Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.S(Cl)(Cl)=O.[CH3:15]O>>[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:15])=[O:9])[N:4]=[CH:3]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c[nH]cn1
Temperature: 25 °C

Procedure:
1H-Imidazol-4-ylacetic acid hydrochloride (20.0 g) was suspended in methanol (200 mL). To this suspension, thionyl chloride (8.87 mL) was added at room temperature, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. To this reaction solution, a saturated aqueous solution of sodium bicarbonate was added, and the solvent was distilled off under reduced pressure. To the obtained residue, tetrahydrofuran and anhydrous magnesium sulfate were added, and insoluble matter was filtered off. The solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (14.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:24]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccc(F)cc4)nc13)C2
Yield: 60 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-fluorophenyl)benzoxazole-4-carboxamide was prepared from 2-(4-fluorophenyl)benzoxazole-4-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 60% yield as a white solid: mp 197-199° C.; 1H NMR (500 MHz, CDCl3) δ 8.95 (m, 1H), 8.26 (m, 2H), 8.21 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (dd, J=8.1, 1.0 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.29 (m, 1H), 4.60 (m, 1H), 3.11 (m, 2H), 2.66 (m, 2H), 2.54 (s, 3H), 2.15 (m, 1H), 2.04 (m, 2H), 1.59 (m, 2H), 1.51 (m, 2H), 1.17 (m, 2H); MS (ESI) m/z 394 [M+H]+
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]2[CH:22]=[CH:21][C:12]([CH:13]=[C:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[C:30]([CH3:31])=[C:29]([OH:32])[C:28]([CH3:33])=[CH:27][C:25]=1[OH:26].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:33][C:28]1[C:29](=[O:32])[C:30]([CH3:31])=[C:24]([CH3:23])[C:25](=[O:26])[C:27]=1[CH:8]([C:7]1[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:22]=[CH:21][C:12]([CH:13]=[C:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(C)=Cc1ccc(Cc2cccnc2O)cc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(C)=Cc1ccc(C(C2=C(C)C(=O)C(C)=C(C)C2=O)c2cccnc2)cc1
Yield: 83.2 %

Procedure:
To a solution of 1.0 g (3.36 mmol) of ethyl 4-[hydroxy-(3-pyridyl)]methyl-α-methylcinnamate in 10 ml of dichloroethane, 514 mg (3.38 mmol) of 2,3,5-trimethylhydroquinone and 0.28 ml (5.26 mmol) of concentrated sulfuric acid were added and refluxed by heating for 2 hours. The reaction mixture was made weakly alkaline with a saturated solution of sodium hydrogen carbonate, and the organic phase was separated while the aqueous phase was extracted with chloroform and the extract was combined with the organic phase. The organic phase was oxidized with ferric chloride, washed with water, dried, and concentrated. The residue was purified with silica gel column chromatography (isopropyl ether-acetic ester (1:1)), to give 1.2 g (yield 82.7%) of ethyl 4-[3,5,6-trimethyl-1,4-benzoquinone- 2-yl(3-pyridyl)methyl]-α-methylcinnamate. The physical data are shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[C:34]([C:37](O)=[O:38])=[CH:33][N:32]([CH:40]([CH3:42])[CH3:41])[C:31]2=[O:43])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:37]([C:34]2[C:35](=[O:36])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[C:31](=[O:43])[N:32]([CH:40]([CH3:42])[CH3:41])[CH:33]=2)=[O:38])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Nc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc2nccc(Nc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3)c2cc1OC

