Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([CH2:33][O:34][CH3:35])[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:36])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:37]C(=O)CCCC)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([CH2:33][O:34][CH3:35])[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:36])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:37])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Oc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4-c4nnnn4COC)cc3)c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc2ccc(O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2COC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A solution of 2-n-Butyl-3-[[2'-(N-methoxymethyltetrazol-5-yl)biphenyl-4-yl]methyl]-6-valeryloxy-4(3H)-quinazolinone (4.03 g) in a mixture of methanol (20 ml), THF (10 ml) and 1N aqueous sodium hydroxide (20 ml) was stirred at room temperature for 1 hour. After addition of 1N hydrochloric acid (25 ml), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The resulting crystalline product was recrystallized from ethyl acetate-hexane to give colorless crystals (3.13 g, 91%), mp. 157°-159° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH:23]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])=O.C(O)(=O)C>CCO>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19]/[N:20]=[CH:23]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: N#Cc1cccc(C=O)c1
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1cccc(/C=N/OC2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)c1

Procedure:
A solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (130 mg, 0.38 mmol), 3-formylbenzonitrile (45 mg, 0.38 mmol) and acetic acid (0.022 ml, 0.38 mmol) in EtOH (4 ml) was stirred for 1 hour and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc/Hexanes 20/80-50/50) and recrystallized from EtOAc/Hexanes to give (E)-3-((1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxyimino)methyl)benzonitrile (96 mg, 56%, colorless solid, LC: 98%, retention time: 7.94 min (Method A), M/Z: 453.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:10]([C:13]#[N:14])[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.[C:25]1(C)C=CC=CC=1[Mg]Br>O1CCCC1>[CH3:25][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[CH:9]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[CH:10]([C:13]#[N:14])[C:11]#[N:12]
Reactant: COc1cccc(C(c2cccc3ccccc23)C(C#N)C#N)c1
Reactant: Cc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccccc1C(c1cccc2ccccc12)C(C#N)C#N
Reaction time: 1.5 h

Procedure:
A flask was charged with (1-naphthalenylmethylene)-propanedinitrile of Example 3 (408 mg, 2 mmol) and 10 mL anhydrous tetrahydrofuran. To this stirred solution was added, at room temperature, ortho-tolyl magnesium bromide (1.2 mL, 2.4 mmol, 2 M in tetrahydrofuran). The reaction was stirred 1.5 hours, after which it was quenched with 1 N hydrochloric acid and taken up in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated to dryness. Following purification on silica (20% ethyl acetate/hexanes) 455 mg product was isolated as an off white foam.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:16]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:14][CH2:13][CH:12]2[C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:6]([NH2:31])[CH:5]=1.[Li+].[BH4-]>C1COCC1.[OH-].[Na+]>[NH2:31][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[CH2:10][N:11]1[CH:12]([C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:13][CH2:14][CH2:15][CH:16]1[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(N)c1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(CO)cc1N
Temperature: 25 °C
Yield: 38.5 %

Procedure:
To a solution of 3-amino-4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (0.61 g, 1.42 mmol) in THF (14 mL) was added LiBH4 (430 mg, 19.74 mmol) and the mixture was heated to reflux overnight. The mixture was cooled to room temperature, diluted with 1.0 N NaOH (20 mL) and extracted with CH2Cl2 (5×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (2 mm plate, 20:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.220 g (37%) of COMPOUND 59 as a white solid. 1H NMR (CDCl3) δ 1.23 (br s, 1H), 1.47-1.72 (m, 3H), 1.88-1.95 (m, 1H), 2.04-2.18 (m, 2H), 2.35 (s, 6H), 3.32 (s, 2H), 3.73 (dd, 2H, J=11.7, 3.0 Hz), 4.26 (d, 2H, J=3.3 Hz), 4.53 (br s, 2H), 6.03 (s, 1H), 6.07 (d, 1H, J=7.8 Hz), 6.48 (d, 1H, J=7.2 Hz), 6.86 (dd, 2H, J=7.8, 4.8 Hz), 7.15 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=3.9 Hz). 13C NMR (CDCl3) δ 19.44, 25.02, 32.92, 60.69, 65.60, 68.25, 112.98, 115.09, 122.09, 122.80, 129.96, 131.38, 138.18, 140.42, 146.89, 147.51, 161.18; ES-MS m/z 403 (M+H). Anal. Calcd. For C25H30N4O.1.0H2O: C, 71.40; H, 7.67; N, 13.32. Found: C, 71.31; H, 7.55; N, 13.22.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([Cl:11])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)O1>>[Cl:11][C:9]1[S:10][C:5]2[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:3][C:2]([C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[N:29][NH:30]4)=[N:7][C:6]=2[CH:8]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(Cl)cc2n1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: Clc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
40 mg of 2,6-dichloro-4-morpholinothieno[3,2-d]pyrimidine was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 4.4 mg of 134. MS (Q1) 372 (M)+
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.O(C)[Na].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.C1COCC1>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH2:2][CH2:1][OH:12])[CH:11]=[CH:10][C:8]=1[O:9][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCCc1ccccc1
Reactant: COc1cc(CCO)ccc1O
Agent: CO[Na]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCO)ccc1OCCCCc1ccccc1

