ccc(Cl)cc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ccc(Oc2ccc(NC3CCNCC3)cc2)cc1
Reaction time: 17 h
Yield: 203.7 %

Procedure:
In a similar manner as described above in Paragraph A, a solution of 1,1-dimethylethyl 4-[[4-(4-chlorophenoxy)phenyl]amino]-1-piperidinecarboxylate (1.34 g, 3.3 mmol) in dichloromethane (10 mL) was stirred as a solution of 4 M hydrochloric acid in dioxane (3.3 mL, 13.3 mmol) was added. The reaction was stirred for 17 hours. Solvent was removed to yield 1.14 g of N-[4-(4-chlorophenoxy)phenyl]-4-piperidinamine hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)[NH:4][N:3]=1.Cl.[CH:31]1([C:34]2([OH:38])[CH2:37][NH:36][CH2:35]2)[CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>CCCCO.CCOC(C)=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:13]=[C:12]([N:36]3[CH2:37][C:34]([CH:31]4[CH2:33][CH2:32]4)([OH:38])[CH2:35]3)[N:11]=[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[N:9]=2)[NH:4][N:3]=1
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CCCC4)cc3)n2)[nH]n1
Reactant: OC1(C2CC2)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N3CC(O)(C4CC4)C3)nc(Sc3ccc(NC(=O)C4CCCC4)cc3)n2)[nH]n1
Temperature: 100 °C

Procedure:
To a suspension of N-(4-(4-(3-methyl-1H-pyrazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopentanecarboxamide (200 mg, 0.47 mmol) and 3-cyclopropyl azetidin-3-ol hydrochloride (70 mg, 0.47 mmol) in n-BuOH (5 ml) was added diisopropylethylamine (239 mg, 1.88 mmol, 0.30 ml). The mixture was heated to 100° C. for 16 hrs and then allowed to cool to room temperature and diluted with EtOAc (30 ml) and sat NaHCO-3. The organic layer was washed with brine, dried (Na2SO4) and concentrated. Crude product was then purified by flash chromatography EtOAc 5% MeOH:EtOAc to give title compound as an off white solid (70 mg, 30%). 1H NMR (DMSO-d6) 0.30-0.35 (2H, m), 0.39-0.44 (2H, m), 1.16-1.21 (1H, m), 1.56-1.75 (6H, m), 1.83-1.90 (2H, m), 2.00 (3H, s), 2.76-2.82 (1H, m), 3.65 (4H, dd), 5.35 (1H, s), 5.58 (1H, s), 7.47 (2H, d), 7.72 (2H, d), 9.19 (1H, s), 10.06 (1H, s), 11.65 (1H, s). ES+ 506.
Reaction SMILES: C(O)C.CCOCC.[Br-].[CH3:10][N:11]([CH3:49])[C:12]1[CH:48]=[CH:47][C:15]([CH:16]=[N:17][N:18]2[CH:22]=[CH:21][N+:20](CC(C3C=CC(N(C)C)=CC=3)=O)=[C:19]2[C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[CH:14][CH:13]=1.C(#N)C>>[CH3:49][N:11]([CH3:10])[C:12]1[CH:48]=[CH:47][C:15]([CH:16]=[N:17][N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[C:35]2[CH:36]=[C:37]([O:45][CH3:46])[C:38]([O:43][CH3:44])=[C:39]([O:41][CH3:42])[CH:40]=2)=[CH:14][CH:13]=1
Reactant: COc1cc(-c2n(N=Cc3ccc(N(C)C)cc3)cc[n+]2CC(=O)c2ccc(N(C)C)cc2)cc(OC)c1OC
Agent: [Br-]
Solvent: CCOCC
Solvent: CCO
Solvent: CC#N
Product: COc1cc(-c2nccn2N=Cc2ccc(N(C)C)cc2)cc(OC)c1OC

Procedure:
In an analogous manner, from 1-[[p-(dimethylamino)benzylidene]amino]-2-(3,4,5-trimethoxyphenyl)imidazole, there is obtained after 2 days at 50° in acetonitrile 3-[[p-(dimethylamino)benzylidene]amino]-1-[p-(dimethylamino)phenacyl]-2-(3,4,5-trimethoxyphenyl)imidazolium bromide of melting point 232° (ethanol/ether).