Procedure:
This compound was synthesized using N-(6,7-dimethoxyquinolin-4-yl)-benzene-1,4-diamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid the method for example 134. mp=190-193° C.; LCMS m/z=570 (M+1); 1H NMR (DMSO-d6) δ: 10.85 (s, 1H), 8.65 (brs, 2H), 8.26 (d, 1H, J=5.3 Hz), 7.71 (d, 2H, J=8.8 Hz), 7.65 (s, 1H), 7.27-7.47 (m, 7H), 7.23 (s, 1H), 6.75 (d, 1H, J=5.3 Hz), 4.72-4.84 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 1.42 (d, 7H, J=6.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.I[CH2:11][CH3:12].[H-].[Li+]>>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([O:9][CH2:11][CH3:12])[CH:3]=1
Reactant: Oc1cc(O)cc(Br)c1
Reactant: CCI
Agent: [H-]
Agent: [Li+]
Product: CCOc1cc(O)cc(Br)c1
Yield: 32 %

Procedure:
A similar procedure as described in Example 43, step 2 was used, starting from 5-bromo-benzene-1,3-diol (9.2 g, 48.67 mmol), iodoethane (8.13 g, 51.1 mmol), and lithium hydride (720 mg, 97.34 mmol) to afford 3-bromo-5-ethoxy-phenol (3.38 g, 32%) as a light yellow oil: ES(+)-HRMS m/e calcd for C8H9BrO2 (M+Na)+ 217. found 217.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][CH:4]2[CH2:5][C:2]([F:8])([F:1])[CH2:3]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCC1CC(F)(F)C1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC1CC(F)(F)C1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A round bottom flask was charged with (3,3-difluorocylobutyl)methanol (1.0 g, 8.2 mmol, 1.0 equiv), 4-bromobenzenesulphonyl chloride (2.2 g, 8.6 mmol, 1.05 equiv) and CH2Cl2 (50 mL). The mixture was cooled to 0° C. and triethylamine (2.07 g, 2.89 mL, 20.5 mmol, 2.5 equiv) was added via syringe. The mixture stirred for 12 h with warming to rt. After this time 1.0 M aq HCl (50 mL) was added. The layers were separated, the organic layer was extracted with CH2Cl2 (50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The compound was purified by flash chromatography on silica, eluting with 0-30% EtOAc in hexanes. This afforded (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate (2.7 g, 95%) as an off white solid.
Reaction SMILES: C(O[CH2:5][C:6]1[C@H:7]2[CH2:20][CH2:19][C@@H:18]([CH3:21])[C@H:8]2[C@H:9]([O:12][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[O:10][CH:11]=1)(=O)C.N1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:16]([O:15][CH:13]([O:12][C@H:9]1[C@@H:8]2[C@H:18]([CH3:21])[CH2:19][CH2:20][C@@H:7]2[C:6]([CH3:5])=[CH:11][O:10]1)[CH3:14])[CH3:17]
Reactant: [H][H]
Reactant: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@@H](C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@@H](C)[C@@H]12
Yield: 74.5 %

Procedure:
(1S, 4aS, 7R, 7aR)-4-(acetoxymethyl)-1-[1(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c] pyran (65 mg, 0.00024 mol) obtained in Example 26 was dissolved in 3 ml of ethyl acetate, and 0.05 ml of pyridine and 10% palladium carbon (3 mg) were added. The reaction mixture was stirred for 24 hours in a hydrogen gas atmosphere of 1 atm. After the catalyst was removed by celite filtration, concentration was effected. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off. A colorless oily substance was thus obtained, i.e., (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran (43 mg, yield=82%). This (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-4,7-dimethylcyclopenta[c]pyran had the following physicochemical properties:
Reaction SMILES: [OH-].[Na+].[CH:3]1([N:6]2[C:15]3[C:10](=[C:11]([NH:29]C(=O)C(F)(F)F)[C:12]([F:28])=[C:13]([NH:18][CH2:19][CH2:20][NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]=3[O:16][CH3:17])[C:9](=[O:36])[C:8]([C:37]#[N:38])=[CH:7]2)[CH2:5][CH2:4]1.O>CO>[NH2:29][C:11]1[C:12]([F:28])=[C:13]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:14]([O:16][CH3:17])=[C:15]2[C:10]=1[C:9](=[O:36])[C:8]([C:37]#[N:38])=[CH:7][N:6]2[CH:3]1[CH2:4][CH2:5]1
Reactant: COc1c(NCCNc2ccccn2)c(F)c(NC(=O)C(F)(F)F)c2c(=O)c(C#N)cn(C3CC3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C#N)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
1 M aq. NaOH (1 mL) was added to a suspension of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]-5-(trifluoroacetamido)quinoline-3-carbonitrile (100 mg, 0.198 mmol) in MeOH (5 mL). After stirring at room temperature for 8 h, water (10 mL) was added. The resulting precipitate was collected by filtration, washed with water and MeOH, and dried to give 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carbonitrile (60.1 mg, 74%) as a pale brown solid.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9][CH3:10])[C:5]=2[C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[O:12])[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:25].[Na+]>CC(C)=O.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([S:9]([CH3:10])=[O:25])[C:5]=2[C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)=[O:12])[CH2:3][CH2:2]1
Reactant: CSc1noc(C2CC2)c1C(=O)c1ccc(C(F)(F)F)nc1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(C(F)(F)F)ccc1C(=O)c1c(S(C)=O)noc1C1CC1
Reaction time: 5 h
Yield: 51.9 %