Procedure:
To a solution of homovanillyl alcohol (10 g, 59.3 mmol) in dry methanol (140 ml), there is added 12 ml of 1N NaOCH3 in methanol. After addition of a solution of 1-bromo-4-phenylbutane (12.6 g, 59.3 mmol) in THF (10 ml) the reaction mixture is kept at reflux for 3 hours. After cooling the reaction is quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate (2 times, 500 ml each). The organic layer is dried over MgSO4 and the solvent is removed by evaporation. The crude residue is then purified on silica gel using ethyl acetate/n-hexane (1/1) as mobile phase.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([CH3:52])([CH3:51])[C@H:12]3[C@:25]([CH3:28])([CH2:26][CH:27]=2)[C@@H:24]2[C@:15]([CH3:50])([C@@:16]4([CH3:49])[C@H:21]([CH2:22][CH2:23]2)[C@H:20]2[C@H:29]([C:32]([CH3:34])=[CH2:33])[CH2:30][CH2:31][C@:19]2([C:35]([NH:37][CH2:38][CH2:39][N:40](CC(O)=O)[CH2:41][C:42](O)=O)=[O:36])[CH2:18][CH2:17]4)[CH2:14][CH2:13]3)=[CH:6][CH:5]=1)([OH:3])=[O:2].BrCC[S:56]([OH:59])(=[O:58])=[O:57]>>[CH3:49][C@:16]12[C@@:15]3([CH3:50])[C@@H:24]([C@:25]4([CH3:28])[C@@H:12]([CH2:13][CH2:14]3)[C:11]([CH3:51])([CH3:52])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=3)=[CH:27][CH2:26]4)[CH2:23][CH2:22][C@@H:21]1[C@H:20]1[C@H:29]([C:32]([CH3:34])=[CH2:33])[CH2:30][CH2:31][C@:19]1([C:35](=[O:36])[NH:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][S:56]([OH:59])(=[O:58])=[O:57])[CH2:18][CH2:17]2
Reactant: O=S(=O)(O)CCBr
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC(=O)O)CC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCCS(=O)(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for 2,2′-(2-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxamido)ethylazanediyl)diacetic acid (example 88). using 2-bromoethanesulfonic acid as alkylating reagent. The product was isolated as a white solid (3 mg, 39%). LCMS: m/e 709.37 (M+H)+, 2.04 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.54 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=6.10 Hz, 1H), 4.79 (s, 1H), 4.66 (s, 1H), 3.93-3.75 (m, 2H), 3.74-3.62 (m, 2H), 3.50-3.44 (m, 2H), 3.42 (t, J=5.80 Hz, 2H), 3.20-3.06 (m, 1H), 2.66-2.47 (m, 1H), 1.75 (s, 3H), 2.31-1.10 (m, 21H), 1.09 (s, 3H), 1.06 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH:35]2[CH2:36][CH2:37][O:32][CH2:33][CH2:34]2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1ccc(O)cc1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccc(OC2CCOCC2)cc1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
4-Tert-butoxyphenol (200 mg, 1.203 mmole) and PPh3 (410 mg, 1.564 mmole) were combined in toluene (5 mL). To this was added tetrahydro-2H-pyran-4-ol (0.149 mL, 1.564 mmole). DIAD (0.304 mL, 1.564 mmole) was added dropwise at RT. After stirring overnight the mixture was concentrated. Flash column chromatography (Biotage-SNAP-25 g SiO2, 10% EtOAc/hexanes) gave 4-(4-tert-butoxyphenoxy)tetrahydro-2H-pyran (257 mg, 85%) as a clear oil. 1H NMR (400 MHz, CDCl3): 06.90 (d, J=8.9 Hz, 2 H); 6.83-6.79 (m, 2 H); 4.39 (m, 1 H); 4.03-3.95 (m, 2 H); 3.56 (m, 2 H); 2.04-1.96 (m, 2 H); 1.83-1.72 (m, 2 H); 1.30 (s, 9 H).
Reaction SMILES: [C:1]([C:8]1[CH:36]=[CH:35][C:11](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]\[C:22]3[CH:27]=[CH:26][C:25]([C:28]([O:30]C(C)(C)C)=[O:29])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([O:3]C(C)(C)C)=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:28]([C:25]1[CH:24]=[CH:23][C:22](/[CH:21]=[CH:20]/[C:17]2[CH:18]=[CH:19][C:14](/[CH:13]=[CH:12]\[C:11]3[CH:35]=[CH:36][C:8]([C:1]([OH:3])=[O:2])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)=[CH:27][CH:26]=1)([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C\c2ccc(/C=C/c3ccc(C(=O)OC(C)(C)C)cc3)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(/C=C\c2ccc(/C=C/c3ccc(C(=O)O)cc3)cc2)cc1