Reaction SMILES: [OH:1]CCNCCO.CO[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1COCC1>[C:13]1([S:16]([OH:18])(=[O:1])=[O:17])[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCO
Solvent: C1CCOC1
Product: O=S(=O)(O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 2-(2-hydroxy-ethylamino)-ethanol (7 g, 67 mmol) and 4-methoxybenzenesulfonyl chloride (40 g, 194 mmol) in THF (400 mL) KOH (100 mL, 40%) was added dropwise at 0° C., after stirring over 3 hr the mixture was filtrated and THF was evaporated in vacuo, then extracted with EtOAc (500 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column to afford Benzenesulfonic acid, 4-methoxy-, [[(4-methoxyphenyl)sulfonyl]imino]di-2,1-ethanediyl ester as a colorless gum (20 g, 49%). 1H NMR (DMSO-d6) δ 7.81 (d, J=4.8 Hz, 4H), 7.79 (d, J=5.2 Hz, 2H), 7.01 (d, J=4.8 Hz, 4H), 6.93 (d, J=5.2 Hz, 2H), 4.08 (t, J=6 Hz, 4H), 3.88 (s, 6H), 3.86 (s, 3H), 3.35 (t, J=6 Hz, 4H). MS (ESI) m/z (M+1)+: 615.7.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH2:29]([Sn](CCCC)(CCCC)C=C)[CH2:30]CC.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.[F-].[K+].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>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[CH:29]=[CH2:30])[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1c(CC)nc(CCC)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (10 g), tributyl(vinyl)tin (10 g) and lithium chloride (2.9 g) in N,N-dimethylformamide (200 mL) was added dichlorobis(triphenylphosphine)palladium (0.80 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, 15% aqueous potassium fluoride solution was added, and the mixture was stirred for 2 hr. The insoluble material was filtered off through celite, and the organic layer of the filtrate was separated, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (5.9 g, 68%).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:19][N:18]([CH3:20])[CH2:17][CH2:16][C:4]=2[C:5]2[N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9][C:10]=2[CH:11]=1.[Li][CH:22](CC)C.CI>O1CCCC1>[CH3:15][O:14][C:7]1[C:8]([O:12][CH3:13])=[N:9][C:10]2[CH:11]=[C:2]([CH3:22])[C:3]3[CH2:19][N:18]([CH3:20])[CH2:17][CH2:16][C:4]=3[C:5]=2[N:6]=1
Reactant: COc1nc2cc(Br)c3c(c2nc1OC)CCN(C)C3
Reactant: [Li]C(C)CC
Solvent: CI
Solvent: C1CCOC1
Product: COc1nc2cc(C)c3c(c2nc1OC)CCN(C)C3
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of the product from Example 100 (0.50 g, 1.48 mol) in 20 mL of tetrahydrofuran was cooled to −78° C. and treated dropwise with sec-BuLi (1.7 mL, 1.17 M in cyclohexane). The resulting green-black solution was stirred at −78° C. for 30 minutes. The reaction mixture was treated with MeI (123 μL, 2.00 mmol) and the resulting solution stirred at −78° C. for 30 minutes. The reaction mixture was warmed to room temperature and quenched with saturated aqueous NH4Cl solution (2.0 mL). The reaction mixture was extracted with CHCl3 (4×20 mL) and the combined organic extracts were dried and concentrated. The residue was broken up in heptane and collected by suction filtration to give the title compound as a orange solid (0.196 g, 48% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[OH:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:16]
Reactant: OC1CCCCCC1c1cc(Cl)ccc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=C1CCCCCC1c1cc(Cl)ccc1Cl
Temperature: 20 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 2-(2,5-dichloro-phenyl)-cycloheptanol (0.6 g, 2.32 mmol) in dichloromethane (40 mL) was added Dess-Martin perjodane (1.22 g, 2.78 mmol). The mixture was stirred at 20° C. for 1 h. A mixture of 10% aq sodium bicarbonate solution (10 mL) and 10% aq sodium thiosulfate solution (10 mL) was added, and stirring was continued for 5 min. The organic layer was separated and dried over sodium sulfate. Solvents were removed under reduced pressure and the remaining oil was purified by column chromatography on silica gel using heptane/0-20% ethyl acetate as eluent to give the title compound (0.58 g, ca. 100%) as a pale-yellow oil. MS ISP (m/e): 257.1 [(M+H)+].