Procedure:
1.50 g (0.0043 mol) of (5-cyclopropyl-3-methylsulfanyi-isoxazol-4-yl)-(2-methyl-6-trifluoromethyl-pyridin-3-yl)-methanone are dissolved in 30 ml of acetone/water (2:1 mixture) and 1.02 g (0.0048 mol) of sodium metaperiodate are added in portions at 22° C. After 5 hours, the reaction mixture is concentrated by evaporation using a rotary evaporator. The residue is taken up in water and ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel (eluant: ethyl acetate/hexane 3/1). 0.8 g (51%) of the desired product is obtained in the form of white crystals (m.p. 96-97° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[N:6][CH:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.N>>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[CH:3]=[CH:4][C:5]([O:8][C@@H:9]4[CH:16]5[CH2:17][N:12]6[CH2:13][CH:14]([CH2:18][CH:10]4[CH2:11]6)[CH2:15]5)=[N:6][CH:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: N
Product: c1cc2cc(-c3ccc(OC4C5CC6CC4CN(C6)C5)nc3)ccc2[nH]1

Procedure:
Prepared from the product of Example 10C (45 mg, 0.14 mmol) and 5-indolylboronic acid (33 mg, 0.204 mmol; Maybridge) according to Method G: MS (DCI/NH3) m/z=346 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[OH:9])=[CH:6][N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:3]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:3]=1
Reactant: OC(c1cccs1)c1cnc(Oc2ccccc2Cl)nc1Cl
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=C(c1cccs1)c1cnc(Oc2ccccc2Cl)nc1Cl

Procedure:
[4-Chloro-2-(2-chloro-phenoxy)-pyrimidin-5-yl]-thiophen-2-yl-methanol (98 mg, 0.28 mmol)was dissolved in 15 mL dry toluene, and 250 mg of MnO2 was added. The reaction mixture was heated to reflux for 30 minutes, and water was removed using a Dean Stark apparatus. The hot reaction mixture was filtered through Celite, and the Celite was washed five times with 3.5 mL of hot EtOAc. The combined organics were evaporated under reduced pressure to yiled 82 mg of [4-Chloro-2-(2-chloro-phenoxy)-pyrimidin-5-yl]-thiophen-2-yl-methanone as an oil. Mass Spec. M+H=352.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH3:13])=O)(C)(C)C.C[Si](C)(C)[N:16]1[C:20](=O)[CH:19]=[CH:18][C:17]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:13][CH:12]1[CH:19]2[CH:18]([CH2:17][NH:16][CH2:20]2)[CH:9]([NH:8][CH3:6])[CH:10]=[CH:11]1
Reactant: CC=CC=CNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N1C(=O)C=CC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNC1C=CC(C)C2CNCC12