Procedure:
131 g of Z,E-1,4-Bis-(4-carbo-tert.-butoxy-styryl)benzene are boiled under reflux with 6.5 g of p-toluenesulphonic acid in 1 l of toluene for 3 hours. The reaction product is evaporated to dryness and heated for a further 4 hours with 30 g of NaOH in 300 ml of water and 600 ml of ethanol. The ethanol is distilled off and the residue is acidified (conc. HCl) after dilution with water. The product is suction filtered and dried.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:9][N:8]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]1[CH3:18].[CH3:19][NH:20][CH3:21]>CO>[CH3:18][N:4]1[C:5]2[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][CH:3]1[CH2:2][N:20]([CH3:21])[CH3:19]
Reactant: CNC
Reactant: CC(C)N1CC(CCl)N(C)c2ccccc2C1=O
Solvent: CO
Product: CC(C)N1CC(CN(C)C)N(C)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of 5.0 g (0.02 mole) of 2-chloromethyl-1,2,3,4-tetrahydro-1-methyl-4-(1-methylethyl)-5H-1,4-benzodiazepin-5-one, and 15.0 g (0.45 mole) of dimethylamine, and 200 ml of methanol were placed in a steel bomb and heated and stirred at 100° C. for 15 hr. After concentrating in vacuo, the residue partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue crystallized in isopropyl ether and was recrystallized twice from the same. It weighed 29.0 g (68%), m.p. 93°-95° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15]([N:31]5[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CCN(C)CC4)c(F)cc3cc2c1=O
Yield: 81.9 %

Procedure:
The 1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-8-(4-methyl---piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 35 but starting from 1.5 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 3 g of 1-methylpiperazine. methylpiperazine. 1.5 g of 1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 230° C.
Reaction SMILES: [F-].[Cs+].[CH3:3]B(O)O.[NH2:7][C:8]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15](I)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>O1CCOCC1>[NH2:7][C:8]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH3:3])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CB(O)O
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(C(F)(F)F)cc1N
Temperature: 80 °C
Yield: 91.9 %

Procedure:
Add cesium fluoride (184.3 g, 1.21 mol), methyl boronic acid (63.7 g, 1.05 mol, 3 mol equiv.) and bis(diphenylphosphinoferrocene)palladium(II) chloride (27.83 g, 35.1 mmol) to a solution of methyl 2-amino-5-iodo-4-trifluoromethylbenzoate (121 g, 351 mmol) in anhydrous 1,4-dioxane (2.5 L) at room temperature under an atmosphere of nitrogen and heat the mixture at 80° C. for 3 h. Allow the mixture to cool to room temperature then partition between ethyl acetate (2.5 L) and water (2.5 L) and filter through a pad of Celite® to remove the fine black suspension. Extract the aqueous phase with ethyl acetate (2×100 mL) and wash the combined organic extracts with brine (1 L). Dry over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure at 45° C. to give a red oil. Purify the residue by column chromatography on silica gel, eluting with isohexane/ethyl acetate (9:1), to give the title compound as a pale yellow crystalline solid (75.25 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 6.93 (s, 1H), 5.70 (s, 2H), 3.90 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].N(C(C)(C)C#N)=NC(C)(C)C#N>>[F:16][CH:2]([F:1])[C:3]([O:11][Si:12]([CH3:15])([CH3:13])[CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4]/[CH:5]=[CH:6]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(F)F
Temperature: 25 °C