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:9]=2[CH:8]=1.[B:36](OC(C)C)([O:41]C(C)C)[O:37]C(C)C>C1COCC1>[CH2:20]([C:10]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9]2[CH:8]=[C:7]([B:36]([OH:41])[OH:37])[CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
n-BuLi (2.5 M in hexane, 12.0 mL, 30.0 mmol) is slowly added to a solution of 2-bromo-9,9-bis(n-octyl)fluorene (12.0 g, 25.6 mmol) in anhydrous THF (50 mL) at −78° C. At this temperature, the reaction mixture is stirred for 1 h before adding tri-iso-propyl borate (9.0 mL, 7.34 g, 39.0 mmol). The resulting mixture is then warmed to room temperature, stirred overnight followed by quenching with 100 mL HCl (2.0 M), and poured into a large amount of water. After extraction with ethyl ether three times, the organic portions are washed with brine before drying over anhydrous MgSO4. Solid residues collected by evaporating off the solvent are purified by column chromatography on silica gel with petroleum ether/ethyl acetate (2:1) to yield 9,9-bis(n-octyl)fluoren-2-yl-boronic acid (2a) as a white solid (10.0 g, 89%).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14]([C:21]([P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])([F:23])[F:22])=[C:15]([Br:20])[CH:16]=2)[CH:11]=1)(=O)OCC)C.[CH:32]([C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38])=O.CC(C)([O-])C.[K+]>C1COCC1>[Br:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[C:21]([P:24]([O:26][CH2:27][CH3:28])([O:29][CH2:30][CH3:31])=[O:25])([F:23])[F:22])[CH:11]=[C:10](/[CH:9]=[CH:32]/[C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38])[CH:19]=[CH:18]2
Reactant: CCOP(=O)(Cc1ccc2cc(Br)c(C(F)(F)P(=O)(OCC)OCC)cc2c1)OCC
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)c1cc2cc(/C=C/c3cccc(C(=O)OC)c3)ccc2cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl{6-bromo-7-[(diethoxyphosphoryl)(difluoro)methyl]-2-naphthyl}methylphosphonate (190 mg), and methyl 3-formylbenzoate (60 mg) in degassed THF (5 mL) at −78° C. was added potassium tert-butoxide (0.35 mL of a 1M solution in THF) and the reaction mixture was stirred for 1 h at 0° C. The mixture was quenched with a saturated solution of NH4Cl, extracted with EtOAc, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography eluting with 25% EtOAc/hexanes to afford the titled product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:21]1[C:22]2[CH:29]=[CH:28][N:27]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6]1>CCO.[Pd]>[NH:7]1[CH2:8][CH2:9][CH2:10][C@@H:5]([N:4]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=4)(=[O:31])=[O:32])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:3][CH2:2][OH:1])[CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CCO)[C@@H]4CCCN(C(=O)OCc5ccccc5)C4)ncnc32)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(CCO)[C@@H]4CCCNC4)ncnc32)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-benzyl 3-((2-hydroxyethyl)(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (1.3 g, 2.4 mmol) in EtOH (10 mL) was added 10% Pd/C (0.8 g) under an atmosphere of N2 and the reaction was placed under an atmosphere of hydrogenated (1 atm.) for 2 h. The mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to afford a residue which was used without further purification (0.9 g, 91%). LCMS [M+1]: 416.