Procedure:
Analogously to Example A, method I, 21.9 g (0.12 mol) of 1-(tert.-butyloxycarbonylamino)-1,3-pentadiene are reacted with 20.3 g (0.12 mol) of N-trimethylsilylmaleimide and the product is then reduced with 15.2 g (0.4 mol) of lithium aluminiumhydride. The crude product is recrystallised from tetrahydrofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OCc1ccccc1
Reactant: CC(C)C(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 80.1 g of 2-(4-nitrophenyl)-3-methylbutanoic acid, 150 ml of benzyl alcohol, 75 ml of toluene and 2 g of p-toluenesulfonic acid monohydrate was boiled under reflux, with azeotropic removal of water, for 10 hours. The toluene and excess benzyl alcohol were removed in vacuum, and the residual oil was dissolved in butyl chloride. The butyl chloride solution was washed with 6% potassium carbonate three times (acidification of the carbonate extract precipitated 5.2 g of the starting carboxylic acid), water and saturated brine. The dried (MgSO4) butyl chloride solution was evaporated to a residual oil. The oil was vacuum distilled, the bulk of it boiling at 197°-200°/0.3 Torr, providing 99 g of 2-(4-nitrophenyl)-3-methylbutanoic acid, benzyl ester as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:49]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=2)=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[O:49]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:63]=2)=[CH:58][CH:57]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.009 g of product in 34% yield: LCMS (ESI) m/z 450 (MH+).
Reaction SMILES: S([Cl:11])(C1C=CC(C)=CC=1)(=O)=O.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N+:14]=1[O-].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(CCl)c(C)c1
Yield: 66.2 %

Procedure:
Tosyl chloride (12.5 g, 65.6 mmol) was added to a solution of 2,3,5-trimethylpyridine 1-oxide (6.0 g, 43.7 mmol), and triethylamine (6.6 g, 65.6 mmol) in DCM (60 ml) at RT under an atmosphere of nitrogen. The reaction mixture was heated to reflux and reflux was maintained 4 h (reaction was monitored by TLC). The reaction was quenched with water and extracted with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexanes and silica gel (230-400 Mesh) to afford 2-(chloromethyl)-3,5-dimethylpyridine (4.5 g, 66.1%,) as a brown thick syrup. 1H NMR: 200 MHz, CDCl3: δ 8.15 (s, 1H), 7.45 (s, 1H), 4.75 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H). MS: [M+H]+: m/z=156.3.
Reaction SMILES: [CH:1]#[CH:2].[SiH:3]([Cl:6])([Cl:5])[Cl:4]>>[Si:3]([CH2:1][CH2:2][Si:3]([Cl:6])([Cl:5])[Cl:4])([Cl:6])([Cl:5])[Cl:4]
Reactant: Cl[SiH](Cl)Cl
Reactant: C#C
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl

Procedure:
An example is the reaction of acetylene with HSiCl3 to give Cl3 SiCH2CH2SiCl3 in the first step of the process. An intermediate produced is CH2 =CHSiCl3, which can be used as starting material in place of acetylene and, when reacted with HSiCl3, leads to the same end product of the first step of the process, Cl3SiCH2CH2SiCl3.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:28])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:24]([NH:23][S:20]([C:15]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:1]([S:20]([CH3:15])(=[O:22])=[O:21])[S:39]([CH3:38])(=[O:41])=[O:40])=[CH:7][N:6]=3)=[C:9]([F:28])[CH:10]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:22])=[O:21])([CH3:25])([CH3:27])[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N(S(C)(=O)=O)S(C)(=O)=O)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 17.25 h