Procedure:
A mixture of 13.0 g. of 4-difluoromethyl-4-trimethylsiloxy-1-octyne, 17.23 ml. of tri-n-butylstannane and 70 mg. of azobisisobutyronitrile is heated under nitrogen in an oil bath at 125°-135° C. for 2 hours. The reaction is cooled to room temperature and vacuum distilled through a short-path apparatus, giving, after a 5 ml. forerun, 35.6 g. of the product as an oil, containing a minor amount of the corresponding cis isomer.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:29]5[CH:30]=[CH:31][N:32]=[C:33]([F:34])[C:28]=5[N:27]([CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:25]=4[N:26]=3)=[N:18][CH:19]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.C(OCC)C>C1COCC1.CO.C(O)C>[CH:35]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[N:18]=[CH:19][C:14]([N:11]5[CH2:12][CH2:13][C@@H:9]([OH:8])[CH2:10]5)=[CH:15][CH:16]=4)[N:22]=[CH:23][C:24]=3[C:29]3[CH:30]=[CH:31][N:32]=[C:33]([F:34])[C:28]2=3)[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: O[C@@H]1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
Compound 278 (58 mg, 106 μmol) was dissolved in THF (2 mL). Tetrabutylammonium fluoride, 1.0M in THF (0.5 mL, 0.500 mmol) was added and the reaction stirred at room temperature for 4 hours. The solvent was removed to give an orange oil. Silica gel chromatography (gradient elution ethyl acetate+2.5% TEA/0-5% methanol) afforded a yellow solid. This residue was taken up in methanol (2 mL) and HCl in ethanol (1.0M, 0.5 mL) was added. Diethyl ether (20 mL) was added to precipitate the product, which was filtered and dried in vacuo to give compound 277 as a yellow solid (23 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1 H) 9.25-9.35 (m, 1 H) 7.94-8.11 (m, 4 H) 7.62-7.77 (m, 2 H) 7.05 (dd, J=8.93, 2.81 Hz, 1 H) 5.37-5.54 (m, 1 H) 4.99 (d, J=3.91 Hz, 1 H) 4.44 (br. s., 1 H) 3.46 (dd, J=10.03, 4.89 Hz, 2 H) 3.05-3.16 (m, 1 H) 2.26-2.42 (m, 3 H) 1.96-2.20 (m, 8 H) 1.85-1.96 (m, 2 H) 1.66-1.83 (m, 3 H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:20]Br>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:20][C:19]2[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: COc1cc(CBr)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
4-Hydroxy thiophenol (12 g, 0.095 mol) and potassium carbonate (15.86 g, 0.115 mol) were dissolved in 250 ml of N,N-dimethylformamide, and cooled to 0° C. To the above solution at 0° C. was added dropwise 25 g (0.095 mol) of 3,4,5-trimethoxybenzyl bromide prepared in step (1) dissolved in 50 ml N,N-dimethylformamide. After stirring for 2 hr, the ice-bath was removed, and the solution was stirred overnight. The whole solution was poured into water, and extracted with 300 ml ethyl acetate. The organic layer was washed twice with 300 ml of water. Drying over magnesium sulfate, filtration, concentration, and chromatographic purification on silica gel column (ethyl acetate/n-hexane=2/3) gave 20 g (yield 68%) of 3,4,5-trimethoxybenzyl 4-hydroxyphenyl thioether as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Cl[C:40]([F:47])([F:46])C(OCC)=O>CCOC(C)=O>[F:46][CH:40]([F:47])[O:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:13][CH:14]=2)=[N:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(O)cn3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3ncc(OC(F)F)cn3)cc2)C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
(R)-tert-Butyl 2-(4-(5-hydroxypyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (0.24 g) and K2CO3 (124 mg) were combined with DMF (2 ml) to give a brown solution. Ethyl 2-chloro-2,2-difluoroacetate (152 mg) was then added. The reaction mixture was stirred at 80° C. for 1.5 h to afford a dark brown suspension. TLC & HPLC showed the reaction was complete. The reaction mixture was poured into EtOAc and washed sequentially with water and with saturated brine. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-(5-(difluoromethoxy)pyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (60 mg, 24%) as a yellow oil. MS (ISP): 423.1 ([M+H]+), 367.0 ([M+H—C4H8]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.S(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C(O)CCC>[CH2:4]([O:9][C:8](=[O:10])[C:6]1[CH:5]=[C:4]([Cl:11])[N:3]=[C:2]([Cl:1])[CH:7]=1)[CH2:5][CH2:6][CH3:7]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Yield: 208.1 %

Procedure:
To a suspension of 2,6-dichloropyridine-4-carboxylic acid (16 g) (CAS RN: [5398-44-7]) in n-butanol (150 mL) was added thionylchloride (9.1 mL) dropwise. The reaction mixture was heated to reflux for 1.5 hours, cooled to room temperature and then a saturated aqueous solution of NaHCO3 (160 mL) was added (pH˜7). The mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2,6-dichloro-isonicotinic acid butyl ester (21.51 g) as crude product, which was directly subjected to the next step.