Procedure:
To a 20 mL vial were added a stir-bar, 4′-(5-aminopyrazin-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide (49 mg, 0.12 mmol), dry DCM (2.0 mL), DIPEA, (0.10 mL, 0.58 mmol), and methanesulfonyl chloride (0.020 mL, 0.25 mmol). The mixture was stirred at rt for 17.25 h before subjecting it to FCC to give impure title compound. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.[CH3:17][C:18]1[O:19]CC[N:22]=1.P(=O)(O)(O)O.[OH-].[Na+]>O>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O:19][CH:18]([NH2:22])[CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CC1=NCCO1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCc1ccccc1OC(C)N
Temperature: 200 °C

Procedure:
To a 250-ml three-necked flask equipped with a thermometer, stirrer, condenser and nitrogen inlet were charged 66 g. of nonylphenol and 30 g. of 2-methyl-2-oxazoline. The mixture was heated to 200° C. for six hours. About 80 g. of 85% phosphoric acid and 20 g. of water were then added. The mixture was heated to reflux for eight hours. The resulting reaction mixture was neutralized with sodium hydroxide solution. The resulting product was washed with water and then dried. 2-Nonylphenoxyethanamine was obtained in quantitative yield and the product purity by NMR spectroscopy analysis was found to be about 98%.
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:36][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3]
Reactant: CC(O)c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (±)-2-(1-hydroxyethyl)-pyridine (Bull. Chem. Soc. Jpn. 1990, 63, 461-465) (10.0 g, 81.3 mmol) in DCM (120 mL) at 0° C., add with stirring triphenylphosphine (22.39 g, 85.365 mmol) followed by NBS (15.2 g, 85.4 mmol) in portions. Warm the reaction mixture to ambient temperature and continue stirring for 3 h. Concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (19:1) to give the title compound.
Reaction SMILES: CN(C[CH2:11][CH2:12][N:13]([CH3:33])[C:14]1[C:22]2[O:21][CH:20]=[CH:19][C:18]=2[CH:17]=[C:16]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:15]=1)C(=O)OC(C)(C)C.N1(C2C3OC=CC=3C=C(N)C=2)CCC[CH2:36][CH2:35]1>>[N:13]1([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([NH:23][S:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:15]=2)[CH2:12][CH2:11][CH2:36][CH2:35][CH2:33]1
Reactant: CN(CCCN(C)c1cc(NS(=O)(=O)c2ccccc2)cc2ccoc12)C(=O)OC(C)(C)C
Reactant: Nc1cc(N2CCCCC2)c2occc2c1
Product: O=S(=O)(Nc1cc(N2CCCCC2)c2occc2c1)c1ccccc1

Procedure:
The synthesis was performed according to the procedure of Intermediate 3 starting from 7-piperidin-1-yl-1-benzofuran-5-amine (Intermediate 6). Yield: 70 mg (39%). 1H NMR (400 MHz, CDCl3) δ ppm 1.57-1.62 (m, 2H), 1.70-1.78 (m, 4H), 3.16 (t, 4H), 6.39 (br s, 1H), 6.41 (d, 1H), 6.63 (d, 1H), 6.83 (d, 1H), 7.37-7.43 (m, 2H), 7.49-7.54 (m, 1H), 7.57 (d, 1H), 7.68-7.72 (m, 2H); MS (ESI+) for C19H20N2O3S m/z 357 (M+H)+; HPLC 97% (System A).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH2:7][C@H:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CO>[OH:1][CH:2]([CH2:18][N:32]1[CH2:33][CH2:34][CH:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[CH2:30][CH2:31]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH2:7][C@H:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: O=C1OCC[C@@H]1Cc1ccccc1OCC1CO1
Solvent: CO
Product: O=C1OCC[C@@H]1Cc1ccccc1OCC(O)CN1CCC(c2ccc3ccccc3c2)CC1
Yield: 46.8 %

Procedure:
(2S)-α-(2′-(2,3-Epoxypropan-1-yloxy)benzyl)-γ-butyrolactone (1.5 g) and 4-(naphthalen-2-yl)piperidine (1.5 g) were dissolved in methanol (50 ml) and the reaction mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the obtained oil was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.3 g).